Neurogliaform and Ivy Cells: a Major Family of Nnos Expressing Gabaergic Neurons

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Title Neurogliaform and Ivy Cells: A Major Family of nNOS Expressing GABAergic Neurons

Permalink https://escholarship.org/uc/item/4wt1f820

Journal Frontiers in Neural Circuits, 6

ISSN 1662-5110

Authors Armstrong, Caren Krook-Magnuson, Esther Soltesz, Ivan

Publication Date 2012-05-16

DOI 10.3389/fncir.2012.00023

License https://creativecommons.org/licenses/by/4.0/ 4.0

Peer reviewed

eScholarship.org Powered by the California Digital Library University of California REVIEW ARTICLE published: 16 May 2012 NEURAL CIRCUITS doi: 10.3389/fncir.2012.00023 Neurogliaform and Ivy cells: a major family of nNOS expressing GABAergic neurons

Caren Armstrong*, Esther Krook-Magnuson and Ivan Soltesz

Department of Anatomy and Neurobiology, University of California Irvine, Irvine, CA, USA

Edited by: Neurogliaform and Ivy cells are members of an abundant family of neuronal nitric oxide Ludovic Tricoire, Université Pierre et synthase (nNOS) expressing GABAergic interneurons found in diverse brain regions.These Marie Curie, France cells have a deﬁning dense local axonal plexus, and display unique synaptic properties Reviewed by: Gianmaria Maccaferri, Northwestern including a biphasic postsynaptic response with both a slow GABAA component and a University, USA GABAB component following even a single action potential. The type of transmission dis- Thomas Klausberger, MRC University played by these cells has been termed “volume transmission,” distinct from both tonic of Oxford, UK and classical synaptic transmission. Electrical connections are also notable in that, unlike Linda Overstreet-Wadiche, University of Alabama Birmingham, USA other GABAergic cell types, neurogliaform family cells will form gap junctions not only with Marco Capogna, Medical Research other neurogliaform cells, but also with non-neurogliaform family GABAergic cells. In this Council, UK review, we focus on neurogliaform and Ivy cells throughout the hippocampal formation, *Correspondence: where recent studies highlight their role in feedforward inhibition, uncover their ability to Caren Armstrong, Department of display a phenomenon called persistent ﬁring, and reveal their modulation by opioids. The Anatomy and Neurobiology, University of California, 192 Irvine unique properties of this family of cells, their abundance, rich connectivity, and modulation Hall, Irvine, CA 92697-1280, USA. by clinically relevant drugs make them an attractive target for future studies in vivo during e-mail: [email protected] different behavioral and pharmacological conditions.

Keywords: feedforward inhibition, persistent ﬁring, opioid, GABAB, GABAA,slow

INTRODUCTION GABAergic cell types. Neurogliaform cells have a dense local The neurogliaform family of cells is one of the major groups axonal plexus and generally small, round, somata (Figure 1). of GABAergic neurons expressing nitric oxide synthase (nNOS). The axons of neurogliaform cells have frequent, small en pas- Neurogliaform cells, originally described by Cajal as arachniform sant boutons, which despite their small size can form synaptic cells (Ramón y Cajal, 1922; Ramón y Cajal, 1999), together with contacts (Vida et al., 1998; Fuentealba et al., 2008; Olah et al., the closely related Ivy cells, which were only recently characterized 2009). The synapses formed by neurogliaform family cell bou- (Fuentealba et al., 2008), are estimated to be the most abundant tons, however, do not necessarily form classical synapses like those GABAergic cell type in area CA1 of the hippocampus (Fuentealba of other GABAergic cell classes, in that the synaptic cleft at identi- et al., 2008). However, the neurogliaform family of cells is found in ﬁed synapses is unusually wide and some boutons, complete with large numbers not only throughout CA1, but also across a range of synaptic vesicles, do not have an easily identiﬁable postsynaptic brain regions, including the entire hippocampal formation (Vida target in the classical sense (Vida et al., 1998; Olah et al., 2009). et al., 1998; Price et al., 2005; Elfant et al., 2008; Price et al., 2008; Their unique synaptic and axonal morphologies underlie some Karayannis et al., 2010; Szabadics et al., 2010; Armstrong et al., key features of neurogliaform synaptic transmission (Figure 2), 2011; Krook-Magnuson et al., 2011; Markwardt et al., 2011), the namely (1) the ability of neurogliaform cells to mediate GABAer- neocortex (Tamas et al., 2003; Simon et al., 2005; Olah et al., 2007; gic volume transmission, affecting virtually any processes within Szabadics et al.,2007; Olah et al.,2009),the piriform cortex (Suzuki their dense axonal plexus, (2) the production of a slow GABAA and Bekkers, 2012), striatum (Ibanez-Sandoval et al., 2011), and current in the postsynaptic cell (GABAA,slow), and (3) the post- the habenula of the thalamus (Weiss and Veh, 2011). Thus, these synaptic GABAB response to even a single neurogliaform action cells are not only abundant, but also widespread. Yet their func- potential (Tamas et al., 2003; Price et al., 2005; Szabadics et al., tion in the context of local circuit dynamics is only beginning to 2007; Price et al., 2008; Olah et al., 2009; Karayannis et al., 2010; be unraveled. Capogna and Pearce, 2011). Here, in addition to reviewing the known anatomical, synap- Neurogliaform cells’ ability to induce a biphasic current in tic, neuromodulatory, and connective properties of neurogli- the postsynaptic cell, including both a GABAA-mediated and a aform family cells, we discuss their potential network functions, GABAB-mediated component, is a property which has been con- particularly in the hippocampal formation. sistently observed across brain regions (Tamas et al., 2003; Price et al.,2005; Olah et al.,2007; Szabadics et al.,2007;Armstrong et al., UNIQUE AXONS, UNIQUE CONNECTIONS 2011). The GABAA and GABAB-mediated components can be sep- + Despite their wide distribution, cells within the neurogliaform arated based on reversal potential, since the K -mediated GABAB − family have very similar characteristics across brain regions, and component and the largely Cl -mediated GABAA component these unique characteristics clearly set them apart from other reverse at different membrane potentials. Additionally,the GABAA

