Inhibition of presynaptic calcium transients in cortical inputs to the dorsolateral striatum by metabotropic GABAB and mGlu2/3 receptors

摘要

Cortical inputs to the dorsolateral striatum (DLS) are dynamically regulated during skill learning and habit formation, and are dysregulated in disorders characterized by impaired action control. Therefore, a mechanistic investigation of the processes regulating corticostriatal transmission is key to understanding DLS-associated circuit function, behaviour and pathology. Presynaptic GABAB and group II metabotropic glutamate (mGlu2/3) receptors exert marked inhibitory control over corticostriatal glutamate release in the DLS, yet the signalling pathways through which they do so are unclear. We developed a novel approach using the genetically encoded calcium (Ca²⁺) indicator GCaMP6 to assess presynaptic Ca²⁺ in corticostriatal projections to the DLS. Using simultaneous photometric presynaptic Ca²⁺ and striatal field potential recordings, we report that relative to P/Q-type Ca²⁺ channels, N-type channels preferentially contributed to evoked presynaptic Ca²⁺ influx in motor cortex projections to, and excitatory transmission in, the DLS. Activation of GABAB or mGlu2/3 receptors inhibited both evoked presynaptic Ca²⁺ transients and striatal field potentials. mGlu2/3 receptor-mediated depression did not require functional N-type Ca²⁺ channels, but was attenuated by blockade of P/Q-type channels. These findings reveal presynaptic mechanisms of inhibitory modulation of corticostriatal function that probably contribute to the selection and shaping of behavioural repertoires.Key points class="unordered" style="list-style-type:disc"> Plastic changes at cortical inputs to the dorsolateral striatum (DLS) underlie skill learning and habit formation, so characterizing the mechanisms by which these inputs are regulated is important for understanding the neural basis of action control. We developed a novel approach using the genetically encoded calcium (Ca²⁺) indicator GCaMP6 and brain slice photometry to assess evoked presynaptic Ca²⁺ transients in cortical inputs to the DLS and study their regulation by GABAB and mGlu2/3 receptors. GABAB and mGlu2/3 receptor activation caused clear reductions in electrical stimulus-evoked presynaptic Ca²⁺ transients in corticostriatal inputs to the DLS. Functional P/Q-type voltage-gated Ca²⁺ channels were required for the normal inhibitory action of corticostriatal mGlu2/3 receptors. We provide direct evidence of presynaptic Ca²⁺ inhibition by G protein-coupled receptors at corticostriatal projections.