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Synapse-Specific Compartmentalization of Signaling Cascades for Ltp Induction in Ca3 Interneurons

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Synapse-Specific Compartmentalization of Signaling Cascades for Ltp Induction in Ca3 Interneurons Neuroscience 290 (2015) 332–345 SYNAPSE-SPECIFIC COMPARTMENTALIZATION OF SIGNALING CASCADES FOR LTP INDUCTION IN CA3 INTERNEURONS E. J. GALVA´N, a* T. PE´REZ-ROSELLO, b protein kinase C (PKC). Specifically, LTP at RC and MF G. GO´MEZ-LIRA, a E. LARA, a R. GUTIE´RREZ a AND synapses on the same SR/LM interneuron was blocked by c G. BARRIONUEVO postsynaptic injections of chelerythrine (10 lM). These data a Departamento de Farmacobiologı´a, Cinvestav Sede Sur, indicate that both forms of LTP share a common Me´xico City, Mexico mechanism involving PKC-dependent signaling modulation. Ó 2015 IBRO. Published by Elsevier Ltd. All rights reserved. b Department of Physiology, Northwestern University, Chicago, IL, USA c Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA Key words: recurrent commissural LTP and LTD, calcium impermeable AMPARs, CaMKII; PKA; PKC, CA3 interneurons, Abstract—Inhibitory interneurons with somata in strata rad- feed-forward inhibition. iatum and lacunosum-moleculare (SR/L-M) of hippocampal area CA3 receive excitatory input from pyramidal cells via the recurrent collaterals (RCs), and the dentate gyrus gran- INTRODUCTION ule cells via the mossy fibers (MFs). Here we demonstrate that Hebbian long-term potentiation (LTP) at RC synapses The majority of excitatory synapses in hippocampal area on SR/L-M interneurons requires the concomitant activation CA3 originate from the extensive recurrent collateral of calcium-impermeable AMPARs (CI-AMPARs) and (RC) axons of pyramidal cells (Amaral and Witter, 1989; N-methyl-D-aspartate receptors (NMDARs). RC LTP was pre- Ishizuka et al., 1990). The RC circuitry underlies many vented by voltage clamping the postsynaptic cell during autoassociative network models that simulate pattern high-frequency stimulation (HFS; 3 trains of 100 pulses completion, i.e. the recall of activity patterns stored in area delivered at 100 Hz every 10 s), with intracellular injections CA3 via mossy fibers (MFs), the axons of dentate gyrus of the Ca2+ chelator BAPTA (20 mM), and with the NMDAR antagonist D-AP5. In separate experiments, RC and MF granule cells (Marr, 1971; McNaughton and Morris, inputs converging onto the same interneuron were sequen- 1987; O’Reilly and McClelland, 1994; Rolls, 1996). One tially activated. We found that RC LTP induction was key assumption in these computational models is that blocked by inhibitors of the calcium/calmodulin-dependent RC synapses exhibit N-methyl-D-aspartate receptor protein kinase II (CaMKII; KN-62, 10 lM or KN-93, 10 lM) (NMDAR)-mediated long-term potentiation (LTP) to recre- but MF LTP was CaMKII independent. Conversely, the appli- ate the original episode (O’Reilly and McClelland, 1994). cation of the protein kinase A (PKA) activators forskolin/ Indeed, NMDAR activation in area CA3 is required for IBMX (50 lM/25 lM) potentiated MF EPSPs but not RC memory recall (Nakazawa et al., 2002; Fellini et al., EPSPs. Together these data indicate that the aspiny den- 2009), and the induction of RC LTP in CA3 pyramidal cells drites of SR/L-M interneurons compartmentalize synapse- (Harris and Cotman, 1986; Zalutsky and Nicoll, 1990; specific Ca2+ signaling required for LTP induction at RC and MF synapses. We also show that the two signal trans- Magee and Johnston, 1997; Debanne et al., 1998; Bains duction cascades converge to activate a common effector, et al., 1999). The retrieval of previously stored activity pat- terns also relies on the inhibitory input from local interneu- rons to constrain the activation of non-assembly pyramidal *Corresponding author. Address: Departamento de Farmacobiologı´a, cells (Sahay et al., 2011). Therefore, preservation of the Cinvestav Sede Sur, Calz. Tenorios No. 235, Col. Granjas Coapa, Me´xico City 14330, Mexico. Tel: +52-(55)-5483-2852; fax: +52- excitatory-to-inhibitory balance for optimal pattern separa- (55)-5483-2863. tion requires that RC synapses undergo near simulta- E-mail address: [email protected] (E. J. Galva´n). neous LTP on pyramidal cells and feed-forward Abbreviations: AC, adenylyl cyclase; ACSF, artificial cerebrospinal interneurons (Lamsa et al., 2005). However, previous fluid; ANOVA, analysis of variance; CaMKII, calcium/calmodulin- dependent protein kinase II; CI-AMPAR, calcium-impermeable investigations of synaptic plasticity at RC synapses on AMPAR; CP-AMPAR, calcium permeable AMPAR; DCG-IV, CA3 interneurons have yielded varying results. Early stud- (2S,20R,30R)-2-(20,30-dicarboxycyclopropyl)glycine; DIC, differential ies reported NMDAR-independent LTD at RC synapses intensity contrast; EDTA, ethylenediaminetetraacetic acid; FSK, forskolin; HEPES, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; on stratum radiatum (SR) interneurons (Laezza et al., HFS, high-frequency stimulation; ISI, inter-stimulus interval; LTP, long- 1999). In contrast, NMDAR-dependent RC LTD in SR term potentiation; MF, mossy fiber; NMDAR, N-methyl-D-aspartate interneurons was detected during persistent bursting receptor; PFA, paraformaldehyde; PKA, protein kinase A; PKC, protein activity in the disinhibited slice (Stoop et al., 2003). A more kinase C; PPF, paired pulse facilitation; PPR, paired pulse ratio; RC, recurrent collateral; RI, rectification index; SR/L-M, strata radiatum and recent study on the same interneuron synapse uncovered lacunosun-moleculare; VGCC, voltage-gated calcium channel. the bidirectional induction of NMDAR-dependent plasticity http://dx.doi.org/10.1016/j.neuroscience.2015.01.024 0306-4522/Ó 2015 IBRO. Published by Elsevier Ltd. All rights reserved. 