Cav2.1-mediated NMDA receptor signaling in short-term memory

The Cav2.1 channel is highly expressed in the nervous system and regulates the presynaptic modulation of the glutamate release machinery. N-methyl-D-aspartate (NMDA)-receptor signaling mediates short-term memory. Because Cav2.1 and NMDA receptors are present at a variety of synapses, the use of systemic injections makes it difficult to evaluate the behavioral performance. In this regard, studies using microinfusions into specific neural regions are a useful tool to understand the relevant neuronal circuits. The antiepileptic drug levetiracetam has been reported to inhibit presynaptic Cav2.1 functions, reducing glutamate release. Rolling Nagoya mice carrying a mutation in the α1 subunit of the Cav2.1 (Cav2.1α1) demonstrate severe ataxia from about 2 weeks of age. Heterozygous rolling Nagoya (rol/+) mice show normal spontaneous alternations in behavior in the Y-maze test, a measure of short-term spatial memory. In this study, we have shown that a dose of levetiracetam injected into the hippocampus did not affect the controls but decreased the spontaneous alternation in rol/+ mice. The results suggest that the Cav2.1α1 mutation, through a decrease in the Ca²⁺ influx, lowers the threshold for learning impairment and that Cav2.1-mediated NMDA receptor signaling in the hippocampus is involved in short-term spatial memory. The combination of the sub-threshold pharmacological and genetic approach presented here is easily performed and can be used to study functional signaling pathways in neuronal circuits.