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FIGURE 1 | Characteristics of neurogliaform family cells. Neurogliaform (see text). (G) Light microscopic image, showing the characteristic and Ivy cells in the hippocampus: (A) dentate gyrus neurogliaform cell, (B) neurogliaform axonal arborization, with multiple axonal branches passing CA3 Ivy cell, (C) CA1 Ivy cell, (D) CA1 neurogliaform cell; these cells are through a single plane of focus and frequent, small en passant boutons [same characterized by their dense local axonal plexus (black: axon; blue: somata and cell as (A), scale bar 20 μm]. (H) In addition to the classical late-spiking dendrites). These cells also show a characteristic late-spiking firing pattern in pattern characteristic of these cells, a high percentage of neurogliaform and response to depolarizing current steps [insets, (A,C,D); scale bars 20 mV, Ivy cells display the recently described phenomenon referred to as persistent 200 ms]. ML, molecular layer; GCL, granule cell layer; so, stratum oriens; sp, firing. After hundreds of action potentials induced by repeated depolarizing stratum pyramidale; sl, stratum lucidum; sr, stratum radiatum; slm, stratum current steps (note that only the last depolarizing step is shown here), the cell lacunosum-moleculare. Cells represented in (A,B) are from rat. Examples in continues to fire action potentials after the cessation of depolarizing input (C,D) are from mouse. (E) Schematic diagram of the hippocampus, illustrating (bottom trace: schematic of current injection; top trace: current clamp the approximate relative locations of cells in (A–D) (scale bar = 100 μm). Note recording, dashed line indicates −60 mV). Note the apparent low action that the Ivy cell reconstructed in (C) targets proximal dendrites, while the potential threshold (arrow). Due to the long duration of the persistent firing neurogliaform cell in (D) targets distal dendrites of CA1 pyramidal cells. (F) state, the trace has segments omitted (indicated by hash marks) for Recorded, biocytin-filled cells confirmed as neurogliaform cells in the dentate illustration purposes. Reproduced and modified with permission from gyrus (three separate cells, numbered 1–3) express a variety of markers, Armstrong et al. (2011) (A,F,G), Szabadics et al. (2010) (B), and including COUP TFII, nNOS, reelin, and NPY (scale bar = 20 μm) among others Krook-Magnuson et al. (2011) (C,D,H).

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FIGURE 2 | Unique synaptic properties of neurogliaform cells. (A) Action NGFC (black traces) and a non-NGFC (green traces) can be appreciated potentials in a neurogliaform cell (top trace, example from neocortex) (example from dentate gyrus). Left traces: a hyperpolarizing current step

produce a slow IPSC (GABAA,slow – bottom trace) in the postsynaptic cell. (B) (Pre, current clamp responses shown in the upper traces of each example), In contrast, action potentials in fast-spiking basket cell (top trace) produce evokes an outward current in the electrically connected cell (Post, voltage an IPSC with fast kinetics in the postsynaptic cell (bottom trace). (C) clamp responses shown in the lower traces of each example). Right: When Neurogliaform cells (averaged examples from dentate gyrus) produce a an action potential is evoked in the presynaptic non-NGFC, only a short

biphasic postsynaptic response, consisting of a slow GABAA and a GABAB inward current, due to electrical coupling, is observed in the connected

component, which can be distinguished by application of the GABAB NGFC, while both electrical and chemical synaptic responses can be antagonist CGP55845 (red trace). This biphasic response can be seen appreciated in the postsynaptic non-NGFC in response to NGFC stimulation following even a single presynaptic action potential (inset). (D) (upper traces, both pre and postsynaptic traces are averaged). Note the Neurogliaform cells (NGFC, black traces) can form both electrical and electrical responses in the non-NGFC riding on top of the slow chemical synaptic connections with other GABAergic cell types. In this GABA-mediated IPSC. Reproduced and modiﬁed with permission from example, an electrical and unidirectional synaptic connection between a Szabadics et al. (2007) (A,B) and Armstrong et al. (2011) (C,D).

and GABAB-mediated components can be pharmacologically sep- dendritically targeting cells (in this case, Martinotti cells) do not arated using specific antagonists for GABAA and GABAB receptors induce GABAA,slow (Szabadics et al., 2007). Further, while spillover (Figure 2). Importantly, this biphasic GABA-mediated current of GABA does occur, affecting both GABAA,slow and GABAB- results in a large inhibitory charge transfer in the postsynaptic tar- mediated events, the extreme kinetics of the responses are not get, and involves even traditionally extrasynaptic receptors, such as fully explained by GABA spillover. Importantly, the postsynaptic δ subunit-containing GABAA receptors and GABAB receptors, as GABAA,slow response is highly sensitive to low-affinity competitive well as classically synaptic receptors, e.g., benzodiazepine-sensitive GABAA receptor antagonists,indicating that low concentrations of γ subunit-containing GABAA receptors (Szabadics et al., 2007; GABA at the postsynaptic membrane contribute to the slow uni- Olah et al., 2009; Karayannis et al., 2010). tary kinetics of neurogliaform cell connections (Szabadics et al., The kinetics of the neurogliaform cell-evoked GABAA response 2007). These data suggest that the nature of the GABA transient are also considerably slower than the kinetics of responses to other (the spatiotemporal concentration profile of GABA at the synapse) GABAergic cell types, and these events, referred to as GABAA,slow is largely responsible for the kinetics of neurogliaform connec- (Pearce, 1993; reviewed in Capogna and Pearce, 2011), were shown tions (Krook-Magnuson and Huntsman, 2007; Szabadics et al., to arise from neurogliaform cells (Tamas et al., 2003; Price et al., 2007; Karayannis et al., 2010). In turn, this unique GABA tran- 2005; Szabadics et al., 2007). In theory, GABAA,slow could be due to sient can be explained by the morphology of the synapse (i.e., multiple, asynchronous, vesicular release. However, the kinetics of the relatively small area combined with the relatively large dis- the GABAA,slow response are not affected by altering release proba- tances between pre- and post-synaptic processes; Szabadics et al., bility through variation of external Ca2+ concentration, such that 2007; Olah et al., 2009). Interestingly, although in vivo neurogli- vesicular release properties cannot explain the kinetics (Szabadics aform cells do fire in a phase-locked manner with theta rhythms et al., 2007). Dendritic filtering of neurogliaform cell input to (Fuentealba et al., 2010), paired neurogliaform cell connections distal dendrites also cannot explain the slow kinetics, since other in acute slices demonstrate profound depression with repeated

