Abstract
Genetic microdeletion at the 22q11 locus is associated with very high risk for schizophrenia. The 22q11.2 microdeletion (Df(h22q11)/+) mouse model shows cognitive deficits observed in this disorder, some of which can be linked to dysfunction of the prefrontal cortex (PFC). We used behavioral (n = 10 per genotype), electrophysiological (n = 7 per genotype per group), and neuroanatomical (n = 5 per genotype) techniques to investigate schizophrenia-related pathology of Df(h22q11)/+ mice, which showed a significant decrease in the total number of parvalbumin positive interneurons in the medial PFC. The Df(h22q11)/+ mice when tested on PFC-dependent behavioral tasks, including gambling tasks, perform significantly worse than control animals while exhibiting normal behavior on hippocampus-dependent tasks. They also show a significant decrease in hippocampus-medial Prefrontal cortex (H-PFC) synaptic plasticity (long-term potentiation, LTP). Acute platform stress almost abolished H-PFC LTP in both wild-type and Df(h22q11)/+ mice. H-PFC LTP was restored to prestress levels by clozapine (3 mg/kg i.p.) in stressed Df(h22q11)/+ mice, but the restoration of stress-induced LTP, while significant, was similar between wild-type and Df(h22q11)/+ mice. A medial PFC dysfunction may underlie the negative and cognitive symptoms in human 22q11 deletion carriers, and these results are relevant to the current debate on the utility of clozapine in such subjects.
Highlights
The de novo copy number variant (CNV) of humanchromosome 22q11.2 is one of the strongest genetic risk factor for development of sporadic schizophrenia[1]
We have previously demonstrated a direct but graded monosynaptic projection from the ventral CA1 to the Prelimbic region (Prl) of the medial prefrontal cortex (PFC) in mice[20]
There was a significant interaction subgroup × time (p = 0.0023; F(27,144) = 2.136, repeated measures ANOVA). These results indicate a difference in probabilistic learning by Df(h22q11)/+ mice as compared with the Wt mice under uncertainty
Summary
The de novo copy number variant (CNV) of humanchromosome 22q11.2 is one of the strongest genetic risk factor for development of sporadic schizophrenia[1] This CNV results in a deletion of 1.5–3 Mbp including ~35–60 known genes[2], most of which are expressed in the brain. The synteny of the human chromosome 22 to mouse chromosome 16 with a high degree of conservation enables the generation of a mouse model with construct validity To this end, animal models based on either silencing of single genes or deletion of part of this locus have been validated[3] with behavioral and cognitive deficits, including spatial and working memory deficits[4,5], impairment in reversal learning[6], and fear conditioning[7]. This model was extensively analysed in a battery of cognitive tasks by partner research groups within the NEWMEDS consortium
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