Alternative splicing of the Cacna1b gene is implicated in anxiety

Presynaptic Ca_V2.2 channels are targets of neurotransmitters and drugs that activate G-protein coupled receptors (GPCR) to down regulate neurotransmission. In previous studies, we found that two alternatively spliced, mutually exclusive exons (e37a and e37b) control G_i/oPCR inhibition. We showed that both e37a and e37b containing Ca_V2.2 channels are expressed in nociceptors of dorsal root ganglia and that mice lacking e37a show reduced spinal morphine analgesia, consistent with reduced inhibition of presynaptic Ca_V2.2 channels via μ-opioid receptor (G_i/oPCR). We know that e37a isoforms of Ca_V2.2 are expressed in certain regions of the brain, leading us to assess behavior of mice that lack e37a. Here we report that mice lacking e37a isoform exhibit a robust reduced anxiety-like phenotype as compared to WT. E37a lacking mice showed significantly shorter latency times to drink in the novelty-induced hypophagia test (57.2 ± 11.9 s, n = 13) compared to WT mice (116.6 ± 22.8 s, n = 16 (p = 0.02, Student’s t-test). To explore these behavioral differences, we measured various parameters of synaptic transmission at hippocampal synapses linked to anxiety. We found reduced paired-pulse ratio of postsynaptic field potentials (fEPSP) at synpases of medial perforant path-dentate gyrus (mPP-DG) in mice lacking e37a compared to WT, suggesting a greater release of neurotransmitter from presynaptic terminals. These preliminary analyses are consistent with reduced inhibition of Ca_V2.2 channels and increased transmitter release, relative to wild-type synapses. Thus, by regulating the basal activity of Ca_V2.2 channels, GPCRs might play an important role in setting anxiety behavior. Supported by NS055251.