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stimulation (Tamas et al., 2003), an effect which persists in the cells can also differ in their in vivo firing properties and dendritic presence of GABAB antagonists (Karayannis et al., 2010). morphologies (Fuentealba et al., 2008; Fuentealba et al., 2010), The axonal arbors of neurogliaform cells described above are and differences in network functions of neurogliaform and Ivy one of the most distinctive features of these cells. While the axons cells in vivo will be discussed further below. of neurogliaform cells form a unique dense, local plexus, they Even within the different types of neurogliaform family cells, can also cross boundaries of brain regions. For example, neu- there are differences in neuronal markers that can be used for rogliaform cells were recently identified in the molecular layer of identification. Thus, while neuropeptide Y (NPY), nNOS, COUP the dentate gyrus (Armstrong et al., 2011), where importantly, TFII, α-actinin, GABAAα1, GABAAδ, and reelin are notably found it was found that their axons can cross the hippocampal fissure in neurogliaform cells (Figure 1), there is significant heterogeneity and extend into the adjacent CA1 or subiculum (Armstrong et al., in marker expression from cell to cell such that no one marker or 2011). Similarly, axons of neurogliaform cells in the CA1 can cross combination of markers captures, uniquely, all neurogliaform cells into dentate molecular layer (Ceranik et al., 1997; Price et al., 2005; (Deller and Leranth, 1990; Ratzliff and Soltesz, 2001; Price et al., Fuentealba et al., 2010). This extension of axons across bound- 2005; Simon et al., 2005; Fuentealba et al., 2008; Karagiannis et al., aries is a notable feature among GABAergic cells, suggesting that 2009; Olah et al., 2009; Fuentealba et al., 2010; Tricoire et al., 2010). neurogliaform cells may serve to share information between, and Ivy cells of the CA1 seem to share many of the same markers as coordinate the activities of, distinct brain regions. neurogliaform cells, but have not been observed to express reelin Beyond their remarkable chemical synapses, neurogliaform (Fuentealba et al., 2010). Interestingly, the presence or absence of cells are also unusual with regard to their electrical synapses. nNOS may serve as a marker of developmental origin for both Interneurons typically form gap junctions preferentially with neurogliaform and Ivy cells, that is whether the cells arise from members of the same cell type. In contrast, neurogliaform cells fre- the medial or caudal ganglionic eminences, both of which can quently form gap junctions with a wide variety of other GABAergic generate neurogliaform family cells (Tricoire et al., 2010). cell types (Figure 2; Simon et al., 2005; Zsiros and Maccaferri, 2005; Olah et al., 2007; Zsiros and Maccaferri, 2008; Armstrong ELECTROPHYSIOLOGICAL PROPERTIES OF NEUROGLIAFORM et al., 2011). This is important when considering the role of neu- FAMILY CELLS rogliaform cells in hippocampal networks, which will be discussed As might be expected due to their differential inputs and placement below. within the CA1, Ivy and neurogliaform cells of the CA1 differ also in their in vivo firing patterns. In anesthetized animals, when both DIVERSITY AND DIVISIONS theta and gamma oscillations are recorded from the stratum pyra- Despite the similarities in axonal and synaptic properties of indi- midale, individual Ivy cells fire at a low frequency shortly after the vidual cells of the neurogliaform family, there are some notable trough of theta – that is,after CA3 input and just after CA1 pyrami- differences between them as well. Members of the neurogliaform dal cells fire – and during the trough of gamma oscillations, while family may differ in where they reside within a given brain region, staying primarily silent during ripples (Fuentealba et al., 2008; the input they receive, and the domain of the postsynaptic cells Klausberger and Somogyi, 2008; Mizuseki et al., 2009; Fuentealba their axons target, as well as in the neuronal markers that they et al., 2010). On the other hand, neurogliaform cells fire just after express. the peak of theta, following input to CA1 from the entorhinal cor- As mentioned above, the neurogliaform family of cells is com- tex; are phase-coupled with the locally recorded gamma; and are posed of neurogliaform cells and Ivy cells. Neurogliaform cells either unmodulated by, or show a decrease in firing during ripples classically target the distal dendrites of principal cells while Ivy (Buzsaki, 2002; Fuentealba et al., 2010). In awake animals, puta- cells, which have to date been definitively identified in the CA1 and tive Ivy cells recorded using tetrodes have similar firing properties the CA3 of the hippocampus (Fuentealba et al., 2008; Szabadics during theta oscillations and ripples as Ivy cells in anaesthetized and Soltesz, 2009; Szabadics et al., 2010), have a unique position animals (Fuentealba et al., 2008). in and around the pyramidal cell layer, where they may have dif- Despite these differences in firing patterns in vivo, when record- ferent incoming and outgoing connectivity when compared to ings are made from slices in whole-cell patch configuration, both neurogliaform cells. In the CA1, where Ivy cells were first described Ivy and neurogliaform cells exhibit a characteristic late-spiking (Fuentealba et al., 2008), neurogliaform cells in and near the stra- firing pattern, often with a depolarizing ramp and subthresh- tum lacunosum-moleculare receive excitatory inputs from both old oscillations in the gamma frequency range leading up to the the temporo-ammonic pathway and CA3 Schaffer collaterals, and first spikes (Szabadics et al., 2007; Armstrong et al., 2011; Krook- in turn target the distal dendrites of CA1 pyramidal cells (Figures 1 Magnuson et al., 2011; Weiss and Veh, 2011; Figure 1). While and 3; Price et al., 2005; Fuentealba et al., 2010). In contrast, neurogliaform cells of rodents typically do not exhibit a sag upon Ivy cells reside in or near the stratum pyramidale, receive exci- hyperpolarization, neurogliaform cells of humans and monkeys tatory input from local pyramidal cells as well as presumably from do (Olah et al., 2007; Povysheva et al., 2007). CA3 Schaffer collaterals, and target the proximal dendrites of CA1 Both Ivy and neurogliaform cells exhibit the recently described pyramidal cells (Fuentealba et al., 2008). This differential input phenomenon of persistent firing (Krook-Magnuson et al., 2011; means that, while neurogliaform cells near the CA1 lacunosum- Figure 1). Persistent firing is a state of continued firing in the moleculare serve a primarily feedforward inhibitory role, Ivy cells absence of continued input (Sheffield et al., 2011). Experimentally, near the pyramidale are poised to mediate both feedforward and it is induced by repeated somatic current injections, causing the feedback inhibition to CA1 pyramidal cells. Ivy and neurogliaform cell to fire hundreds of action potentials over the span of minutes.

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FIGURE3|Feedforward network functions of neurogliaform family chemical synaptic). (B) shows the response in a dentate gyrus NGFC to cells in the hippocampus. The schematic outlines the connectivity of perforant path stimulation. (C) illustrates that individual mossy fiber boutons hippocampal neurogliaform and Ivy cells with principal cells. Entorhinal (MF,blue trace) form strong unitary connections (left box) with postsynaptic cortical input (green) directly excites NGFCs (red cells) both in the dentate Ivy cells in the CA3 (brown traces) while unitary connections between gyrus and in the CA1.These cells provide feedforward inhibition to principal mossy fiber boutons and fast-spiking basket cells (FSBC, orange traces) are cells (blue) of the dentate gyrus or CA1, respectively. In the dentate, smaller in amplitude. However (right box), while Ivy cells receive relatively neurogliaform family cells targeting proximal dendrites (Ivy, brown) provide fewer individual connections from mossy fibers, FSBCs receive more inhibition to both adult granule cells (GC) and newly born granule cells frequent mossy fiber bouton input. (D) demonstrates, in a paired recording, (nGC). Granule cells of the dentate, as well as granule cells of the CA3 that Ivy cells (action potential, brown trace) provide inhibition to CA3 GCs provide mossy fiber input to CA3 Ivy cells, which provide both feedforward (IPSCs, black traces). (E) shows the effect of the μ-opioid receptor agonist, inhibition to pyramidal cells (Pyr) and feedback inhibition to CA3, but not DAMGO on an Ivy cell (brown trace) to CA1 pyramidal cell (lower traces) dentate, granule cells. Schaffer collateral input to the CA1 contacts CA1 pair. The paired connection (control ACSF,black) is nearly abolished by NGFCs and presumably, Ivy cells which both provide feedforward inhibition application of DAMGO (light blue), and can be restored by addition of the to CA1 pyramidal cells. CA1 pyramidal cells also provide feedback excitation μ-opioid receptor antagonist, CTAP (DAMGO + CTAP,purple). (F) indicates to Ivy cells. Both NGFCs and Ivy cells in the CA1 express the μ-opioid the relative timing of NGFC and Ivy cell firing during theta rhythms recorded receptor (μOR, yellow triangle). In this simplified schematic, excitatory input from the pyramidal cell layer in vivo. NGFCs tend to fire right after the peak to excitatory cells has been omitted. (A) indicates the observed connectivity of theta, shortly following entorhinal input, while Ivy cells tend to fire right of NGFCs (red) in the dentate gyrus with other interneurons (light blue), after the trough, shortly following CA3 input and just after the firing of CA1 consisting of five different connectivity motifs (1: bidirectional chemical cells. Reproduced and modified with permission from Armstrong et al. synaptic; 2: unidirectional chemical synaptic; 3: electrical only; 4 electrical (2011) (A,B); Szabadics and Soltesz (2009) (C); Szabadics et al. (2010) (D), and bidirectional chemical synaptic; and 5: electrical and unidirectional and Krook-Magnuson et al. (2011) (E).

