Human CRMP4 mutation and disrupted Crmp4 expression in mice are associated with ASD characteristics and sexual dimorphism

Abstract

Autism spectrum disorders (ASD) are more common among boys than girls. The mechanisms responsible for ASD symptoms and their sex differences remain mostly unclear. We previously identified collapsin response mediator protein 4 (CRMP4) as a protein exhibiting sex-different expression during sexual differentiation of the hypothalamic sexually dimorphic nucleus. This study investigated the relationship between the sex-different development of autistic features and CRMP4 deficiency. Whole-exome sequencing detected a de novo variant (S541Y) of CRMP4 in a male ASD patient. The expression of mutated mouse CRMP4 S540Y, which is homologous to human CRMP4 S541Y, in cultured hippocampal neurons derived from Crmp4-knockout (KO) mice had increased dendritic branching, compared to those transfected with wild-type (WT) Crmp4, indicating that this mutation results in altered CRMP4 function in neurons. Crmp4-KO mice showed decreased social interaction and several alterations of sensory responses. Most of these changes were more severe in male Crmp4-KO mice than in females. The mRNA expression levels of some genes related to neurotransmission and cell adhesion were altered in the brain of Crmp4-KO mice, mostly in a gender-dependent manner. These results indicate a functional link between a case-specific, rare variant of one gene, Crmp4, and several characteristics of ASD, including sexual differences.

Impaired effective functional connectivity of the sensorimotor network in interictal episodic migraineurs without aura

“…Besides, the migraine attack is a paroxysmal dysfunctional alteration or inflow-outflow dysfunctional modulation of multiple sensory systems [ 9 ]. Various neuroimaging outcomes have demonstrated correlation of functional connectivity between the subregions in SMN, and the central executive network (CEN) [ 6 ], salience network (SN) [ 10 ] as well as default mode network (DMN) [ 11 ] in patients with MwoA. The functional connectivity strength of SMN has been shown to significantly illuminate the perception of pain intensity and therapeutic effect in MwoA [ 12 ].…”

Atrx deletion in neurons leads to sexually-dimorphic dysregulation of miR-137 and spatial learning and memory deficits

“…Sexual dimorphism has been reported in other mouse models with mutations in chromatin remodeling proteins, including CHD8 and MeCP2, where females are unaffected by loss of the protein of interest or are affected differently [75][76][77] . In humans, neurological disorders such as autismspectrum disorders tend to preferentially affect males rather than females, possibly due to combinatorial contributions of hormonal and genetic factors in a phenomenon known as the female protective effect [78][79][80] , and this is regularly supported with mouse models [81][82][83] . The presence of estrogen and estrogen receptor in the female brain has been shown to be neuroprotective and leads to enhanced Schaffer-collateral LTP 84 .…”

Collapsin Response Mediator Proteins: Their Biological Functions and Pathophysiology in Neuronal Development and Regeneration

“…Currently, the nomenclature has been unified by calling the family members ''CRMP1'' through ''CRMP5'' ( Supplementary Table S1); CRMP-62 has been renamed as CRMP2. The CRMP family of proteins are now recognized as multifunctional proteins, not only being involved in neuronal development, regeneration and inflammation, but also in various neurological and psychiatric disease states (Tobe et al, 2017;Tsutiya et al, 2017).…”