332 E. J. Galva´n et al. / Neuroscience 290 (2015) 332–345 333 (LTP/LTD), contingent on the level of postsynaptic depo- glass and had resistances of 5–8 MO when filled with a larization (Laezza and Dingledine, 2004). solution containing (in mM), 120 K-methylsulfate, 10 Hippocampal interneurons with somata in stratum NaCl, 10 KCl, 10 HEPES, 0.5 EGTA, 4 MgÁATP, 0.3 radiatum and lacunosum-moleculare (SR/L-M) of area Na2ÁGTP, 14 phosphocreatine. In some experiments, CA3 belong to a larger population of dendritic targeting biocytin, (0.1%) was added to the pipette solution to GABAergic cells providing feed-forward inhibition to allow subsequent morphological identification and pyramidal cells (Lacaille and Schwartzkroin, 1988; reconstruction of the interneurons (Fig. 1A). For the Williams et al., 1994; Vida et al., 1998). MF synapses AMPAR rectification experiments (Fig. 1B–F), the on SR/L-M interneurons exhibit NMDAR-independent intracellular solution was modified to contain (in mM), LTP induced by cytosolic Ca2+ increase from the coacti- 120 Cesium Methanesulfonate, 10 KCl, 10 HEPES, 0.5 vation of L-type voltage-gated calcium channels (VGCCs) EGTA, 8 phosphocreatine, 4 Mg-ATP, 0.3 Na2-GTP and and mGluR1. This form of MF LTP requires postsynaptic 0.5 QX-314. Osmolarity was adjusted to 295– activation of protein kinases A (PKA) and C (PKC) 300 mOsm with pH 7.2–7.3. Access resistance was (Galvan et al., 2011). Here we show that RC synapses monitored throughout the length of experiments using a on SR/L-M interneurons exhibit a form of Hebbian LTP 5-ms, 5-mV voltage steps. Interneurons were accepted that requires calcium entry via NMDARs. High-frequency for analysis only if the seal resistance was >1 GX and stimulation (HFS) of RC and MF inputs synapsing on the the series resistance did not change >15% of its initial same interneuron revealed that blockade of calcium/cal- value during the course of the experiment. modulin-dependent protein kinase II (CaMKII) prevented RC and MF EPSPs were evoked by extracellular LTP induction at RC but not at MF synapses. Conversely, stimulation via concentric bipolar electrodes (12.5-lm PKA stimulation resulted in a potentiation of MF synapses inner pole diameter, 125-lm outer pole diameter; FHC but did not affect RC synapses. We conclude that the asp- Inc., ME, USA). To activate the RC input, the electrode iny dendrites of SR/L-M interneurons are able to compart- was positioned in the stratum radiatum near the border mentalize the initial Ca2+ signaling cascades that trigger between CA3b and CA3a. To activate the MF input, the LTP at two different synaptic inputs. Nevertheless, PKC electrode was placed in the suprapyramidal blade of the inhibition prevented the induction of both forms of LTP dentate gyrus (SDG; Fig. 1A). RC EPSPs exhibited suggesting that PKC activation provides a point of conver- shorter latency and time-to-peak than MF EPSPs gence of signaling cascades originating from RC and MF (latency = 1.74 ± 0.12 ms and 3.32 ± 0.13; p < 0.001; synaptic activity. time to peak = 3.7 ± 0.22 ms and 5.61 ± 0.41; p < 0.001 for RC and MF EPSPs, respectively) as previously reported (Laezza and Dingledine, 2004; EXPERIMENTAL PROCEDURES Calixto et al., 2008). Pairs of stimuli were delivered at 60-ms inter-stimulus interval (ISI) to each input separately. Ethical approval Each pair consisted of monophasic pulses (100–400 lA; For the electrophysiological recordings, animal use was in 85–100-ls duration) applied at 0.25–0.16 Hz. We applied accordance with the University Institutional Animal Care stimulation current intensities that evoked monosynaptic and Use Committee. Male Sprague–Dawley rats RC and MF EPSP amplitudes 630% of the threshold (35 ± 5 days old; Zivic Miller Company, Portersville, PA) amplitude required to elicit action potentials in the were deeply anaesthetized (Nembutal, IP, 5 mg/100 g recorded interneurons. Cells with composite postsynaptic body weight) and perfused intracardially with a modified responses were discarded from the study. For each input artificial cerebrospinal fluid (ACSF) in which sucrose paired pulse facilitation (PPF) was calculated as the ratio was substituted for NaCl (in mM): 210 sucrose, 2.8 KCl, (PPR at 60-ms ISI) of the amplitude of the second EPSP 1.25 NaH2PO4, 26 NaHCOO3,10D-Glucose, 1 CaCl2,4 over the first EPSP in the pair. The rectification index MgCl2,at4°C. Following 1–2 min of perfusion, animals (RI) of the synaptic responses was obtained from the ratio were decapitated and the brains removed.
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