Dissociated features of social cognition altered in mouse models of schizophrenia: Focus on social dominance and acoustic communication

International audienceSocial and communication impairments are common features of psychiatric disorders. Animal models of schizophrenia display various social deficits due to difference in tests, mouse strains and drugs. Moreover, communication deficits have not been studied. Our objectives were to assess and compare three major features of social cognition in different mouse models of schizophrenia: interest for a social stimulus, organization and acceptance of social contact, and acoustic communication to question whether mouse models for schizophrenia with social dysfunction also exhibit vocal communication defects. To achieve these aims we treated acutely C57BL/6J mice either with MK-801 or ketamine and tested WT and microtubule-associated protein 6 -MAP6- KO mice in two complementary social tasks: the 3-chamber test which measures social motivation and the social interaction task -SIT- which relies on prefrontal cortex activity and measures the ability to organize and respond to a real interaction, and which promotes ultrasonic vocalizations. Our results reveal that schizophrenia models have intact interest for a social stimulus in the 3-chamber test. However, thanks to principal component analyses of social interaction data, we demonstrate that social motivation and the ability to act socially rely on distinct mechanisms in revealing a decrease in dominance and communication in pharmacological schizophrenia models along with social withdraw, classically observed in schizophrenia, in MK-801 model. In this latter model, some social parameters can be significantly improved by aripiprazole, an atypical antipsychotic. Our social protocol, combined with fine-tuned analysis, is expected to provide an innovative framework for testing future treatments in preclinical models

: MAP6 dosage controls cognitive abilities

International audienceBackground: STOP/MAP6 null (KO) mice recapitulate behavioral abnormalities related to positive and negative symptoms and cognitive deficits of schizophrenia. Here, we investigated whether decreased expression of STOP/MAP6 proteins in heterozygous mice (only one allele expressed) would result in abnormal behavior related to those displayed by STOP null mice. Methods : Using a comprehensive test battery, we investigated the behavioral phenotype of STOP heterozygous (Het) mice compared with STOP KO and wild type (WT) mice on animals raised either in standard conditions (controls) or submitted to maternal deprivation. Results : Control Het mice displayed prominent deficits in social interaction and learning, resembling KO mice. In contrast, they exhibited short-lasting locomotor hyperreactivity to acute mild stress and no impaired locomotor response to amphetamine, much like WT mice. Additionally, perinatal stress deteriorated Het mouse phenotype by exacerbating alterations related to positive symptoms such as their locomotor reactivity to acute mild stress and psychostimulant challenge. Conclusion : Results show that the dosage of susceptibility genes modulates their putative phenotypic contribution and that STOP expression has a high penetrance on cognitive abilities. Hence, STOP Het mice might be useful to investigate cognitive defects related to those observed in mental diseases and ultimately might be a valuable experimental model to evaluate preventive treatments

Omics analysis of mouse brain models of human diseases

International audienceThe identification of common gene/protein profiles related to brain alterations, if they exist, may indicate theconvergence of the pathogenic mechanisms driving brain disorders. Six genetically engineered mouse linesmodelling neurodegenerative diseases and neuropsychiatric disorders were considered. Omics approaches, includingtranscriptomic and proteomic methods, were used. The gene/protein lists were used for inter-diseasecomparisons and further functional and network investigations. When the inter-disease comparison was performedusing the gene symbol identifiers, the number of genes/proteins involved in multiple diseases decreasedrapidly. Thus, no genes/proteins were shared by all 6 mouse models. Only one gene/protein (Gfap) was sharedamong 4 disorders, providing strong evidence that a common molecular signature does not exist among braindiseases. The inter-disease comparison of functional processes showed the involvement of a fewmajor biologicalprocesses indicating that brain diseases of diverse aetiologies might utilize common biological pathways in thenervous system, without necessarily involving similar molecules

Deletion of the microtubule-associated protein 6 (MAP6) results in skeletal muscle dysfunction

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A key function for microtubule-associated-protein 6 in activity-dependent stabilisation of actin filaments in dendritic spines

Emerging evidence indicates that microtubule-associated proteins (MAPs) are implicated in synaptic function; in particular, mice deficient for MAP6 exhibit striking deficits in plasticity and cognition. How MAP6 connects to plasticity mechanisms is unclear. Here, we address the possible role of this protein in dendritic spines. We find that in MAP6-deficient cortical and hippocampal neurons, maintenance of mature spines is impaired, and can be restored by expressing a stretch of the MAP6 sequence called Mc modules. Mc modules directly bind actin filaments and mediate activity-dependent stabilisation of F-actin in dendritic spines, a key event of synaptic plasticity. In vitro, Mc modules enhance actin filament nucleation and promote the formation of stable, highly ordered filament bundles. Activity-induced phosphorylation of MAP6 likely controls its transfer to the spine cytoskeleton. These results provide a molecular explanation for the role of MAP6 in cognition, enlightening the connection between cytoskeletal dysfunction, synaptic impairment and neuropsychiatric illnesses

Cacnb4 directly couples electrical activity to gene expression, a process defective in juvenile epilepsy.

International audienceCalcium current through voltage-gated calcium channels (VGCC) controls gene expression. Here, we describe a novel signalling pathway in which the VGCC Cacnb4 subunit directly couples neuronal excitability to transcription. Electrical activity induces Cacnb4 association to Ppp2r5d, a regulatory subunit of PP2A phosphatase, followed by (i) nuclear translocation of Cacnb4/Ppp2r5d/PP2A, (ii) association with the tyrosine hydroxylase (TH) gene promoter through the nuclear transcription factor thyroid hormone receptor alpha (TRα), and (iii) histone binding through association of Cacnb4 with HP1γ concomitantly with Ser(10) histone H3 dephosphorylation by PP2A. This signalling cascade leads to TH gene repression by Cacnb4 and is controlled by the state of interaction between the SH3 and guanylate kinase (GK) modules of Cacnb4. The human R482X CACNB4 mutation, responsible for a form of juvenile myoclonic epilepsy, prevents association with Ppp2r5 and nuclear targeting of the complex by altering Cacnb4 conformation. These findings demonstrate that an intact VGCC subunit acts as a repressor recruiting platform to control neuronal gene expression