Excitatory But Not Inhibitory Synaptic Transmission Is Reduced in Lethargic (Cacnb4lh) and Tottering (Cacna1atg) Mouse Thalami

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Abstract
Excitatory but not inhibitory synaptic transmission is reduced in lethargic ( Cacnb4lh) and tottering ( Cacna1atg) mouse thalami. Recent studies of the homozygous tottering ( Cacna1atg) and lethargic mouse ( Cacnb4lh) models of absence seizures have identified mutations in the genes encoding the α1A and β4 subunits, respectively, of voltage-gated Ca2+channels (VGCCs). β subunits normally regulate Ca2+currents via a direct interaction with α1 (pore-forming) subunits of VGCCs, and VGCCs are known to play a significant role in controlling the release of transmitter from presynaptic nerve terminals in the CNS. Because the gene mutation in Cacnb4lhhomozygotes results in loss of the β4 subunit’s binding site for α1 subunits, we hypothesized that synaptic transmission would be altered in the CNS of Cacnb4lhhomozygotes. We tested this hypothesis by using whole cell recordings of single cells in an in vitro slice preparation to investigate synaptic transmission in one of the critical neuronal populations that generate seizure activity in this strain, the somatosensory thalamus. The primary finding reported here is the observation of a significant decrease in glutamatergic synaptic transmission mediated by both N-methyl-d-aspartate (NMDA) and non-NMDA receptors in somatosensory thalamic neurons of Cacnb4lhhomozygotes compared with matched, nonepileptic mice. In contrast, there was no significant decrease in GABAergic transmission in Cacnb4lhhomozygotes nor was there any difference in effects mediated by presynaptic GABABreceptors. We found a similar decrease in glutamatergic but not GABAergic responses in Cacna1atghomozygotes, suggesting that the independent mutations in the two strains each affected P/Q channel function by causing defective neurotransmitter release specific to glutamatergic synapses in the somatosensory thalamus. This may be an important factor underlying the generation of seizures in these models.