Interneuron Heterotopia in the Lis1 Mutant Mouse Cortex Underlies a Structural and Functional Schizophrenia-Like Phenotype.

Raquel Garcia-Lopez,Ana Pombero,Emilio Geijo-Barrientos,Alicia Estirado,Salvador Martinez

doi:10.3389/fcell.2021.693919

Raquel Garcia-Lopez, Ana Pombero + Show 3 more

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https://doi.org/10.3389/fcell.2021.693919

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Abstract

LIS1 is one of the principal genes related to Type I lissencephaly, a severe human brain malformation characterized by an abnormal neuronal migration in the cortex during embryonic development. This is clinically associated with epilepsy and cerebral palsy in severe cases, as well as a predisposition to developing mental disorders, in cases with a mild phenotype. Although genetic variations in the LIS1 gene have been associated with the development of schizophrenia, little is known about the underlying neurobiological mechanisms. We have studied how the Lis1 gene might cause deficits associated with the pathophysiology of schizophrenia using the Lis1/sLis1 murine model, which involves the deletion of the first coding exon of the Lis1 gene. Homozygous mice are not viable, but heterozygous animals present abnormal neuronal morphology, cortical dysplasia, and enhanced cortical excitability. We have observed reduced number of cells expressing GABA-synthesizing enzyme glutamic acid decarboxylase 67 (GAD67) in the hippocampus and the anterior cingulate area, as well as fewer parvalbumin-expressing cells in the anterior cingulate cortex in Lis1/sLis1 mutants compared to control mice. The cFOS protein expression (indicative of neuronal activity) in Lis1/sLis1 mice was higher in the medial prefrontal (mPFC), perirhinal (PERI), entorhinal (ENT), ectorhinal (ECT) cortices, and hippocampus compared to control mice. Our results suggest that deleting the first coding exon of the Lis1 gene might cause cortical anomalies associated with the pathophysiology of schizophrenia.

Highlights

Abnormal neuronal migration during brain development results in several brain organization alterations
To study the GABAergic system in Lis1/sLis1 mutant mice, we quantified the number of PV, CR, CB and glutamic acid decarboxylase 67 (GAD67)-positive neurons in the medial prefrontal cortex (mPFC) and hippocampus (Hi) of mice brains at 30 days (P30)
Reduction of Number of Cells Expressing GAD67 Is Observed in the Anterior Cingulate Area and Hippocampus in Lis1/sLis1 Mutant Mice The number of cells expressing GABA-synthesizing enzyme glutamic acid decarboxylase 67 (GAD67), responsible for most GABA synthesis, was studied in Lis1/sLis1 mutant and control mice by using the mutant strain Gad67-Gfp × Lis1/sLis1

Summary

Introduction

Abnormal neuronal migration during brain development results in several brain organization alterations. One of the most significant cortical abnormalities is lissencephaly (Reiner et al, 1995; Kato and Dobyns, 2003; Barkovich et al, 2005; Wynshaw-Boris, 2007) This developmental alteration produces severe symptoms that include seizures, intellectual retardation, and a higher risk of developing psychotic disorders like schizophrenia (Dobyns et al, 1993; Tabarés-Seisdedos et al, 2008). Other GABAergic subtypes of interneurons, such as cholecystokinin, vasoactive intestinal peptide, somatostatin, neuropeptide Y, and calbindin (CB) have been reported to be less expressed in the mPFC of SZ patients (Hashimoto et al, 2003, 2008; Fung et al, 2010, 2014) These deficits in the GABAergic interneurons seem to be related to the alteration of PFC-dependent cognitive functions in SZ patients. PFC is implicated in important cognitive processes such as attention, memory, and behavioral changes (Heidbreder and Groenewegen, 2003; Gabbott et al, 2005; Briand et al, 2007)

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