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

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.

Abnormalities in Cortical GABAergic Interneurons of the Primary Motor Cortex Caused by Lis1 (Pafah1b1) Mutation Produce a Non-drastic Functional Phenotype

“…The possibility that different LIS1 alterations may produce different pathologies is highly relevant since some authors have proposed that alterations in some portions of the gene encoding for LIS1 may be implicated in neurological disorders less severe than lissencephaly, such as schizophrenia, autism, and bipolar disorder ( Reiner et al, 2006 ; Tabares-Seisdedos et al, 2006 ; Tabares-Seisdedos et al, 2008 ). In a recent work performed using a mouse lacking the LisH domain from one allele (the Lis1/sLis1 mouse) we reported some structural alterations compatible with the ones described in schizophrenic patients ( García-López et al, 2021 ): a reduction in the number of GABAergic interneurons in the anterior cingulate cortex, a disbalance in cellular activation as assessed by c-fos expression, and alteration of behavioral tests related to these cellular deficiencies. These abnormalities are consistent with findings in schizophrenic patients ( Hasimoto et al, 2003 , 2008 ; Fung et al, 2014 ; Glausier et al, 2014 ).…”

“…The relative amount of PV positive cells was also significantly decreased in the superficial layers, while increased in the deeper layers. The alteration in the number and distribution of interneurons seems to be a general feature of the Lis1/sLis1 neocortex, since in the prefontal cortex a lower number of PV and CR positive GABAergic neurons were detected ( García-López et al, 2021 ). Although these neuronal markers (PV, CB, and CR) reveal overlapping populations of GABAergic neurons we explore the total population of cortical GABAergic neurons.…”

“…However, mutations in NDE1 , which is one of the major LIS1-proteins interactors, result in a wide spectrum of brain diseases, including schizophrenia ( Bradshaw and Hayashi, 2017 ). Overall, we described in the neocortex of the animal model Lis1/sLis1 a series of alterations analogous to different cohorts of patients or animal models of non-drastic neurobiological disorders ( García-López et al, 2021 ).…”

“…It has been shown the presence of excitatory and inhibitory synaptic abnormalities in the hippocampus ( Jones and Baraban, 2007 , 2009 ; Wang and Baraban, 2008 ; Greenwood et al, 2009 ; Hunt et al, 2012 ; Sudarov et al, 2018 ) and cortex ( Valdés-Sánchez et al, 2007 ; Sudarov et al, 2013 ). In addition to postnatal synaptic abnormalities, a mouse model presenting a deletion in the LisH domain from one allele showed a decrease in the number of some GABAergic interneuron subtypes in the anterior cingulate area and abnormalities in the septo-hippocampal cholinergic projection ( García-López et al, 2015 ; 2021 ). However, there is still a lack of knowledge regarding the pathophysiology of LIS1 dysfunction and the relationship between alterations in different portions of the LIS1 protein and their structural and functional consequences in the postnatal brain (genotype-phenotype relationship).…”

“…This work is aimed to determine the impact of a deletion of the LisH domain on the anatomical organization and electrophysiological properties of the anterior cortical portion, specifically in the primary motor cortex. We selected this cortical area to extend the findings of García-López et al (2021) to a non-associative cortical area, the primary motor cortex. The primary motor cortex has the advantage that, in addition to structural methods, it can be studied with electrophysiological (functional) techniques, such as “ in vitro ” slice electrophysiology and field potential recordings in the intact brain; this would allow a more complete understanding of the alterations caused by the deletion of the LisH domain.…”