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Fast Synaptic Signaling by Nicotinic Acetylcholine and Serotonin 5-HT3 Receptors in Developing Visual Cortex

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Fast Synaptic Signaling by Nicotinic Acetylcholine and Serotonin 5-HT3 Receptors in Developing Visual Cortex The Journal of Neuroscience, November 1, 1997, 17(21):8353–8362 Fast Synaptic Signaling by Nicotinic Acetylcholine and Serotonin 5-HT3 Receptors in Developing Visual Cortex Birgit Roerig, Darin A. Nelson, and Lawrence C. Katz Howard Hughes Medical Institute and Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710 Cholinergic and serotonergic fiber systems invade the devel- synaptic events in pyramidal cells and interneurons of all cor- oping visual cortex several weeks before eye opening; both tical layers. The number of cells receiving such inputs increased transmitters have been implicated in plasticity of neocortical with the ingrowth of thalamic afferents, and the frequencies of circuits. These transmitters have been presumed to act pre- the spontaneous events increased at eye opening. Thus, both dominantly through second messenger-coupled receptors, be- acetylcholine and serotonin can mediate fast synaptic trans- cause fast cholinergic or serotonergic neurotransmission has mission in the visual cortex; the early onset of these mecha- never been observed in neocortex. However, acetylcholine and nisms suggests a role during initial stages of circuit formation serotonin also act on ligand-gated ion channels; the nicotinic and during subsequent experience-dependent remodeling of acetylcholine receptor and the serotonin 5-HT3 receptor, re- cortical connections. spectively. Here, using whole-cell patch-clamp techniques in Key words: visual cortex; ferret; whole-cell recording; sero- developing ferret visual cortex, we pharmacologically isolated tonin; acetylcholine; nicotinic acetylcholine receptor; 5-HT3 re- fast, spontaneous, and evoked cholinergic and serotonergic ceptor; development; synaptic current Beginning at embryonic stages the mammalian neocortex is with second messenger coupled receptors (Hasselmo, 1995), and densely innervated by cholinergic, serotonergic, and noradrener- many of their functions in the developing nervous system are gic brainstem afferents. Their presence suggests roles for these indeed mediated via G-protein-coupled postsynaptic receptor neuromodulators in circuit formation and synaptogenesis. These types (Gu and Singer, 1993, 1995; Liu et al., 1994). However, both systems undergo laminar rearrangements during cortical devel- acetylcholine and serotonin can also activate fast, ionotropic opment (D’Amato et al., 1987; Henderson, 1991; Voigt and De receptor subtypes. The predominant physiological role of these Lima, 1991a,b; Shaw et al., 1984, 1986) and, especially in rodents, receptors, the nicotinic acetylcholine receptor and the serotoner- are associated with the layout of thalamocortical projections in gic 5-HT3 receptor, is generally considered to be presynaptic primary sensory areas (D’Amato et al., 1987; Fuchs, 1989; Schlag- modulation of transmitter release (Kawa, 1994; Role and Berg, gar and O’Leary, 1994; Broide et al., 1995). These transmitters 1996). Neuronal nicotinic ACh receptors facilitate the release of have indeed been repeatedly implicated in the plasticity of neo- various neurotransmitters (Role and Berg, 1996) including gluta- cortical circuits, modulating ocular dominance columns (Kasa- mate in the prefrontal cortex (Vidal and Changeux, 1993); sero- matsu and Pettigrew, 1976; Bear and Singer, 1986; Imamura and tonin 5-HT3 receptor activation, on the other hand, increases Kasamatsu, 1989; Gu and Singer, 1993, 1995; Liu et al., 1994) and GABA release in hippocampal interneurons (Kawa, 1994). thalamocortical and intracortical synaptic transmission (Broecher Despite the prominent cholinergic and serotonergic fiber sys- et al., 1992; Vidal and Changeux, 1993; Read et al., 1994; Rhoades tems in neocortex, fast events mediated by these neurotransmit- et al., 1994). Cholinergic transmission in particular may play a ters have not been detected, although there have been occasional critical role during visual system development. Cholinergic syn- observations of fast postsynaptic transmission in other regions of aptic currents, mediated by nicotinic receptors, trigger propaga- the adult mammalian CNS (Sugita et al., 1992, Zhang et al., tion of spontaneous waves of excitation in developing ferret 1993). Using whole-cell recording techniques and optical record- retinal ganglion cells (Feller et al., 1996), which may shape con- ing of synaptic activity in slices of developing ferret primary nectivity in other regions, including visual cortex. Moreover, visual cortex, we uncovered fast postsynaptic currents mediated thalamic fiber ingrowth triggers nicotinic acetylcholine receptor by both acetylcholine and serotonin. This adds a new