Spike timing-dependent plasticity (STDP) is a Hebbian learning rule important for synaptic refinement during development and for learning and memory in the adult. Given the importance of the hippocampus in memory, surprisingly little is known about the mechanisms and functions of hippocampal STDP. In the present work, we investigated the requirements for induction of hippocampal spike timing-dependent long-term potentiation (t-LTP) and spike timing-dependent long-term depression (t-LTD) and the mechanisms of these 2 forms of plasticity at CA3-CA1 synapses in young (P12–P18) mouse hippocampus. We found that both t-LTP and t-LTD can be induced at hippocampal CA3-CA1 synapses by pairing presynaptic activity with single postsynaptic action potentials at low stimulation frequency (0.2 Hz). Both t-LTP and t-LTD require NMDA-type glutamate receptors for their induction, but the location and properties of these receptors are different: While t-LTP requires postsynaptic ionotropic NMDA receptor function, t-LTD does not, and whereas t-LTP is blocked by antagonists at GluN2A and GluN2B subunit-containing NMDA receptors, t-LTD is blocked by GluN2C or GluN2D subunit-preferring NMDA receptor antagonists. Both t-LTP and t-LTD require postsynaptic Ca2+ for their induction. Induction of t-LTD also requires metabotropic glutamate receptor activation, phospholipase C activation, postsynaptic IP3 receptor-mediated Ca2+ release from internal stores, postsynaptic endocannabinoid (eCB) synthesis, activation of CB1 receptors and astrocytic signaling, possibly via release of the gliotransmitter d-serine. We furthermore found that presynaptic calcineurin is required for t-LTD induction. t-LTD is expressed presynaptically as indicated by fluctuation analysis, paired-pulse ratio, and rate of use-dependent depression of postsynaptic NMDA receptor currents by MK801. The results show that CA3-CA1 synapses display both NMDA receptor-dependent t-LTP and t-LTD during development and identify a presynaptic form of hippocampal t-LTD similar to that previously described at neocortical synapses during development.

Critical periods of synaptic plasticity facilitate the reordering and refining of neural connections during development, allowing the definitive synaptic circuits responsible for correct adult physiology to be established. Presynaptic spike timing-dependent long-term depression (t-LTD) exists in the hippocampus, which depends on the activation of NMDARs and that probably fulfills a role in synaptic refinement. This t-LTD is present until the third postnatal week in mice, disappearing in the fourth week of postnatal development. We were interested in the mechanisms underlying this maturation related loss of t-LTD and we found that at CA3-CA1 synapses, presynaptic NMDA receptors (pre-NMDARs) are tonically active between P13 and P21, mediating an increase in glutamate release during this critical period of plasticity. Conversely, at the end of this critical period (P22-P30) and coinciding with the loss of t-LTD, these pre-NMDARs are no longer tonically active. Using immunogold electron microscopy, we demonstrated the existence of pre-NMDARs at Schaffer collateral synaptic boutons, where a decrease in the number of pre-NMDARs during development coincides with the loss of both tonic pre-NMDAR activation and t-LTD. Interestingly, this t-LTD can be completely recovered by antagonizing adenosine type 1 receptors (A1R), which also recovers the tonic activation of pre-NMDARs at P22-P30. By contrast, the induction of t-LTD was prevented at P13-P21 by an agonist of A1R, as was tonic pre-NMDAR activation. Furthermore, we found that the adenosine that mediated the loss of t-LTD during the fourth week of development is supplied by astrocytes. These results provide direct evidence for the mechanism that closes the window of plasticity associated with t-LTD, revealing novel events probably involved in synaptic remodeling during development.

