Altered balance between excitatory and inhibitory inputs onto CA1 pyramidal neurons from SV2A‐deficient but not SV2B‐deficient mice

Abstract

Synaptic vesicle protein 2 (SV2) is a glycoprotein that exists in three isoforms, SV2A, SV2B, and SV2C. SV2A knockout (KO) mice and SV2A/SV2B double KO (DKO) mice, but not SV2B KO animals, start to experience severe seizures and weight loss 7 days after birth and die at about postnatal day (P)14-P23. Because excitatory and inhibitory inputs play a major role in controlling neuronal excitability in the hippocampus, we examined the effects of SV2A and/or SV2B deletions on glutamatergic and GABA(A) neurotransmission in hippocampal CA1 pyramidal neurons. Spontaneous and miniature excitatory and inhibitory postsynaptic currents (sEPSCs, mEPSCs, sIPSCs, and mIPSCs, respectively) were recorded using the whole-cell patch-clamp technique in slices from P6-P14 mice. The frequency of sEPSCs was increased in SV2A KO and SV2A/SV2B DKO mice, but their amplitude was unchanged. Such changes were not observed in SV2B KOs. On the contrary, the frequency and amplitude of sIPSCs were decreased in SV2A KO and SV2A/SV2B DKO mice but not in SV2B KO animals, as reported previously for the CA3 region. Kinetic parameters of sIPSCs and sEPSCs were unchanged. Importantly, no changes were observed in any genotype when examining mEPSCs and mIPSCs. We conclude that action potential- and Ca(2+) -dependent glutamatergic and GABAergic synaptic transmission are differentially altered in the hippocampus of SV2A-deficient mice, whereas the mechanism of exocytosis itself is not changed. The altered balance between these major excitatory and inhibitory inputs is probably a contributing factor to seizures in SV2A KO and SV2A/SV2B DKO mice.

Overlapping functions of stonin 2 and SV2 in sorting of the calcium sensor synaptotagmin 1 to synaptic vesicles

“…S3 C and D ) nor the amplitude of mEPSCs (Fig. S3 C and E ) was altered in slices from TKO mice, akin to what has been observed at hippocampal synapses from SV2A single KOs or SV2A/B DKOs (29) but distinct from Syt1 null mice (30). …”

Levetiracetam inhibits oligomeric Aβ-induced glutamate release from human astrocytes

“…Inhibition of SV2A activity might therefore be expected to affect both glutamatergic and GABAergic synaptic transmission. Moreover, deletion of the SV2A gene has been shown to manifest opposite effects on glutamatergic and GABAergic neurotransmission, with decreased GABAergic synaptic currents [20] but increased glutamatergic transmission [21]. Thus, LEV might be acting as a positive allosteric modulator of SV2A, resulting in decreased glutamate release.…”

Development and Validation of a New Mouse Model to Investigate the Role of SV2A in Epilepsy

“…However, SV2A-KO mouse studies have demonstrated that SV2A deletion results also in the reduced action potential-dependent release of the inhibitory neurotransmitter GABA in this hippocampal region. This imbalance between excitatory and inhibitory neurotransmission in the hippocampus could be responsible for seizures, at least concerning those observed in SV2A-KO mice [10, 12]. The possibility thus exists that GriK4:SV2A-cKO does not affect the neuronal population responsible for epilepsy, as the GABAergic system is preserved.…”

“…However, miniature inhibitory postsynaptic current (mIPSC) appeared unchanged, meaning that the protein machinery allowing the vesicles filled with GABA is not affected but the coupling molecular machinery between the action potential reaching the synaptic button and the GABAergic-dependent neurotransmission is. [10, 12]. …”