During this time period, there appears to be an integration of spik- without further input for tens of seconds (though in rare instances ing information, eventually resulting in the induction of persistent it can persist for over 10 min; Sheffield et al.,2011). Persistent firing firing. Once this state of persistent firing is achieved,spiking occurs is not affected by blocking GABAA, GABAB, AMPA, and NMDA

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receptors (Sheffield et al., 2011), but induction is inhibited by acti- and synaptic connections; Armstrong et al., 2011; Figure 3). The vation of μ-opioid receptors (Krook-Magnuson et al., 2011). The microcircuit functions of neurogliaform family cells in this con- apparent threshold for firing during persistent firing is very low text remain to be determined. This arrangement could serve a when recording from the soma, and it has been shown that this is number of important roles in the network, possibly synchroniz- due to the action potentials starting in the axons themselves and ing neuronal subgroups, inhibiting nearby neuronal subgroups, or back-propagating to the soma (Sheffield et al., 2011). Somatically acting as low-pass filters on incoming input to distinct cell types recorded spikes have an initial component, representing spiking (Mitchell and Silver, 2003; Zsiros et al., 2007). Computational in the axon, and a subsequent component, indicative of a somato- studies will help to determine the significance of this connectivity dendritic spike (Sheffield et al., 2011). The mechanism permitting for overall network function (Santhakumar et al., 2005; Dyhrfjeld- the integration of spiking information over the span of minutes, Johnsen et al.,2007; Morgan and Soltesz,2008; Ferrante et al.,2009; required for the induction of persistent firing, is a matter of open Cutsuridis and Hasselmo, 2012). debate and investigation, as are the physiological consequences In the dentate, where neurogenesis of granule cells occurs of persistent firing. Importantly, however, not all interneurons throughout life, cells of the neurogliaform family play another display persistent firing (Krook-Magnuson et al., 2011; Sheffield important role, being among the first sources of input to newly et al., 2011). Indeed, less than 20% of fast-spiking parvalbumin born granule cells (Markwardt et al., 2011). Dentate neurogli- expressing basket cells display persistent firing, in contrast to aform family cells not only inhibit adult granule cells directly, but over 80% of neurogliaform family cells (Krook-Magnuson et al., also inhibit other interneurons (indeed, burst firing in neurogli- 2011). aform family cells during 4AP application coincided with robust suppression of spontaneous firing of other interneuronal types) NETWORK AND FUNCTIONAL ROLES OF NEUROGLIAFORM and may therefore also disinhibit mature cells (Markwardt et al., AND IVY CELLS 2011). In this way, neurogliaform family cells might coordinate Neurogliaform family cells have recently been described in the activity of both newly born and adult granule cells,via direct depo- dentate gyrus (Armstrong et al., 2011; Markwardt et al., 2011). larization of newborn granule cells (through depolarizing GABA Neurogliaform cells located in the middle and outer molecular effects) and coincident disinhibition of mature cells (Markwardt layers receive entorhinal input and synapse on distal dendrites of et al., 2011). The advent of novel ways to probe the roles of specific granule cells, meaning that they are capable of providing feed- neuronal subgroups in vivo, such as optogenetic methods, provide forward inhibition (Armstrong et al., 2011; Figures 1 and 3). ways of investigating how neurogliaform family cells may enhance Compared to granule cells, neurogliaform cells in the dentate or direct the integration of newly born cells into the network, molecular layer receive fewer spontaneous inputs (consisting of and to better understand under what conditions neurogliaform excitatory and inhibitory events at roughly equal frequencies) cells have a predominately inhibitory action on adult granule cells to their small dendritic arbors than granule cells. However, like (e.g., feedforward inhibition), and under what conditions neu- granule cells, they do receive direct perforant path input from rogliaform cells produce a net disinhibition of granule cells (by the entorhinal cortex. This perforant path input is facilitating at inhibiting other interneurons). high frequencies, and suggests that neurogliaform cells may act Just as neurogliaform cells can mediate feedforward inhibi- to inhibit granule cells primarily during high frequency incoming tion to dentate granule cells, Ivy cells in the CA3 region are activity (Armstrong et al., 2011). similarly positioned to mediate feedforward inhibition to CA3 In regions like the dentate gyrus, where granule cells exhibit pyramidal cells (Szabadics and Soltesz, 2009). In paired record- sparse firing, feedforward GABAergic input has been predicted ings between mossy fiber boutons of granule cells and postsy- to play a major role in normal function (Ferrante et al., 2009), naptic CA3 interneurons, Ivy cells received fewer, but stronger including for spatial navigation, as well as in pathological states, unitary connections from mossy fibers than fast-spiking basket such as in epilepsy. Because neurogliaform cells target the distal cells (Szabadics and Soltesz, 2009). This arrangement suggests dendrites of principal cells, they may have stronger effects on the that individual large amplitude inputs from individual mossy processing of incoming input in dendritic compartments than on fibers to Ivy cells may be capable of inducing feedforward inhi- spike timing control per se. However, inhibitory dendritic input, in bition to CA3 pyramidal cells, while other interneurons, such as addition to its role in dendritic processing, has also recently been fast-spiking basket cells, require greater convergent input from a shown to have major effects on the firing of postsynaptic cells number of mossy fiber terminals in order to produce feedfor- (Lovett-Barron et al., 2012). Thus, new studies will be necessary to ward inhibition. Interestingly, granule cells have recently been determine what the major effect of neurogliaform cell activation identified within the CA3, where their excitatory inputs from may be during concurrent dendritic input to granule cells from entorhinal cortex and mossy fiber outputs to both glutamatergic other sources. and GABAergic cells of the CA3, as well as their electrophysi- The fact that neurogliaform cells form both chemical and elec- ological properties, are similar to those of granule cells located trical synapses with other classes of GABAergic neurons means in the dentate (Szabadics et al., 2010). Unlike dentate granule that they can display a variety of connectivity motifs. In the cells, however, CA3 granule cells have reciprocal connections with dentate gyrus molecular layer, for example, every possible two- CA3 Ivy cells, as well as with other GABAergic cells of the CA3 cell connectivity motif between neurogliaform cells and other (Szabadics et al., 2010; Figure 3). Therefore, CA3 granule cells types of interneurons was observed (electrical only, unidirectional represent a unique, local glutamatergic neuronal subtype which synaptic, bidirectional synaptic, and combinations of electrical in addition to both exciting CA3 pyramidal cells and GABAergic

