Overexpression of the mammalian homolog of the unc-18 gene (munc18-1) has been described in the brain of subjects with schizophrenia. Munc18-1 protein is involved in membrane fusion processes, exocytosis and neurotransmitter release. A transgenic mouse strain that overexpresses the protein isoform munc18-1a in the brain was characterized. This animal displays several schizophrenia-related behaviors, supersensitivity to hallucinogenic drugs and deficits in prepulse inhibition that reverse after antipsychotic treatment. Relevant brain areas (that is, cortex and striatum) exhibit reduced expression of dopamine D₁ receptors and dopamine transporters together with enhanced amphetamine-induced in vivo dopamine release. Magnetic resonance imaging demonstrates decreased gray matter volume in the transgenic animal. In conclusion, the mouse overexpressing brain munc18-1a represents a new valid animal model that resembles functional and structural abnormalities in patients with schizophrenia. The animal could provide valuable insights into phenotypic aspects of this psychiatric disorder.

Munc18-1 and syntaxin-1 are crucial interacting molecules for synaptic membrane fusion and neurotransmitter release. Contrasting abnormalities of sev

Maternal immune activation (MIA) induces a variety of behavioral and brain abnormalities in offspring of rodent models, compatible with neurodevelopmental disorders, such as schizophrenia or autism. However, it remains controversial whether MIA impairs reversal learning, a basic expression of cognitive flexibility that seems to be altered in schizophrenia. In the present study, MIA was induced by administration of a single dose of polyriboinosinic‐polyribocytidylic acid (Poly (I:C) (5 mg/kg i.p.)) or saline to mouse pregnant dams in gestational day (GD) 9.5. Immune activation was monitored through changes in weight and temperature. The offspring were evaluated when they reached adulthood (8 weeks) using a touchscreen‐based system to investigate the effects of Poly (I:C) on discrimination and reversal learning performance. After an initial pre‐training, mice were trained to discriminate between two different stimuli, of which only one was rewarded (acquisition phase). When the correct response reached above 80% values for two consecutive days, the images were reversed (reversal phase) to assess the adaptation capacity to a changing environment. Maternal Poly (I:C) treatment did not interfere with the learning process but induced deficits in reversal learning compared to control saline animals. Thus, the accuracy in the reversal phase was lower, and Poly (I:C) animals required more sessions to complete it, suggesting impairments in cognitive flexibility. This study advances the knowledge of how MIA affects behavior, especially cognitive domains that are impaired in schizophrenia. The findings support the validity of the Poly (I:C)‐based MIA model as a tool to develop pharmacological treatments targeting cognitive deficits associated with neurodevelopmental disorders. image

Antipsychotic-induced low availability of group II metabotropic glutamate receptors (including mGlu₂R and mGlu₃R) in brains of schizophrenia patients may explain the limited efficacy of mGlu_2/3R ligands in clinical trials. Studies evaluating mGlu_2/3R levels in well-designed, large postmortem brain cohorts are needed to address this issue. Postmortem samples from the dorsolateral prefrontal cortex of 96 schizophrenia subjects and matched controls were collected. Toxicological analyses identified cases who were (AP+) or were not (AP-) receiving antipsychotic treatment near the time of death. Protein and mRNA levels of mGlu₂R and mGlu₃R, as well as GRM2 and GRM3 promoter-attached histone posttranslational modifications, were quantified. Experimental animal models were used to compare with data obtained in human tissues. Compared to matched controls, schizophrenia cortical samples had lower mGlu₂R protein amounts, regardless of antipsychotic medication. Downregulation of mGlu₃R was observed in AP- schizophrenia subjects only. Greater predicted occupancy values of dopamine D₂ and serotonin 5HT_2A receptors correlated with higher density of mGlu₃R, but not mGlu₂R. Clozapine treatment and maternal immune activation in rodents mimicked the mGlu₂R, but not mGlu₃R regulation observed in schizophrenia brains. mGlu₂R and mGlu₃R mRNA levels, and the epigenetic control mechanisms did not parallel the alterations at the protein level, and in some groups correlated inversely. Insufficient cortical availability of mGlu₂R and mGlu₃R may be associated with schizophrenia. Antipsychotic treatment may normalize mGlu₃R, but not mGlu₂R protein levels. A model in which epigenetic feedback mechanisms controlling mGlu₃R expression are activated to counterbalance mGluR loss of function is described.