Parvalbumin interneuron dysfunction in a thalamo-prefrontal cortical circuit in Disc1 locus impairment mice

Delevich, K., Jaaro-Peled, H., Penzo, M., Sawa, A., Li, B. (February 2020) Parvalbumin interneuron dysfunction in a thalamo-prefrontal cortical circuit in Disc1 locus impairment mice. eNeuro. ISSN 2373-2822

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Abstract

Altered cortical excitation-inhibition (E-I) balance resulting from abnormal parvalbumin interneuron (PV IN) function is a proposed pathophysiological mechanism of schizophrenia (SZ) and other major psychiatric disorders. Preclinical studies have indicated that disrupted-in-schizophrenia-1 (DISC1) is a useful molecular lead to address the biology of prefrontal cortex dependent cognition and PV IN function. To date, prefrontal cortical inhibitory circuit function has not been investigated in depth in Disc1 locus impairment (LI) mouse models. Therefore, we used a Disc1 LI mouse model to investigate E-I balance in medial prefrontal cortical (mPFC) circuits. We found that inhibition onto layer 3 excitatory pyramidal neurons in the mPFC was significantly reduced in Disc1 LI mice. This reduced inhibition was accompanied by decreased GABA release from local PV, but not somatostatin (SOM) interneurons, and by impaired feedforward inhibition in the mediodorsal thalamus (MD) to mPFC circuit. Our mechanistic findings of abnormal PV IN function in a Disc1 LI model provide insight into biology that may be relevant to neuropsychiatric disorders including schizophrenia.SIGNIFICANCE STATEMENT A popular theory suggests that dysregulation of fast-spiking parvalbumin interneurons (PV INs) and elevated excitation-inhibition (E-I) balance contribute to the pathophysiology of various psychiatric disorders. Previous studies suggest that genetic perturbations of the disrupted-in-schizophrenia-1 (Disc1) gene affect prefrontal cortex-dependent cognition and PV IN function, but synaptic and circuit physiology data are lacking. Here, we provide evidence that the presynaptic function of PV INs in the medial prefrontal cortex is altered in Disc1 LI mice and that E-I balance is elevated within a thalamofrontal circuit known to be important for cognition. These findings may contribute to our understanding of the biology that gives rise to cognitive symptoms in a range of neuropsychiatric disorders.

Item Type:	Paper
Additional Information:	eNeuro
Subjects:	organism description > animal organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types > interneurons organs, tissues, organelles, cell types and functions > cell types and functions > cell types > interneurons organs, tissues, organelles, cell types and functions > cell types and functions > cell types > interneurons organism description > animal > mammal organism description > animal > mammal > rodent > mouse organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons > neuronal circuits organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons > neuronal circuits organs, tissues, organelles, cell types and functions > cell types and functions > cell types > neurons > neuronal circuits organs, tissues, organelles, cell types and functions organs, tissues, organelles, cell types and functions > tissues types and functions > prefrontal cortex organism description > animal > mammal > rodent bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > DISC1 organs, tissues, organelles, cell types and functions > tissues types and functions
CSHL Authors:	Li, Bo Delevich, Kristen
Communities:	CSHL labs > Li lab School of Biological Sciences > Publications
Depositing User:	Adrian Gomez
Date:	4 February 2020
Date Deposited:	12 Feb 2020 15:05
Last Modified:	29 Jan 2024 21:04
PMCID:	PMC7054897
Related URLs:	https://www.eneuro.org/content/early/202...
URI:	https://repository.cshl.edu/id/eprint/38966

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