The excitability of a neuron is regulated by the balance of excitatory and inhibitory inputs that impinge on it. Such modulation can occur either presynaptically or postsynaptically. Here, we show that an excitatory transmitter can increase the release of an inhibitory transmitter and thus paradoxically produces a long-lasting enhancement of inhibitory synaptic transmission. This occurs at a nearphysiological temperature. These findings from cerebellar stellate neurons reveal a novel form of long-term potentiation that is induced by the activation of NMDA-type glutamate receptors and that requires both glutamate and glycine. Our results indicate that Ca 2ϩ entry into the presynaptic terminals during the activation of presynaptic NMDARs is necessary to induce the potentiation. This presynaptic modulation provides a mechanism by which an excitatory transmitter can induce a long-term increase in the release of an inhibitory transmitter and thus modify the activity of a simple neuronal circuit.

Calcium influxes through ionotropic glutamate receptors (AMPA and NMDA receptors, AMPARs and NMDARs) are considered to be critical for the shaping and refinement of neural circuits during synaptogenesis. Using a combined morphological and electrophysiological approach, we evaluated this hypothesis at the level of the nucleus tractus solitarii (NTS), a brainstem structure that is a gateway for many visceral sensory afferent fibres. We confirmed that in the NTS, the first excitatory synapses appeared at embryonic day 18. We next characterized the biophysical properties of NTS AMPARs. Throughout perinatal development, both evoked and miniature EPSCs recorded in the presence of an NMDAR blocker were insensitive to polyamines and had linear current-voltage relationships. This demonstrated that AMPARs at NTS excitatory synapses were calcium-impermeable receptors composed of a majority of GluR 2 subunits. We then investigated the influence of calcium influxes through NMDARs on the development of NTS synaptic transmission. We found that NMDAR expression at synaptic sites did not precede AMPAR expression. Moreover, NMDAR blockade in utero did not prevent the development of AMPAR synaptic currents and the synaptic clustering of GluR 2 subunits. Thus, our data support an alternative model of synaptogenesis that does not depend on calcium influxes through either AMPARs or NMDARs. This model may be particularly relevant to the formation of neural networks devoted to basic behaviours required at birth for survival.

Information processing in the CNS is controlled by the activity of neuronal networks composed of principal neurons and interneurons. Activity-dependent modification of synaptic transmission onto principal neurons is well studied, but little is known about the modulation of inhibitory transmission between interneurons. However, synaptic plasticity at this level has clear implications for the generation of synchronized activity. We investigated the molecular mechanism(s) and functional consequences of an activity-induced lasting increase in GABA release that occurs between inhibitory interneurons (stellate cells) in the cerebellum. Using whole-cell recording and cerebellar slices, we found that stimulation of glutamatergic inputs (parallel fibers) with a physiological-like pattern of activity triggered a lasting increase in GABA release from stellate cells. This activity also potentiated inhibitory transmission between synaptically connected interneurons. Extracellular recording revealed that the enhanced inhibitory transmission reduced the firing frequency and altered the pattern of action potential activity in stellate cells. The induction of the sustained increase in GABA release required activation of NMDA receptors. Using pharmacological and genetic approaches, we found that presynaptic cAMP/PKA (protein kinase A) signaling and RIM1␣, an active zone protein, is the critical pathway that is required for the lasting enhancement of GABA release. Thus, a common mechanism can underlie presynaptic plasticity of both excitatory and inhibitory transmission. This activity-dependent regulation of synaptic transmission between inhibitory interneurons may serve as an important mechanism for interneuronal network plasticity.

Early‐born γ‐aminobutyric acid (GABA) neurons (EBGNs) are major components of the hippocampal circuit because at early postnatal stages they form a subpopulation of “hub cells” transiently supporting CA3 network synchronization (Picardo et al. [2011] Neuron 71:695–709). It is therefore essential to determine when these cells acquire the remarkable morphofunctional attributes supporting their network function and whether they develop into a specific subtype of interneuron into adulthood. Inducible genetic fate mapping conveniently allows for the labeling of EBGNs throughout their life. EBGNs were first analyzed during the perinatal week. We observed that EBGNs acquired mature characteristics at the time when the first synapse‐driven synchronous activities appeared in the form of giant depolarizing potentials. The fate of EBGNs was next analyzed in the adult hippocampus by using anatomical characterization. Adult EBGNs included a significant proportion of cells projecting selectively to the septum; in turn, EBGNs were targeted by septal and entorhinal inputs. In addition, most EBGNs were strongly targeted by cholinergic and monoaminergic terminals, suggesting significant subcortical innervation. Finally, we found that some EBGNs located in the septum or the entorhinal cortex also displayed a long‐range projection that we traced to the hippocampus. Therefore, this study shows that the maturation of the morphophysiological properties of EBGNs mirrors the evolution of early network dynamics, suggesting that both phenomena may be causally linked. We propose that a subpopulation of EBGNs forms into adulthood a scaffold of GABAergic projection neurons linking the hippocampus to distant structures. J. Comp. Neurol. 524:2440–2461, 2016. © 2016 Wiley Periodicals, Inc.

NMDA-only synapses, called silent synapses, are thought to be the initial step in synapse formation in several systems. However, the underlying mechanism and the role in circuit construction are still a matter of dispute. Using combined morphological and electrophysiological approaches, we searched for silent synapses at the level of the nucleus tractus solitarii (NTS), a brainstem structure that is a gateway for many visceral sensory afferent fibers. Silent synapses were detected at birth by using electrophysiological recordings and minimal stimulation protocols. However, anatomical experiments indicated that nearly all, if not all, NTS synapses had AMPA receptors. Based on EPSC fluctuation measurements and differential blockade by low-affinity competitive and noncompetitive glutamate antagonists, we then demonstrated that NTS silent synapses were better explained by glutamate spillover from neighboring fibers and/or slow dynamic of fusion pore opening. Glutamate spillover at immature NTS synapses may favor crosstalk between active synapses during development when glutamate transporters are weakly expressed and contribute to synaptic processing as well as autonomic circuit formation.

Glutamate directly activates N-methyl-d-aspartate (NMDA) receptors on presynaptic inhibitory interneurons and enhances GABA release, altering the excitatory-inhibitory balance within a neuronal circuit. However, which class of NMDA receptors is involved in the detection of glutamate spillover is not known. GluN2D subunit-containing NMDA receptors are ideal candidates as they exhibit a high affinity for glutamate. We now show that cerebellar stellate cells express both GluN2B and GluN2D NMDA receptor subunits. Genetic deletion of GluN2D subunits prevented a physiologically relevant, stimulation-induced, lasting increase in GABA release from stellate cells [long-term potentiation of inhibitory transmission (I-LTP)]. NMDA receptors are tetramers composed of two GluN1 subunits associated to either two identical subunits (di-heteromeric receptors) or to two different subunits (tri-heteromeric receptors). To determine whether tri-heteromeric GluN2B/2D NMDA receptors mediate I-LTP, we tested the prediction that deletion of GluN2D converts tri-heteromeric GluN2B/2D to di-heteromeric GluN2B NMDA receptors. We find that prolonged stimulation rescued I-LTP in GluN2D knockout mice, and this was abolished by GluN2B receptor blockers that failed to prevent I-LTP in wild-type mice. Therefore, NMDA receptors that contain both GluN2D and GluN2B mediate the induction of I-LTP. Because these receptors are not present in the soma and dendrites, presynaptic tri-heteromeric GluN2B/2D NMDA receptors in inhibitory interneurons are likely to mediate the cross talk between excitatory and inhibitory transmission.

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