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cells to drive feedforward inhibition, also receive feedback input changes in the hippocampal opioid system can have significant from the CA3 GABAergic network. Ivy cells providing simultane- functional consequences. ous feedforward inhibition to CA3 pyramidal cells and feedback In addition to new insights into the neuromodulation of neu- inhibition of CA3 granule cells, may have important implica- rogliaform family output, the expression of such neuroactive tions for oscillatory activity and spike timing within this brain markers as NPY and nNOS suggests that neurogliaform fam- region. ily cells may be important sources of both NPY and NO in the Finally, neurogliaform cells in CA1 are also positioned to brain. NPY is a neuropeptide with a range of reported func- mediate feedforward inhibition, as they receive input from both tions, including stimulating dentate neurogenesis (Howell et al., CA3 and entorhinal cortex, and in turn inhibit CA1 pyrami- 2007). Additionally, NPY is implicated in anxiolysis, in the mech- dal cells (in addition to interneurons; Vida et al., 1998; Price anisms of antidepressants (reviewed in Heilig, 2004), and in et al., 2005; Price et al., 2008). Feedforward inhibition in CA1 response to stress–veterans exposed to traumatic experiences but can be very strong; following the stimulation of the temporo- who had higher plasma levels of NPY experienced fewer stress- ammonic pathway, a predominately inhibitory response is gener- related sequelae such as post-traumatic stress disorder (PTSD) ated in CA1 pyramidal cells (Soltesz and Jones, 1995). Relevant and depression than those with lower NPY levels (Morgan et al., to our discussion, this inhibitory response consists of both post- 2002; Yehuda et al., 2006). Interestingly, NPY may also be impor- synaptic GABAA and GABAB components (Empson and Heine- tant in epilepsy; both the level of NPY protein and its receptor mann, 1995), which may implicate involvement of neurogliaform subtypes are robustly changed after seizures, and NPY overex- cells. pression is protective against acute and chronic seizures. This suggests that neurogliaform family cells may be important in sup- NEUROMODULATORS AND NEUROGLIAFORM FAMILY CELLS pressing seizure activity in epilepsy (Vezzani et al., 1999; Bacci Neuromodulatory influences onto and arising from neurogli- et al., 2002; Noè et al., 2008; Noe et al., 2010; Kovac et al., aform family cells are only beginning to be uncovered. One recent 2011). interesting finding involves the effects of opioids on these cells The expression of nNOS by cells of the neurogliaform fam- in the CA1. In studies of input to CA1 from CA3 and entorhi- ily is especially interesting since it is not yet known how the nal cortex, it was noted that stimulating the temporo-ammonic interneuronal production of NO may contribute to overall net- pathway one theta cycle before stimulating Schaffer collateral work activity. While the known functions of NO in neuronal and input leads to inhibition of the second excitatory input to CA1 non-neuronal tissues are numerous, the roles of nNOS and NO in pyramidal cells in a GABAB-dependent, opioid-sensitive man- specific GABAergic cell types, such as neurogliaform family cells, ner (Dvorak-Carbone and Schuman, 1999; McQuiston, 2011). has yet to be determined. However, NO is a well-known retrograde In the context of the known properties of neurogliaform fam- modulator,and nNOS in neurogliaform cells may therefore involve ily cells, this observation suggests that neurogliaform cells could synapse- and cell type-specific regulation of transmission from be modulated by opioids. In fact, both Ivy and neurogliaform both excitatory and inhibitory inputs. This may serve to modulate cells were recently found to be highly modulated by μ-opioid levels of neurogliaform activity (and thus levels of GABAergic vol- receptors (Krook-Magnuson et al., 2011). Activation of μ-opioid ume transmission) during specific input patterns (Szabadits et al., receptors produced both somatic hyperpolarization and inhibi- 2007; Feil and Kleppisch,2008; Maggesissi et al.,2009; Zanelli et al., tion of neurotransmitter release from terminals. Indeed, in paired 2009; Szabadits et al., 2011), or to affect long term synaptic plas- recordings between Ivy and pyramidal cells, activation of μ-opioid ticity (Shin and Linden, 2005; Anwyl, 2006; Lange et al., 2012). In receptors nearly abolished the Ivy cell-mediated inhibitory post- addition, the known vasodilatory role of NO in the peripheral cir- synaptic current (IPSC; Figure 3). Together these findings and culatory system and in the CNS (Hall and Behbehani, 1998; Cauli others suggest not only that neurogliaform cells can mediate et al., 2004; Corsani et al., 2008; Melikian et al., 2009) suggests feedforward inhibition, and that feedforward inhibition interacts the possibility that neurogliaform family cells might play a major with the timing of impinging excitatory inputs to CA1 pyrami- role in increasing perfusion to regions that are particularly active dal cells, but also that this inhibition is highly modulated by (Tamas et al., 2003; Simon et al., 2005). More studies are clearly opioids. This has implications both for understanding the mech- needed to definitively address the role of nNOS in the function of anisms of action of drugs of abuse that act at the μ-opioid neurogliaform family cells. receptor (such as heroin), as well as for the physiological function of CA1 during exploration, learning, and memory. Indeed, SUMMARY AND OUTLOOK μ-opioid receptor knock-out mice show reduced radial-arm maze Neurogliaform family cells have unique intrinsic and synaptic and Morris water maze performance (Jamot et al., 2003). Further, properties and are found in a range of brain regions, including alterations in the hippocampal opioid system are also seen, for throughout the hippocampal formation. A number of roles for example, in epilepsy and Alzheimer’s, indicating a potential role neurogliaform family cells have been proposed. In addition to in these disorders (Laorden et al., 1985; Gall, 1988; Gall et al., functions related to their expression of NPY and nNOS, roles in 1988; D’Intino et al., 2006; Rocha et al., 2007; Cuellar-Herrera influencing network synchrony and oscillatory activity have been et al., 2012). Moreover, in a model of Alzheimer’s it was found proposed (Tamas et al., 2003; Simon et al., 2005; Zsiros et al., 2007; that the reported increase in enkephalin (an endogenous ligand Fuentealba et al., 2008; Price et al., 2008; Olah et al., 2009; Karayan- for μ-opioid receptors) contributed to the cognitive difficulties nis et al., 2010). Their modulation by μ-opioid receptors suggests associated with the disease (Meilandt et al., 2008), indicating that that volume transmission by neurogliaform family cells may play

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a major role in the effects of opiates, and may be of importance et al., 1997; Price et al., 2005; Fuentealba et al., 2010; Armstrong for future pharmacological insights. et al., 2011). Interestingly, some GABAergic populations have been observed The role of neurogliaform family cells as important feedfor- to select postsynaptic partners based on long-range projection pat- ward inhibitors is supported by in vitro and existing in vivo data, terns. For example, in the entorhinal cortex, CCK-positive basket but the wide connectivity and unique properties of these cells cells selectively target only those principal cells which project to with other interneurons complicates our understanding of their contralateral extrahippocampal structures,avoiding principal cells true network functions. Ultimately, more studies, including stud- which project to the ipsilateral hippocampus and form the per- ies in vivo in awake, behaving animals are needed to determine forant path (Varga et al., 2010). In contrast, due to their unique how neurogliaform and Ivy cells behave in information process- volume neurotransmission, neurogliaform cells are likely to indis- ing and network activities during different behavioral states. A criminately inhibit all cells with processes within their axonal comprehensive understanding of the roles of these unique neu- arbors. Thus, neurogliaform cells may represent a GABAergic cell rons and their peculiar connective properties promises to shed class which coordinates the activity, or level of activity, between light on new mechanisms by which microcircuits interact within neurons processing information destined for distinct brain regions and across brain areas. (Krook-Magnuson et al.,2012). This idea is particularly interesting when considering that cells with different long-range projection ACKNOWLEDGMENTS patterns may intermingle within a single cell layer (Varga et al., This work was supported by the US National Institutes of Health 2010). Moreover, as neurogliaform cells have been found to cross grants NS35915, NS074702, and NS74432, the Epilepsy Founda- boundaries (e.g., the hippocampal ﬁssure), they may also directly tion (to Caren Armstrong), and the George E. Hewitt Foundation regulate concurrent activity in distinct brain regions (Ceranik for Medical Research (to Esther Krook-Magnuson).

