P/Q-Type, But Not N-Type, Calcium Channels Mediate GABA Release From Fast-Spiking Interneurons to Pyramidal Cells in Rat Prefrontal Cortex

Abstract

The Cav2.1 (P/Q-) and Cav2.2 (N-type) voltage-gated calcium channels (VGCCs) play a predominant role in neurotransmitter release at central synapses, but their distribution is not uniform across different types of synapses. Although the functional significance of the differential distribution of N- and P/Q-type VGCCs is poorly understood, distinct types of VGCCs appear to differentially affect synaptic properties. For example, P/Q-type VGCCs are located closer to release sites and are less affected by G-protein-mediated inhibition than are N-type VGCCs. Thus P/Q-type VGCCs might be beneficial at synapses with high probability of release and precise timing of neurotransmission, such as the inhibitory inputs from parvalbumin-containing fast-spiking (FS) interneurons to pyramidal cells (PCs) in the neocortex. To determine whether VGCCs types predominate at synapses from FS interneurons to PCs in rat prefrontal cortex, whole cell paired recordings (n = 14) combined with intracellular labeling and fluorescence immunohistochemistry for parvalbumin were performed in acute slices. Bath application of the specific N-type VGCC blocker omega-conotoxin-GVIa (1 microM) did not alter inhibitory postsynaptic potential amplitude, failure rate, or synaptic dynamics; in contrast, application of P/Q-type VGCC blocker omega-agatoxin-IVa (0.5 microM) completely and irreversibly blocked neurotransmission. These results indicate that P/Q-type VGCCs mediate the GABA release from parvalbumin-positive FS interneurons to PCs in the rat neocortex.

CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms

“…15,40,41 Ca V 2.1 channels have been shown to mediate synaptic release from a variety of neuronal cell types, both excitatory and inhibitory, in the cortex, hippocampus, thalamus and cerebellum. 15,[42][43][44][45][46][47][48][49] The loss of Ca V 2.1 channels is compensated by upregulation of other voltage-gated calcium channels at most central synapses, 15,44,[47][48][49] although with different efficiency, 50 resulting in synaptic dysfunction of particular cell types leading to pathological manifestations. In cerebellar networks, Ca V 2.1 channels regulate the whole-cell calcium current density and the intrinsic excitability of Purkinje cells and granule cells, 44,51-53 and exert major control over glutamate release at the parallel fiber onto Purkinje-cell synapses.…”

“…[59][60][61][62][63] In the neocortex and hippocampus, Ca V 2.1 channels have been demonstrated to mediate GABA release and synaptic efficiency from cortical GABAergic parvalbumin-positive fast-spiking interneurons (FS-INs) 15,42,43,47 as well as from cortical pyramidal cells. 15 We recently demonstrated that a selective deletion of Cacna1a from cortical and hippocampal GABAergic interneurons, while sparing the thalamus and cerebellum, selectively impairs GABA release from FS-INs, despite an upregulation of N-type channels, and that this is sufficient to cause generalized epilepsy in conditional mutant mice.…”

Laminar-Specific Maturation of GABAergic Transmission and Susceptibility to Visual Deprivation Are Related to Endocannabinoid Sensitivity in Mouse Visual Cortex

“…In part of the experiments, DL-2-amino-5-phosphonovaleric acid (APV; Sigma-Aldrich), an NMDA receptor antagonist, at 100 M and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; Sigma-Aldrich), an AMPA receptor antagonist, at 20 M were added to the ACSF to directly record monosynaptic IPSCs to exclude the possibility of the contribution of polysynaptic recruitment to synaptic inhibition. In experiments in which we attempted to isolate eISPCs from fast-spiking GABAergic (FS-GABA) neurons, conotoxin (Ctx; Sigma-Aldrich) at 300 nM was used to block the N-type voltagedependent Ca 2ϩ channels that are known to mediate GABA release from non-FS interneurons (Wilson et al, 2001;Zaitsev et al, 2007).…”

“…The eIPSCs are thought to be induced by GABA released from the two types of presynaptic terminals, axon terminals of FS and non-FS interneurons (Jiang et al, 2010). To exclusively record the component of eIPSCs that was elicited through axons of FS interneurons, a blocker for N-type voltage-dependent Ca 2ϩ channels, Ctx, was applied to slices at 300 nM, because this type of Ca 2ϩ channel is known to mediate GABA release from non-FS interneurons, and thus Ctx does not affect GABA release from FS interneurons (Wilson et al, 2001;Zaitsev et al, 2007). In layer 2/3 of the KO mice, the input-output relationship of eIPSCs recorded in this way was significantly different from that in wild-type mice at P28 -P30 when eIPSCs were matured (Fig.…”

How feedback inhibition shapes spike-timing-dependent plasticity and its implications for recent Schizophrenia models

“…The feedback inhibition performed via the interneuron is modelled as a first order system to minimise the complexity of the solution and because the interneurons react virtually instantly (Zaitsev et al, 2007). Of central interest is here the decay of their inhibition because this is controlled by the internal calcium buffer parvalbumin (PV).…”