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

Abstract

Running title: CYFIP1 and bilateral brain connectivity. SUMMARYCopy-number variants of the CYFIP1 gene in humans have been linked to Autism and Schizophrenia, two neuropsychiatric disorders characterized by defects in brain connectivity. CYFIP1 regulates molecular events underlying post-synaptic functions. Here, we show that CYFIP1 plays an important role in brain functional connectivity and callosal functions. In particular, we find that Cyfip1 heterozygous mice have reduced brain functional connectivity and defects in white matter architecture, typically relating to phenotypes found in patients with Autism, Schizophrenia and other neuropsychiatric disorders. In addition, Cyfip1 deficient mice present deficits in the callosal axons, namely reduced myelination, altered pre-synaptic function, and impaired bilateral-connectivity related behavior. Altogether, our results show that Cyfip1 haploinsufficiency compromises brain connectivity and function, which might explain its genetic association to neuropsychiatric disorders. 3The corpus callosum (CC) is the largest axonal commissure in the human brain and connects both cerebral hemispheres. Appropriate callosal microstructure and function are required for bilateral functional connectivity 1,2 . Agenesis of the corpus callosum (ACC), callosotomy or defects in callosal integrity have been linked with deficits in social communication 3 , social behavior 4 , motor coordination and learning 5-7 , and cognitive performance 8,9 . Similarly, corpus callosum abnormalities have been found in patients with diverse neuropsychiatric disorders such as Autism Spectrum Disorders (ASD), Schizophrenia (SCZ), Fragile X syndrome (FXS), attention-deficit hyperactivity disorder (ADHD), Prader-Willi syndrome and 22q11.2 deletion syndrome 3,10-13 . Interestingly, over the last decade, magnetic resonance imaging (MRI) studies in patients with ASD and SCZ have identified functional connectivity and microstructural defects in the white matter as a hallmark of these disorders. Resting state functional MRI (rsfMRI), a measure of brain functional connectivity (FC), is altered in ASD and SCZ patients, showing predominantly reduced longrange functional connectivity [14][15][16][17][18][19] . Additionally, diffusion tensor imaging (DTI), a measure of axonal integrity and connectivity, is also affected in patients with ASD and SCZ 20-23 . In particular, DTI revealed abnormalities in the corpus callosum of these patients 21,24 .Furthermore, reduced myelination has also been observed in patients with ASD and SCZ 25,26 .Recently, copy-number variations (CNV) of the chromosomal region 15q11.2 have been associated with the development of neuropsychiatric disorders, especially ASD and SCZ.The proximal region of the long arm of chromosome 15 contains several breakpoints, resulting in different rearrangements 27 . The smallest region that has been linked to neuropsychiatric disorders is contained between the breakpoints BP1 and BP2, i.e., the 15q11.2 locus. CNVs of this region are quite frequent (~1% of the ...

Measuring the Non-linear Directed Information Flow in Schizophrenia by Multivariate Transfer Entropy

“…The disease is a chronic psychotic disorder that disrupts the patient's thoughts and affect their total well-being (Patel et al, 2014;Ure et al, 2018). Previous studies have demonstrated a coherent or uniform reduction in the brain regions of the SCZ patients, including the insula, superior temporal gyrus, amygdala, parahippocampus, inferior and medial frontal gyri, hippocampus, and anterior cingulate cortex (ACC) (Ehrlich et al, 2014;Alonso-Solís et al, 2015;Domínguez-Iturza et al, 2018). In neurophysiological research, it is more interesting to explore the specific performance of the SCZ under certain task like oddball paradigm involving the P300 (Alvarado-González et al, 2016), as the P300 serves as the reliable biomarker to identify the SCZ from healthy control (HC) (Somani and Shukla, 2012).…”