REFERENCES S., and Vannucchi, M. G. (2008). L., and Soltesz, I. (2007). Topologi- Studer, M., Morales, M., and Somo- Anwyl, R. (2006). Induction and expres- Inducible nitric oxide synthase cal determinants of epileptogenesis gyi, P. (2010). Expression of COUP- sion mechanisms of postsynap- appears and is co-expressed with the in large-scale structural and func- TFII nuclear receptor in restricted tic NMDA receptor-independent neuronal isoform in interneurons of tional models of the dentate gyrus GABAergic neuronal populations in homosynaptic long-term depres- the rat hippocampus after transient derived from experimental data. J. the adult rat hippocampus. J. Neu- sion. Prog. Neurobiol. 78, 17–37. ischemia induced by middle cerebral Neurophysiol. 97, 1566–1587. rosci. 30, 1595–1609. Armstrong, C., Szabadics, J., Tamas, artery occlusion. Exp. Neurol. 211, Elfant, D., Pal, B. Z., Emptage, N., Gall, C. (1988). Seizures induce G., and Soltesz, I. (2011). Neu- 433–440. and Capogna, M. (2008). Specific dramatic and distinctly different rogliaform cells in the molecu- Cuellar-Herrera, M., Velasco, A. L., inhibitory synapses shift the balance changes in enkephalin, dynorphin, lar layer of the dentate gyrus as Velasco, F., Chavez, L., Orozco- from feedforward to feedback inhi- and CCK immunoreactivities in feed-forward gamma-aminobutyric Suarez, S., Armagan, G., Turunc, E., bition of hippocampal CA1 pyra- mouse hippocampal mossy fibers. J. acidergic modulators of entorhinal- Bojnik, E.,Yalcin,A., Benyhe, S., Bor- midal cells. Eur. J. Neurosci. 27, Neurosci. 8, 1852–1862. hippocampal interplay. J. Comp. sodi, A., Alonso-Vanegas, M., and 104–113. Gall, C. M., Pico, R. M., and Lauterborn, Neurol. 519, 1476–1491. Rocha, L. (2012). Mu opioid recep- Empson, R. M., and Heinemann, U. J. C. (1988). Focal hippocampal Bacci, A., Huguenard, J. R., and Prince, tor mRNA expression, binding, and (1995). The perforant path projec- lesions induce seizures and long- D. A. (2002). Differential modu- functional coupling to G-proteins tion to hippocampal area CA1 in lasting changes in mossy fiber lation of synaptic transmission by in human epileptic hippocampus. the rat hippocampal-entorhinal cor- enkephalin and CCK immunore- neuropeptide Y in rat neocortical Hippocampus 22, 122–127. tex combined slice. J. Physiol. (Lond.) activity. Peptides 9(Suppl. 1), neurons. Proc. Natl. Acad. Sci. U.S.A. Cutsuridis,V.,and Hasselmo,M. (2012). 484(Pt 3), 707–720. 79–84. 99, 17125–17130. GABAergic contributions to gating, Feil, R., and Kleppisch, T. (2008). Hall, C. W., and Behbehani, M. M. Buzsaki, G. (2002). Theta oscillations timing, and phase precession of hip- “NO/cGMP-dependent modula- (1998). Synaptic effects of nitric in the hippocampus. Neuron 33, pocampal neuronal activity during tion of synaptic transmission,” oxide on enkephalinergic, GABAer- 325–340. theta oscillations. Hippocampus. Pharmacology of Neurotransmit- gic, and glutamatergic networks of Capogna, M., and Pearce, R. A. D’Intino, G., Vaccari, F., Sivilia, S., ter Release, eds T. C. Südhof the rat periaqueductal gray. Brain (2011). GABAA, slow: causes and Scagliarini, A., Gandini, G., Gia- and K. Starke (Berlin: Springer), Res. 805, 69–87. consequences. Trends Neurosci. 34, rdino, L., and Calza, L. (2006). A 529–560. Heilig, M. (2004). The NPY system in 101–112. molecular study of hippocampus in Ferrante, M., Migliore, M., and Ascoli, stress, anxiety and depression. Neu- Cauli, B., Tong, X.-K., Rancillac, A., dogs with convulsion during canine G. A. (2009). Feed-forward inhibi- ropeptides 38, 213–224. Serluca, N., Lambolez, B., Rossier, distemper virus encephalitis. Brain tion as a buffer of the neuronal Howell, O. W., Silva, S., Scharfman, J., and Hamel, E. (2004). Cortical Res. 1098, 186–195. input-output relation. Proc. Natl. H. E., Sosunov, A. A., Zaben, M., GABA interneurons in neurovascu- Deller, T., and Leranth, C. (1990). Acad. Sci. U.S.A. 106, 18004–18009. Shatya, A., Mckhann Ii, G., Herzog, lar coupling: relays for subcortical Synaptic connections of neuropep- Fuentealba, P., Begum, R., Capogna, H., Laskowski, A., and Gray, W. P. vasoactive pathways. J. Neurosci. 24, tide Y (NPY) immunoreactive neu- M., Jinno, S., Marton, L. F., (2007). Neuropeptide Y is impor- 8940–8949. rons in the hilar area of the rat Csicsvari, J., Thomson, A., Somogyi, tant for basal and seizure-induced Ceranik, K., Bender, R., Geiger, J. R., hippocampus. J. Comp. Neurol. 300, P., and Klausberger, T. (2008). Ivy precursor cell proliferation in the Monyer, H., Jonas, P., Frotscher, M., 433–447. cells: a population of nitric-oxide- hippocampus. Neurobiol. Dis. 26, and Lubke, J. (1997). A novel type Dvorak-Carbone, H., and Schuman, E. producing, slow-spiking GABAergic 174–188. of GABAergic interneuron connect- M. (1999). Patterned activity in stra- neurons and their involvement in Ibanez-Sandoval, O., Tecuapetla, F., ing the input and the output regions tum lacunosum moleculare inhibits hippocampal network activity. Neu- Unal, B., Shah, F., Koos, T., and Tep- of the hippocampus. J. Neurosci. 17, CA1 pyramidal neuron firing. J. ron 57, 917–929. per, J. M. (2011). A novel function- 5380–5394. Neurophysiol. 82, 3213–3222. Fuentealba, P., Klausberger, T., Karayan- ally distinct subtype of striatal neu- Corsani, L., Bizzoco, E., Pedata, F., Gian- Dyhrfjeld-Johnsen, J., Santhakumar, V., nis,T.,Suen,W.Y.,Huck,J.,Tomioka, ropeptide Y interneuron. J. Neurosci. friddo, M., Faussone-Pellegrini, M. Morgan, R. J., Huerta, R., Tsimring, R., Rockland, K., Capogna, M., 31, 16757–16769.

