• Neuroscience · Mar 2023

    Maturation of GABAergic Synaptic Transmission from Neocortical Parvalbumin Interneurons Involves NMDA receptor Recruitment of Cav2.1 Channels.

    • Mahendra Singh, Kiran Sapkota, Kenji Sakimura, Masanobu Kano, Rita M Cowell, Linda Overstreet-Wadiche, John J Hablitz, and Kazu Nakazawa.
    • Department of Neuroscience, Scientific Platforms, Southern Research, Birmingham, AL 35205, USA; Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. Electronic address: msingh@southernresearch.org.
    • Neuroscience. 2023 Mar 1; 513: 385338-53.

    AbstractN-methyl-D-aspartate receptor (NMDAR) hypofunction during brain development is likely to contribute to the manifestation of schizophrenia (SCZ) in young adulthood. The cellular targets of NMDAR hypofunction appear to be at least in part corticolimbic fast-spiking (FS) interneurons. However, functional alterations in parvalbumin (PV)-positive FS interneurons following NMDAR hypofunction are poorly understood. Paired patch-clamp recordings from murine cortical PV interneurons and pyramidal neurons revealed that genetic deletion of NMDAR subunit Grin1 in prospective PV interneurons before the second postnatal week impaired evoked- and synchronized-GABA release. Whereas intrinsic excitability and spiking characteristics were also disturbed by Grin1 deletion, neither restoring their excitability by K+ channel blockade nor increasing extracellular Ca2+ rescued the GABA release. GABA release was also insensitive to the Cav2.1 channel antagonist ω-agatoxin IVA. Heterozygous deletion of Cacna1a gene (encoding Cav2.1) in PV interneurons produced a similar GABA release phenotype as the Grin1 mutants. Treatment with the Cav2.1/2.2 channel agonist GV-58 augmented somatic Ca2+ currents and GABA release in Cacna1a-haploinsufficient PV interneurons, but failed to enhance GABA release in the Grin1-deleted PV interneurons. Taken together, our results suggest that Grin1 deletion in prospective PV interneurons impairs proper maturation of membrane excitability and Cav2.1-recruited evoked GABA release. This may increase synaptic excitatory/inhibitory ratio in principal neurons, contributing to the emergence of SCZ-like phenotypes.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.

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