Behaviour-dependent neuronal network activity in a novel CYFIP1 haplo-insufficient rat model of psychiatric risk

• Main Author: Heckenast, Julia
• Published: Cardiff University 2018
• Subjects: BF Psychology
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.753567

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.