Frontiers in Neural Circuits www.frontiersin.org May 2012 | Volume 6 | Article 23 | 8 Armstrong et al. Neurogliaform cells in the hippocampus

Jamot, L., Matthes, H. W., Simonin, F., dendritic inhibition. Nat Neurosci. Noe, F., Vaghi, V., Balducci, C., Fitzsi- effects of subacute electrical stimu- Kieffer, B. L., and Roder, J. C. (2003). 15, 423–430. mons, H., Bland, R., Zardoni, D., lation. Seizure 16, 645–652. Differential involvement of the mu Maggesissi, R. S., Gardino, P. F., Sperk, G., Carli, M., During, M. J., Santhakumar, V., Aradi, I., and Soltesz, and kappa opioid receptors in spa- Guimarães-Souza, E. M., Paes-De- and Vezzani, A. (2010). Anticonvul- I. (2005). Role of mossy fiber sprout- tial learning. Genes Brain Behav. 2, Carvalho, R., Silva, R. B., and Calaza, sant effects and behavioural out- ing and mossy cell loss in hyper- 80–92. K. C. (2009). Modulation of GABA comes of rAAV serotype 1 vector- excitability: a network model of Karagiannis, A., Gallopin, T., David, C., release by nitric oxide in the chick mediated neuropeptide Y overex- the dentate gyrus incorporating cell Battaglia, D., Geoffroy, H., Rossier, retina: different effects of nitric pression in rat hippocampus. Gene types and axonal topography. J. Neu- J., Hillman, E. M., Staiger, J. F., oxide depending on the cell popu- Ther. 17, 643–652. rophysiol. 93, 437–453. and Cauli, B. (2009). Classifica- lation. Vision Res. 49, 2494–2502. Olah, S., Fule, M., Komlosi, G., Varga, Sheffield, M. E., Best, T. K., Mensh, B. D., tion of NPY-expressing neocorti- Markwardt, S. J., Dieni, C. V., Wadiche, C., Baldi, R., Barzo, P., and Tamas,G. Kath,W. L., and Spruston, N. (2011). cal interneurons. J. Neurosci. 29, J. I., and Overstreet-Wadiche, L. (2009). Regulation of cortical micro- Slow integration leads to persistent 3642–3659. (2011). Ivy/neurogliaform interneu- circuits by unitary GABA-mediated action potential firing in distal axons Karayannis, T., Elfant, D., Huera- rons coordinate activity in the neu- volume transmission. Nature 461, of coupled interneurons. Nat. Neu- Ocampo, I., Teki, S., Scott, R. rogenic niche. Nat. Neurosci. 14, 1278–1281. rosci. 14, 200–207. S., Rusakov, D. A., Jones, M. V., 1407–1409. Olah, S., Komlosi, G., Szabadics, J., Shin, J. H., and Linden, D. J. (2005). and Capogna, M. (2010). Slow McQuiston, A. R. (2011). Mu opi- Varga, C., Toth, E., Barzo, P., and An NMDA receptor/nitric oxide cas- GABA transient and receptor oid receptor activation normalizes Tamas, G. (2007). Output of neu- cade is involved in cerebellar LTD desensitization shape synaptic temporo-ammonic pathway driven rogliaform cells to various neuron but is not localized to the parallel responses evoked by hippocampal inhibition in hippocampal CA1. types in the human and rat cere- fiber terminal. J. Neurophysiol. 94, neurogliaform cells. J. Neurosci. 30, Neuropharmacology 60, 472–479. bral cortex. Front. Neural Circuits 4281–4289. 9898–9909. Meilandt, W. J., Yu, G. Q., Chin, J., 1:4. doi:10.3389/neuro.04.004.2007 Simon, A., Olah, S., Molnar, G., Klausberger, T., and Somogyi, P. (2008). Roberson, E. D., Palop, J. J., Wu, Pearce, R. A. (1993). Physiological Szabadics, J., and Tamas, G. (2005). Neuronal diversity and temporal T., Scearce-Levie, K., and Mucke, L. evidence for two distinct GABAA Gap-junctional coupling between dynamics: the unity of hippocam- (2008). Enkephalin elevations con- responses in rat hippocampus. Neu- neurogliaform cells and various pal circuit operations. Science 321, tribute to neuronal and behavioral ron 10, 189–200. interneuron types in the neocortex. 53–57. impairments in a transgenic mouse Povysheva, N. V., Zaitsev, A. V., Kro- J. Neurosci. 25, 6278–6285. Kovac, S., Megalogeni, M., and Walker, model of Alzheimer’s disease. J. Neu- ner, S., Krimer, O. A., Rotaru, D. Soltesz, I., and Jones, R. S. (1995). The M. (2011). In vitro effects of neurosci. 28, 5007–5017. C., Gonzalez-Burgos, G., Lewis, D. direct perforant path input to CA1: ropeptide Y in rat neocortical and Melikian, N., Seddon, M. D., Casadei, A., and Krimer, L. S. (2007). Elec- excitatory or inhibitory? Hippocam- hippocampal tissue. Neurosci. Lett. B., Chowienczyk, P. J., and Shah, trophysiological differences between pus 5, 101–103. 492, 43–46. A. M. (2009). Neuronal nitric oxide neurogliaform cells from monkey Suzuki, N., and Bekkers, J. M. (2012). Krook-Magnuson, E., and Huntsman, synthase and human vascular regu- and rat prefrontal cortex. J. Neuro- Microcircuits mediating feedfor- M. M. (2007). The transience of lation. Trends Cardiovasc. Med. 19, physiol. 97, 1030–1039. ward and feedback synaptic inhibi- interneuron circuit diversity just 256–262. Price, C. J., Cauli, B., Kovacs, E. R., tion in the piriform cortex. J. Neu- “sped” up. Proc. Natl. Acad. Sci. Mitchell, S. J., and Silver, R. A. (2003). Kulik, A., Lambolez, B., Shigemoto, rosci. 32, 919–931. U.S.A. 104, 16723–16724. Shunting inhibition modulates neu- R., and Capogna, M. (2005). Neu- Szabadics, J., and Soltesz, I. (2009). Krook-Magnuson, E., Luu, L., Lee, S. ronal gain during synaptic excita- rogliaform neurons form a novel Functional specificity of mossy fiber H., Varga, C., and Soltesz, I. (2011). tion. Neuron 38, 433–445. inhibitory network in the hip- innervation of GABAergic cells in Ivy and neurogliaform interneurons Mizuseki, K., Sirota, A., Pastalkova, E., pocampal CA1 area. J. Neurosci. 25, the hippocampus. J. Neurosci. 29, are a major target of mu-opioid and Buzsaki, G. (2009). Theta oscil- 6775–6786. 4239–4251. receptor modulation. J. Neurosci. 31, lations provide temporal windows Price, C. J., Scott, R., Rusakov, D. A., Szabadics, J., Tamas, G., and Soltesz, 14861–14870. for local circuit computation in the and Capogna, M. (2008). GABA(B) I. (2007). Different transmitter Krook-Magnuson, E., Varga, C., Lee, entorhinal-hippocampal loop. Neu- receptor modulation of feedfor- transients underlie presynaptic cell S. H., and Soltesz, I. (2012). New ron 64, 267–280. ward inhibition through hippocam- type specificity of GABAA,slow and dimensions of interneuronal spe- Morgan Iii, C. A., Rasmusson, A. M., pal neurogliaform cells. J. Neurosci. GABAA, fast. Proc. Natl. Acad. Sci. cialization unmasked by principal Wang, S., Hoyt, G., Hauger, R. L., and 28, 6974–6982. U.S.A. 104, 14831–14836. cell heterogeneity. Trends Neurosci. Hazlett, G. (2002). Neuropeptide- Ramón y Cajal, S. (1922). Studien über Szabadics, J., Varga, C., Brunner, J., 35, 175–184. Y, cortisol, and subjective distress die Sehrinde der Katze. J. Psychol. Chen, K., and Soltesz, I. (2010). Lange, M. D., Doengi, M., Lesting, J., in humans exposed to acute stress: Neurol. 29, 161–181. Granule cells in the CA3 area. J. Pape, H. C., and Jüngling, K. (2012). replication and extension of pre- Ramón y Cajal, S. (1999). Texture of Neurosci. 30, 8296–8307. Heterosynaptic long-term potentia- vious report. Biol. Psychiatry 52, the Nervous System of Man and Szabadits, E., Cserép, C., Ludányi, A., tion at interneuron-principal neu- 136–142. the Vertebrates. Barcelona: Spring- Katona, I., Gracia-Llanes, J., Freund, ron synapses in the amygdala Morgan, R. J., and Soltesz, I. (2008). Verlag/Wein Springer. T. F., and Nyíri, G. (2007). Hip- requires nitric oxide signalling. J. Nonrandom connectivity of the Ratzliff, A. D., and Soltesz, I. (2001). pocampal GABAergic synapses pos- Physiol. (Lond.) 590, 131–143. epileptic dentate gyrus predicts a Differential immunoreactivity sess the molecular machinery for Laorden, M. L., Olaso, M. J., Miralles, major role for neuronal hubs in for alpha-actinin-2, an N- retrograde nitric oxide signaling. J. F. S., and Puig, M. M. (1985). Cere- seizures. Proc. Natl. Acad. Sci. U.S.A. methyl-D-aspartate-receptor/actin Neurosci. 27, 8101–8111. brospinal fluid leucine-enkephalin- 105, 6179–6184. binding protein, in hippocampal Szabadits, E., Cserép, C., Szonyi, A., like levels in febrile convulsions. Noè, F., Pool, A.-H., Nissinen, J., Gobbi, interneurons. Neuroscience 103, Fukazawa, Y., Shigemoto, R., Watan- Methods Find Exp. Clin. Pharmacol. M., Bland, R., Rizzi, M., Balducci, 337–349. abe, M., Itohara, S., Freund, T. 7, 75–77. C., Ferraguti, F., Sperk, G., Dur- Rocha, L., Cuellar-Herrera, M., Velasco, F., and Nyiri, G. (2011). NMDA Lovett-Barron, M., Turi, G. F., Kaifosh, ing, M. J., Pitkänen, A., and Vez- M., Velasco, F., Velasco, A. L., receptors in hippocampal GABAer- P., Lee, P. H., Bolze, F., Sun, X. zani,A. (2008). Neuropeptide Y gene Jimenez, F., Orozco-Suarez, S., and gic synapses and their role in nitric H., Nicoud, J. F., Zemelman, B. therapy decreases chronic sponta- Borsodi, A. (2007). Opioid recep- oxide signaling. J. Neurosci. 31, V., Sternson, S. M., and Losonczy, neous seizures in a rat model of tor binding in parahippocampus of 5893–5904. A. (2012). Regulation of neuronal temporal lobe epilepsy. Brain 131, patients with temporal lobe epilepsy: Tamas, G., Lorincz, A., Simon, A., input transformations by tunable 1506–1515. its association with the antiepileptic and Szabadics, J. (2003). Identified

