| Summary: | 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.
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