The autism- and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity and behaviour

Domínguez-Iturza, Nuria; Lo, Adrian C.; Shah, Disha; Armendáriz, Marcelo; Vannelli, Anna; Mercaldo, Valentina; Trusel, Massimo; Li, Ka Wan; Gastaldo, Denise; Santos, Ana Rita; Callaerts-Végh, Zsuzsanna; D’Hooge, Rudi; Mameli, Manuel; Linden, Annemie Van der; Smit, August B.; Achsel, Tilmann; Bagni, Claudia

doi:10.1038/s41467-019-11203-y

Cited by 66 publications

(43 citation statements)

References 97 publications

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“…We also found brain sizes comparable in both WTs and crmp2 −/− mice, similar as reported in the CRMP2 knockout mice , although we detected a non‐significant tendency for a thinner cortex in the knockout mice (not shown) in agreement with the hypoplastic corpus callosum and anterior commissure. Changes in interhemispheric connectivity have recently been linked to ASD and schizophrenia through CYFIP1, a CRMP2 binding partner . Importantly, we demonstrate that CRMP2 knockout leads to defects in axonal pruning and dendritic spine remodeling compatible with ASD rather than schizophrenia (Figs , and ).…”

Section: Discussionmentioning

confidence: 51%

CRMP 2 mediates Sema3F‐dependent axon pruning and dendritic spine remodeling

et al. 2020

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Regulation of axon guidance and pruning of inappropriate synapses by class 3 semaphorins are key to the development of neural circuits. Collapsin response mediator protein 2 (CRMP2) has been shown to regulate axon guidance by mediating semaphorin 3A (Sema3A) signaling; however, nothing is known about its role in synapse pruning. Here, using newly generated crmp2−/− mice we demonstrate that CRMP2 has a moderate effect on Sema3A‐dependent axon guidance in vivo, and its deficiency leads to a mild defect in axon guidance in peripheral nerves and the corpus callosum. Surprisingly, crmp2−/− mice display prominent defects in stereotyped axon pruning in hippocampus and visual cortex and altered dendritic spine remodeling, which is consistent with impaired Sema3F signaling and with models of autism spectrum disorder (ASD). We demonstrate that CRMP2 mediates Sema3F signaling in primary neurons and that crmp2−/− mice display ASD‐related social behavior changes in the early postnatal period as well as in adults. Together, we demonstrate that CRMP2 mediates Sema3F‐dependent synapse pruning and its dysfunction shares histological and behavioral features of ASD.

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Section: Discussionmentioning

confidence: 51%

CRMP 2 mediates Sema3F‐dependent axon pruning and dendritic spine remodeling

et al. 2020

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“…Despite these molecular functions, in vivo neurobiological mechanisms underlying CYFIP ‐associated brain disorders remain largely unknown and have thus far been investigated mainly for CYFIP1 13–15 . Moreover, CYFIP1 and CYFIP2 have distinct expressions and functions in vivo, 16–19 strongly encouraging further investigation of CYFIP2 in brain function and dysfunction.…”

