Behaviour-dependent neuronal network activity in a novel Cyfip1 haploinsufficient rat model of psychiatric risk

Advances in psychiatric genetics have begun to reveal the complex biological underpinnings of psychiatric disorders. Rare but penetrant copy number variants offer particularly direct mechanistic clues. The deletion at 15q11.2(BP1-BP2) has a 13% penetrance for developmental delay, congenital malformation, autism or schizophrenia. Reduced dosage of CYFIP1, one of four genes within this deletion, has emerged as a likely contributor to cognitive dysfunction seen in 15q11.2(BP1- BP2) deletion patients. However, the route from CYFIP1 haploinsufficiency to impaired behaviour has not been fully mapped. While synaptic deficits have been identified in mice haploinsufficient for Cyfip1 (Cyfip1+/-), circuit-level phenotypes have not been investigated. Using multi-site chronic electrode implants I recorded local field potential data simultaneously from prefrontal cortex, hippocampus and nucleus accumbens in a novel Cyfip1+/- rat model during a behavioural task and during sleep. Cyfip1+/- rats show normal performance accuracy on a discrete-trial alternation T maze task, but require more trials to achieve criterion during training. Task- dependent hippocampal-prefrontal network coordination remains intact in well-trained Cyfip1+/- rats, although theta-gamma phase-amplitude coupling within dorsal hippocampus is reduced compared to WTs. While circadian patterns and sleep architecture appear normal, hippocampal non-REM ripples are diminished in Cyfip1+/- rats compared to WTs, and preliminary data from the related Fmr1 (Fragile X Mental retardation 1) knockout rat also show aberrant ripples. Disrupted interactions are seen in the cortico-hippocampal-accumbal network, most prominently during approach to sucrose reward locations. Altered N-methyl-D- aspartate receptor signalling is implicated, as Cyfip1+/- rats show an exaggerated response to acute ketamine injection in the form of an enhanced surge in high frequency oscillations in nucleus accumbens and prelimbic cortex. Overall, abnormal behaviour- and ketamine-dependent network dynamics in hippocampus, prefrontal cortex and nucleus accumbens of Cyfip1+/- rats are reminiscent of some features of neuropsychiatric disorders, and lend weight to causal roles for CYFIP1 haploinsufficiency in predisposing patients to cognitive dysfunction

Linking haploinsufficiency of the autism- and schizophrenia-associated gene Cyfip1 with striatal-limbic-cortical network dysfunction and cognitive inflexibility

Impaired behavioural flexibility is a core feature of neuropsychiatric disorders and is associated with underlying dysfunction of fronto-striatal circuitry. Reduced dosage of Cyfip1 is a risk factor for neuropsychiatric disorder, as evidenced by its involvement in the 15q11.2 (BP1–BP2) copy number variant: deletion carriers are haploinsufficient for CYFIP1 and exhibit a two- to four-fold increased risk of schizophrenia, autism and/or intellectual disability. Here, we model the contributions of Cyfip1 to behavioural flexibility and related fronto-striatal neural network function using a recently developed haploinsufficient, heterozygous knockout rat line. Using multi-site local field potential (LFP) recordings during resting state, we show that Cyfip1 heterozygous rats (Cyfip1+/−) harbor disrupted network activity spanning medial prefrontal cortex, hippocampal CA1 and ventral striatum. In particular, Cyfip1+/− rats showed reduced influence of nucleus accumbens and increased dominance of prefrontal and hippocampal inputs, compared to wildtype controls. Adult Cyfip1+/− rats were able to learn a single cue-response association, yet unable to learn a conditional discrimination task that engages fronto-striatal interactions during flexible pairing of different levers and cue combinations. Together, these results implicate Cyfip1 in development or maintenance of cortico-limbic-striatal network integrity, further supporting the hypothesis that alterations in this circuitry contribute to behavioural inflexibility observed in neuropsychiatric diseases including schizophrenia and autism

Linking haploinsufficiency of the autism- and schizophrenia-associated gene Cyfip1 with striatal-limbic-cortical network dysfunction and cognitive inflexibility

Impaired behavioural flexibility is a core feature of neuropsychiatric disorders and is associated with underlying dysfunction of fronto-striatal circuitry. Reduced dosage of Cyfip1 is a risk factor for neuropsychiatric disorder, as evidenced by its involvement in the 15q11.2 (BP1–BP2) copy number variant: deletion carriers are haploinsufficient for CYFIP1 and exhibit a two- to four-fold increased risk of schizophrenia, autism and/or intellectual disability. Here, we model the contributions of Cyfip1 to behavioural flexibility and related fronto-striatal neural network function using a recently developed haploinsufficient, heterozygous knockout rat line. Using multi-site local field potential (LFP) recordings during resting state, we show that Cyfip1 heterozygous rats (Cyfip1+/−) harbor disrupted network activity spanning medial prefrontal cortex, hippocampal CA1 and ventral striatum. In particular, Cyfip1+/− rats showed reduced influence of nucleus accumbens and increased dominance of prefrontal and hippocampal inputs, compared to wildtype controls. Adult Cyfip1+/− rats were able to learn a single cue-response association, yet unable to learn a conditional discrimination task that engages fronto-striatal interactions during flexible pairing of different levers and cue combinations. Together, these results implicate Cyfip1 in development or maintenance of cortico-limbic-striatal network integrity, further supporting the hypothesis that alterations in this circuitry contribute to behavioural inflexibility observed in neuropsychiatric diseases including schizophrenia and autism

Decoding advances in psychiatric genetics: a focus on neural circuits in rodent models

Appropriately powered genome-wide association studies combined with deep-sequencing technologies offer the prospect of real progress in revealing the complex biological underpinnings of schizophrenia and other psychiatric disorders. Meanwhile, recent developments in genome engineering, including CRISPR, constitute better tools to move forward with investigating these genetic leads. This review aims to assess how these advances can inform the development of animal models for psychiatric disease, with a focus on schizophrenia and in vivo electrophysiological circuit-level measures with high potential as disease biomarkers