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PSD-95 deficiency alters GABAergic inhibition in the prefrontal cortex.
- Source :
-
Neuropharmacology [Neuropharmacology] 2020 Nov 15; Vol. 179, pp. 108277. Date of Electronic Publication: 2020 Aug 18. - Publication Year :
- 2020
-
Abstract
- Postsynaptic Density Protein-95 (PSD-95) is a major scaffolding protein in the excitatory synapses in the brain and a critical regulator of synaptic maturation for NMDA and AMPA receptors. PSD-95 deficiency has been linked to cognitive and learning deficits implicated in neurodevelopmental disorders such as autism and schizophrenia. Previous studies have shown that PSD-95 deficiency causes a significant reduction in the excitatory response in the hippocampus. However, little is known about whether PSD-95 deficiency will affect gamma-aminobutyric acid (GABA)ergic inhibitory synapses. Using a PSD-95 transgenic mouse model (PSD-95 <superscript>+/-</superscript> ), we studied how PSD-95 deficiency affects GABA <subscript>A</subscript> receptor expression and function in the medial prefrontal cortex (mPFC) during adolescence. Our results showed a significant increase in the GABA <subscript>A</subscript> receptor subunit α1. Correspondingly, there are increases in the frequency and amplitude in spontaneous inhibitory postsynaptic currents (sIPSCs) in pyramidal neurons in the mPFC of PSD-95 <superscript>+/-</superscript> mice, along with a significant increase in evoked IPSCs, leading to a dramatic shift in the excitatory-to-inhibitory balance in PSD-95 deficient mice. Furthermore, PSD-95 deficiency promotes inhibitory synapse function via upregulation and trafficking of NLGN2 and reduced GSK3β activity through tyr-216 phosphorylation. Our study provides novel insights on the effects of GABAergic transmission in the mPFC due to PSD-95 deficiency and its potential link with cognitive and learning deficits associated with neuropsychiatric disorders.<br /> (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Disks Large Homolog 4 Protein genetics
Inhibitory Postsynaptic Potentials drug effects
Mice
Mice, Transgenic
Neural Inhibition drug effects
Prefrontal Cortex drug effects
gamma-Aminobutyric Acid pharmacology
Disks Large Homolog 4 Protein deficiency
Inhibitory Postsynaptic Potentials physiology
Neural Inhibition physiology
Prefrontal Cortex metabolism
Receptors, GABA metabolism
gamma-Aminobutyric Acid metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1873-7064
- Volume :
- 179
- Database :
- MEDLINE
- Journal :
- Neuropharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 32818520
- Full Text :
- https://doi.org/10.1016/j.neuropharm.2020.108277