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

Abstract

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.