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confidence: 99%

Haploinsufficiency of Cyfip2 Causes Lithium‐Responsive Prefrontal Dysfunction

Lee

Zhang

Park

et al. 2020

Annals of Neurology

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Objective Genetic variants of the cytoplasmic FMR1‐interacting protein 2 (CYFIP2) encoding an actin‐regulatory protein are associated with brain disorders, including intellectual disability and epilepsy. However, specific in vivo neuronal defects and potential treatments for CYFIP2‐associated brain disorders remain largely unknown. Here, we characterized Cyfip2 heterozygous (Cyfip2+/−) mice to understand their neurobehavioral phenotypes and the underlying pathological mechanisms. Furthermore, we examined a potential treatment for such phenotypes of the Cyfip2+/− mice and specified a neuronal function mediating its efficacy. Methods We performed behavioral analyses of Cyfip2+/− mice. We combined molecular, ultrastructural, and in vitro and in vivo electrophysiological analyses of Cyfip2+/− prefrontal neurons. We also selectively reduced CYFIP2 in the prefrontal cortex (PFC) of mice with virus injections. Results Adult Cyfip2+/− mice exhibited lithium‐responsive abnormal behaviors. We found increased filamentous actin, enlarged dendritic spines, and enhanced excitatory synaptic transmission and excitability in the adult Cyfip2+/− PFC that was restricted to layer 5 (L5) neurons. Consistently, adult Cyfip2+/− mice showed increased seizure susceptibility and auditory steady‐state responses from the cortical electroencephalographic recordings. Among the identified prefrontal defects, lithium selectively normalized the hyperexcitability of Cyfip2+/− L5 neurons. RNA sequencing revealed reduced expression of potassium channel genes in the adult Cyfip2+/− PFC. Virus‐mediated reduction of CYFIP2 in the PFC was sufficient to induce L5 hyperexcitability and lithium‐responsive abnormal behavior. Interpretation These results suggest that L5‐specific prefrontal dysfunction, especially hyperexcitability, underlies both the pathophysiology and the lithium‐mediated amelioration of neurobehavioral phenotypes in adult Cyfip2+/− mice, which can be implicated in CYFIP2‐associated brain disorders. ANN NEUROL 2020;88:526–543

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“…CYFIP1 is considered a likely contributor to 15q11.2 BP1-BP2-associated phenotypes. Dysregulations in this gene result in alterations in dendritic spine morphology and branching (45,46) as well as myelination (47,48). CYFIP1 interacts in two distinct complexes (45): the WAVE regulatory complex, which regulates actin remodeling during neural wiring (49), and the CYFIP1-eIF4E complex, which through interactions with the fragile X mental retardation 1 protein (FMRP) regulates translation of FMRP-target mRNAs (50).…”

Section: Discussionmentioning

confidence: 99%

Analysis of diffusion tensor imaging data from UK Biobank confirms dosage effect of 15q11.2 copy-number variation on white matter and shows association with cognition

Silva

Kirov

Kendall

et al. 2020

Preprint

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BackgroundCopy-number variations at the 15q11.2 BP1-BP2 locus are present in 0.5 to 1.0% of the population, and the deletion is associated with a range of neurodevelopmental disorders. Previously, we showed a reciprocal effect of 15q11.2 copy-number variation on fractional anisotropy, with widespread increases in deletion carriers. We aim to replicate and expand these findings, using a larger sample of participants (n=30,930), higher resolution imaging, and examining the implications for cognitive performance.MethodsDiffusion tensor imaging measures from participants with no neurological/psychiatric diagnoses were obtained from the UK Biobank database. We compared 15q11.2 BP1-BP2 deletion (n=103) and duplication (n=119) carriers to a large cohort of control individuals with no neuropsychiatric copy-number variants (n=29,870). Additionally, we assessed how changes in white matter mediated the association between carrier status and cognitive performance.ResultsDeletion carriers showed increases in fractional anisotropy in the internal capsule and cingulum, and decreases in the posterior thalamic radiation, compared to both duplication carriers and controls (who had intermediate values). Deletion carriers had lower scores across cognitive tasks compared to controls, which were mildly influenced by white matter alterations. Reduced fractional anisotropy in the posterior thalamic radiation partially contributed to worse cognitive performance in deletion carriers.ConclusionsThis study, together with our previous findings, provides convergent evidence for a dosage-dependent effect of 15q11.2 BP1-BP2 on white matter microstructure. Additionally, changes in white matter were found to partially mediate cognitive ability in deletion carriers, providing a link between white matter changes in 15q11.2 BP1-BP2 carriers and cognitive function.

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The autism- and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity and behaviour

Cited by 66 publications

References 97 publications

CRMP 2 mediates Sema3F‐dependent axon pruning and dendritic spine remodeling

CRMP 2 mediates Sema3F‐dependent axon pruning and dendritic spine remodeling

Haploinsufficiency of Cyfip2 Causes Lithium‐Responsive Prefrontal Dysfunction

Analysis of diffusion tensor imaging data from UK Biobank confirms dosage effect of 15q11.2 copy-number variation on white matter and shows association with cognition

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