Abstract
Chromosome 16p11.2 duplications dramatically increase risk for schizophrenia, but the mechanisms remain largely unknown. Here, we show that mice with an equivalent genetic mutation (16p11.2 duplication mice) exhibit impaired hippocampal-orbitofrontal and hippocampal-amygdala functional connectivity. Expression of schizophrenia-relevant GABAergic cell markers (parvalbumin and calbindin) is selectively decreased in orbitofrontal cortex, while somatostatin expression is decreased in lateral amygdala. When 16p11.2 duplication mice are tested in cognitive tasks dependent on hippocampal-orbitofrontal connectivity, performance is impaired in an 8-arm maze "N-back" working memory task andin a touchscreen continuous performance task. Consistent with hippocampal-amygdala dysconnectivity, deficits in ethologically relevant social behaviors are also observed. Overall, the cellular/molecular, brain network, and behavioral alterations markedly mirror those observed in schizophrenia patients. Moreover, the data suggest that 16p11.2 duplications selectively impact hippocampal-amygdaloid-orbitofrontal circuitry, supporting emerging ideas that dysfunction in this network is a core element of schizophrenia and defining a neural circuit endophenotype for the disease.
Highlights
Available drug treatments for schizophrenia (SZ) are effective against the positive symptoms, at least in the majority of patients, but are largely ineffective against the negative and cognitive symptoms
There is some evidence that individual SZ risk genes/copy-number variants (CNVs) (Dawson et al, 2015a; Sigurdsson et al, 2010) impact on functional brain network structure and hippocampal-prefrontal cortex (PFC) connectivity in mice
16p11.2 DUP mice exhibited selective alterations in constitutive cerebral metabolism limited to the serotonergic raphe, and the striatum (Figure S2), showing significant hypometabolism in the median raphe (MR) nucleus (p = 0.032, ANOVA), and hypermetabolism in the dorsolateral striatum (DLST, p = 0.003, ANOVA) and ventromedial striatum (VMST, p = 0.015, ANOVA)
Summary
Available drug treatments for schizophrenia (SZ) are effective against the positive symptoms (hallucinations, delusions), at least in the majority of patients, but are largely ineffective against the negative (anhedonia, avolition, self-neglect, social withdrawal) and cognitive (impaired working memory [WM]and attention) symptoms. It is clear that in rare cases, single human copy-number variants (CNVs), where small chromosomal sections are present in one or three instead of two copies, can dramatically perturb CNS function on their own and substantially increase disease risk. Of these CNVs, the 22q11 (velocardiofacial/DiGeorge Syndrome) deletion CNV has received considerable attention, as it substantially increases risk of SZ (penetrance 6.5–18 [95% confidence interval, CI]) (Kirov et al, 2014). When mice modeling the 22q11 deletion are assessed in cognitive tasks, any deficits observed are likely to reflect aspects of general ID, rather than a specific SZ-related impairment
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