Abstract
Copy number variation (CNV) at the 15q11.2 region has been identified as a significant risk locus for neurological and neuropsychiatric conditions such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the individual roles for genes at this locus in nervous system development, function and connectivity remain poorly understood. Haploinsufficiency of one gene in this region, Cyfip1, may provide a model for 15q11.2 CNV-associated neuropsychiatric phenotypes. Here we show that altering CYFIP1 expression levels in neurons both in vitro and in vivo influences dendritic complexity, spine morphology, spine actin dynamics and synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor lateral diffusion. CYFIP1 is highly enriched at synapses and its overexpression in vitro leads to increased dendritic complexity. Neurons derived from Cyfip1 heterozygous animals on the other hand, possess reduced dendritic complexity, increased mobile F-actin and enhanced GluA2-containing AMPA receptor mobility at synapses. Interestingly, Cyfip1 overexpression or haploinsufficiency increased immature spine number, whereas activity-dependent changes in spine volume were occluded in Cyfip1 haploinsufficient neurons. In vivo, Cyfip1 heterozygous animals exhibited deficits in dendritic complexity as well as an altered ratio of immature-to-mature spines in hippocampal CA1 neurons. In summary, we provide evidence that dysregulation of CYFIP1 expression levels leads to pathological changes in CNS maturation and neuronal connectivity, both of which may contribute to the development of the neurological symptoms seen in ASD and SCZ.
Highlights
To address whether cytoplasmic FMRP-interacting protein 1 (CYFIP1)-mediated alterations in spine morphology and actin dynamics impinge on the stability or mobility of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors within synapses, we investigated whether surface GluA2-containing receptor dynamics were different from control in Cyfip1+/− neurons
Activation of Rac[1] releases the inhibitory action of CYFIP1 on WAVE, potentiating Arp2/3-mediated actin polymerization suggesting that changes in CYFIP1 levels could alter signalling events downstream of Rac1.31 Here we demonstrate that CYFIP1 expression levels are important for dendritic arborization and neuronal morphological complexity
In addition to the effects on dendritic morphogenesis that we report here, both WAVE1 and CYFIP1 have previously been implicated in axonal outgrowth.[49,50]
Summary
Copy number variations of the 15q11.2 region of the human genome are implicated in the development of neurological and neuropsychiatric conditions such as autism spectrum disorder (ASD), epilepsy, intellectual disability (ID) and schizophrenia (SCZ).[1,2,3,4,5,6,7] Copy number variation of one gene within 15q11.2, coding for the cytoplasmic FMRP-interacting protein 1 (CYFIP1), has been linked to both ASD and SCZ.[5,8,9] genomewide expression profiling of patients with duplication of 15q11–q13 has demonstrated upregulated Cyfip[1] mRNA in those that suffer from ASD.[10]. One critical modulator of cellular actin dynamics is the ubiquitous heteropentameric WAVE regulatory complex consisting of the proteins WAVE, Abi, Nap[1], HSPC300 and CYFIP1 ( known as SRA-1) or CYFIP2.30 The main role of CYFIP1 in this complex is to maintain the WAVE regulatory complex in an inhibited state until the small GTPase Rac[1], once activated, binds. How both deletions and duplications affecting Cyfip[1] expression produce similar neuropsychiatric phenotypes has not yet been addressed.[34,35].
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