J. Neurochem. (2012) 122, 891–899. Abstract Presynaptic kainate receptors (KARs) modulate the release of glutamate at synapses established between mossy fibers (MF) and CA3 pyramidal cells in the hippocampus. The activation of KAR by low, nanomolar, kainate concentrations facilitates glutamate release. KAR‐mediated facilitation of glutamate release involves the activation of an adenylate cyclase/cyclic adenosine monophosphate/protein kinase A cascade at MF–CA3 synapses. Here, we studied the mechanisms by which KAR activation produces this facilitation of glutamate release in slices and synaptosomes. We find that the facilitation of glutamate release mediated by KAR activation requires an increase in Ca2+ levels in the cytosol and the formation of a Ca2+–calmodulin complex to activate adenylate cyclase. The increase in cytosolic Ca2+ underpinning this modulation is achieved, both, by Ca2+ entering via Ca2+‐permeable KARs and, by the mobilization of intraterminal Ca2+ stores. Finally, we find that, congruent with the Ca2+–calmodulin support of KAR‐mediated facilitation of glutamate release, induction of long‐term potentiation at MF–CA3 synapses has an obligate requirement for Ca2+–calmodulin activity.

We have investigated the mechanisms underlying the facilitatory modulation mediated by kainate receptor (KAR) activation in the cortex, using isolated nerve terminals (synaptosomes) and slice preparations. In cortical nerve terminals, kainate (KA, 100 lM) produced an increase in 4-aminopyridine (4-AP)-evoked gluta

The amygdala is a component of the limbic system that is involved in emotional modulation of behaviour and learning and memory (LeDoux 2000). This structure is central for the acquisition, storage, and expression of conditioned fear memory (Lavond et al. 1993;LeDoux 1996;Davis 1997;McKernan and Shinnick-Gallagher 1997;Rogan et al. 1997;Fendt and Fanselow 1999). Synaptic inputs to the lateral nucleus of the amygdala (LA) from the thalamic medial geniculate nucleus (MGN) and from the auditory cortex are essential for the acquisition of this conditioning (LeDoux et al. 1990a;Romanski and LeDoux 1992;Campeau and Davis 1995). Synaptic transmission in the MGN to LA, is mediated by NMDA and non-NMDA receptors (Li et al. 1996;Weisskopf and LeDoux 1999;Zinebi et al. 2001).Kainate receptors are a family of glutamate receptors that can (postsynaptically) mediate synaptic transmission at some synapses, and (presynaptically) modulate transmitter release (see Rodríguez-Moreno and Sihra 2007a;Jane et al. 2009).In the modulatory context, kainate receptors have been implicated in the modulation of both glutamate and GABA release (see Rodríguez-Moreno and Sihra 2007a,b; Jane Received August 11, 2011; revised manuscript received January 11, 2012; accepted January 11, 2012.Address for correspondence and reprint requests to Dr Antonio Rodríguez-Moreno, Laboratory of Cellular Neuroscience and Plasticity, Department of Physiology, Anatomy and Cellular Biology, University Pablo de Olavide, Ctra. de Utrera, Km. 1, 41013, Sevilla, Spain. E-mail: arodmor@upo.es Abbreviations used: AMPA, a-amino-3-hydroxy-5-methylisoxazole-4-propionate; ATPA, (RS)-2-amino-3(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid; BAPTA, 1,2-bis(o-aminophenoxy)ethane-N,N,N¢, N¢-tetraacetic acid; CV, coefficient of variation; DPCPX, 8-cyclopentyl-1,3-dipropyl-7H-purine-2,6-dione; eEPSCs, evoked excitatory postsynaptic currents; KAR, kainate receptor; LA, lateral nucleus of the amygdala; LTP, long-term potentiation; MGN, medial geniculate nucleus; NBQX, 2,3-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide; PKA, protein kinase A; PKC, protein kinase C; PPR, pair pulse ratio. MéxicoAbstract Kainate receptors (KARs) have been described as modulators of synaptic transmission at different synapses. However, this role of KARs has not been well characterized in the amygdala. We have explored the effect of kainate receptor activation at the synapse established between fibers originating at medial geniculate nucleus and the principal cells in the lateral amygdala. We have observed an inhibition of evoked excitatory postsynaptic currents (eEPSCs) amplitude after a brief application of KARs agonists KA and ATPA. Paired-pulse recordings showed a clear pair pulse facilitation that was enhanced after KA or ATPA application. When postsynaptic cells were loaded with BAPTA, the depression of eEPSC amplitude observed after the perfusion of KAR agonists was not prevented. We have also observed that the inhibition of the eEPSCs by KARs agonists was prevented by pro...