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sources and targets of slow inhibi- at the stratum radiatum-stratum Zsiros, V., Aradi, I., and Maccaferri, G. commercial or financial relationships tion in the neocortex. Science 299, lacunosum-moleculare border in (2007). Propagation of postsynaptic that could be construed as a potential 1902–1905. the CA1 area of the rat hippocampus currents and potentials via gap junc- conflict of interest. Tricoire, L., Pelkey, K. A., Daw, M. in vitro. J. Physiol. (Lond.) 506(Pt 3), tions in GABAergic networks of the I., Sousa, V. H., Miyoshi, G., Jef- 755–773. rat hippocampus. J. Physiol. (Lond.) Received: 29 February 2012; paper pend- fries, B., Cauli, B., Fishell, G., and Weiss, T., and Veh, R. W. (2011). Mor- 578, 527–544. ing published: 22 March 2012; accepted: Mcbain, C. J. (2010). Common phological and electrophysiological Zsiros, V., and Maccaferri, G. (2005). 13 April 2012; published online: 16 May origins of hippocampal Ivy and characteristics of neurons within Electrical coupling between 2012. nitric oxide synthase expressing neu- identified subnuclei of the lateral interneurons with different Citation: Armstrong C, Krook- rogliaform cells. J. Neurosci. 30, habenula in rat brain slices. Neuro- excitable properties in the stra- Magnuson E and Soltesz I (2012) 2165–2176. science 172, 74–93. tum lacunosum-moleculare of the Neurogliaform and Ivy cells: a major Varga, C., Lee, S. Y., and Soltesz, I. Yehuda, R., Brand, S., and Yang, R.- juvenile CA1 rat hippocampus. J. family of nNOS expressing GABAergic (2010). Target-selective GABAergic K. (2006). Plasma neuropeptide Y Neurosci. 25, 8686–8695. neurons. Front. Neural Circuits 6:23. doi: control of entorhinal cortex output. concentrations in combat exposed Zsiros, V., and Maccaferri, G. (2008). 10.3389/fncir.2012.00023 Nat. Neurosci. 13, 822–824. veterans: relationship to trauma Noradrenergic modulation of elec- Copyright © 2012 Armstrong, Krook- Vezzani, A., Sperk, G., and Colmers, W. exposure, recovery from PTSD, trical coupling in GABAergic net- Magnuson and Soltesz. This is an open- F. (1999). Neuropeptide Y: emerg- and coping. Biol. Psychiatry 59, works of the hippocampus. J. Neu- access article distributed under the terms ing evidence for a functional role in 660–663. rosci. 28, 1804–1815. of the Creative Commons Attribution seizure modulation. Trends Neurosci. Zanelli, S., Naylor, M., and Kapur, J. Non Commercial License, which per- 22, 25–30. (2009). Nitric oxide alters GABAer- mits non-commercial use, distribution, Vida, I., Halasy, K., Szinyei, C., Somo- gic synaptic transmission in cul- Conflict of Interest Statement: The and reproduction in other forums, pro- gyi, P., and Buhl, E. H. (1998). Uni- tured hippocampal neurons. Brain authors declare that the research was vided the original authors and source are tary IPSPs evoked by interneurons Res. 1297, 23–31. conducted in the absence of any credited.

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