avenue for expression in cortical neurons (Broide et al., 1996), suggesting a the action of these neurotransmitters in addition to their second role in the development of thalamocortical projection patterns. messenger-mediated effects. The classical concept of the function of cholinergic and mono- aminergic afferents in the CNS emphasizes their interactions MATERIALS AND METHODS Received March 21, 1997; revised Aug. 5, 1997; accepted Aug. 13, 1997. Animals and dissection. Postnatal ferrets [postnatal day 6 (P6)–P57; This work was supported by National Institutes of Health Grant EY07690 (L.C.K.) and a Human Frontier Science Program postdoctoral fellowship (B.R.). We Marshall Farms, New Rose, NY] were deeply anesthetized with Nem- thank Scott Douglas for excellent technical assistance and Julie Kauer, Lori Mac- butal (100 mg/kg, i.p.) and decapitated. Coronal slices (400–500 mm Mahon, and Michael Weliky for critical comments on this manuscript. thickness) of primary visual cortex were prepared using a Vibratome Correspondence should be addressed to Birgit Roerig, Department of Neurobi- (Ted Pella, Inc., Redding, CA). Dissections were made in artificial CSF ology, Duke University Medical Center, Box 3209, Durham, NC 27710. (ACSF; containing, in mM: 248 sucrose, 5 KCl, 5.3 KH2PO4 , 1.3 MgSO4 , Copyright © 1997 Society for Neuroscience 0270-6474/97/178353-10$05.00/0 3.2 CaCl2, 10 dextrose, 25 NaHCO3 , and 1 kynurenic acid) oxygenated 8354 J. Neurosci., November 1, 1997, 17(21):8353–8362 Roerig et al. • Cholinergic and Serotonergic Transmission in Visual Cortex with a mixture of 95% O2 and 5% CO2 , pH 7.4, chilled to 4°C. Slices rents to be distinguished by changing the holding potential. Un- were maintained in an interface chamber at a temperature of 33°C and in der these conditions inhibitory currents reversed near 230 mV, an atmosphere of 95% CO /5% O as described previously (Durack and 2 2 whereas glutamatergic synaptic events reversed near 0 mV. To Katz, 1996). Sucrose ACSF was replaced with standard ACSF (in mM: isolate nicotinic and serotonergic currents pharmacologically, glu- 125 NaCl, 5 KCl, 5.3 KH2PO4 , 1.3 MgSO4 , 3.2 CaCl2, 10 dextrose, and 25 NaHCO3 ) after 1 hr. For patch-clamp and optical recording individ- tamatergic and GABAergic synaptic transmission were blocked ual slices were transferred to a recording chamber and continuously by bath application of the NMDA receptor antagonist D-APV (20 superfused with ACSF at room temperature. mM, a concentration that has been shown to be more than suffi- Electrophysiology. Electrophysiological recordings were performed us- ing standard whole-cell patch-clamp methods (Blanton et al., 1989). The cient to block NMDA receptor-mediated responses both in vitro intracellular solution consisted of (in mM): 110 D-gluconic acid, 110 and in vivo; Davis, 1992), the non-NMDA glutamate receptor CsOH, 11 EGTA, 10 CsCl, 1 MgCl2 ,1CaCl2, 10 HEPES, 1.8 GTP, and antagonist CNQX (50 mM), and the GABAA receptor antagonists 3 ATP, pH 7.2, and contained 0.5% N-(2-aminoethyl)biotinamide (Neu- picrotoxin (50 mM) and bicuculline methiodide (20–50 mM). In- robiotin; Molecular Probes, Eugene, OR). Voltage-clamp recordings were conducted using an Axopatch 1D amplifier (Axon Instruments). teractions of these antagonists with nicotinic acetylcholine or Unless specified otherwise the holding potential was 260 mV. Record- 5-HT3 receptors have never been observed, which makes them ings were filtered at 1 kHz and digitized at 2.5–4 kHz using a TL-1 appropriate tools for isolating cholinergic and serotonergic syn- analog to digital converter in conjunction with pClamp 5.5.1 software aptic currents. GABAA receptor-mediated events were com- (Axon instruments). Series resistances ranged from 11 to 17 MV;a pletely suppressed by 50 mM picrotoxin. After bath application of 30–50% compensation was usually achieved using the amplifier adjust- ments. To exclude nonspecific effects of antagonists, etc., only cells with these antagonists, residual excitatory spontaneous synaptic activ- a stable holding current over the entire recording period were included ity was recorded in 40% of cortical neurons between P18 and P37 in the analysis. The frequency of spontaneous synaptic currents was (18 of 45 tested cells). These synaptic currents were completely determined from 1–6 min continuous recordings. Cumulative probability abolished by 50–100 mMD-tubocurarine, a nicotinic acetylcholine plots were used to analyze amplitude and frequency distributions of synaptic currents. The amplitude and interevent interval distributions receptor antagonist, suggesting the presence of fast synaptic before and after addition of receptor selective antagonists were com- transmission via neuronal nicotinic acetylcholine receptors in pared using a one-way ANOVA. developing ferret visual cortex. The 18 cells displaying Synaptic currents were electrically
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