Loss of the Intellectual Disability and Autism Gene Cc2d1a and Its Homolog Cc2d1b Differentially Affect Spatial Memory, Anxiety, and Hyperactivity

Abstract

Hundreds of genes are mutated in non-syndromic intellectual disability (ID) and autism spectrum disorder (ASD), with each gene often involved in only a handful of cases. Such heterogeneity can be daunting, but rare recessive loss of function (LOF) mutations can be a good starting point to provide insight into the mechanisms of neurodevelopmental disease. Biallelic LOF mutations in the signaling scaffold CC2D1A cause a rare form of autosomal recessive ID, sometimes associated with ASD and seizures. In parallel, we recently reported that Cc2d1a-deficient mice present with cognitive and social deficits, hyperactivity and anxiety. In Drosophila, loss of the only ortholog of Cc2d1a, lgd, is embryonically lethal, while in vertebrates, Cc2d1a has a homolog Cc2d1b which appears to be compensating, indicating that Cc2d1a and Cc2d1b have a redundant function in humans and mice. Here, we generate an allelic series of Cc2d1a and Cc2d1b LOF to determine the relative role of these genes during behavioral development. We generated Cc2d1b knockout (KO), Cc2d1a/1b double heterozygous and double KO mice, then performed behavioral studies to analyze learning and memory, social interactions, anxiety, and hyperactivity. We found that Cc2d1a and Cc2d1b have partially overlapping roles. Overall, loss of Cc2d1b is less severe than loss of Cc2d1a, only leading to cognitive deficits, while Cc2d1a/1b double heterozygous animals are similar to Cc2d1a-deficient mice. These results will help us better understand the deficits in individuals with CC2D1A mutations, suggesting that recessive CC2D1B mutations and trans-heterozygous CC2D1A and CC2D1B mutations could also contribute to the genetics of ID.

CC2D1B Coordinates ESCRT-III Activity during the Mitotic Reformation of the Nuclear Envelope

“…Furthermore, the loss of Lgd function drives the over-proliferation of the imaginal discs, a phenotype that can be rescued by the expression of human CC2D1A or CC2D1B, indicating a functional overlap between these proteins (Drusenheimer et al., 2015). This redundancy was also observed in mammal models, as double CC2D1A/CC2D1B knockout mice died early during embryonic development (Zamarbide et al., 2018), but the deletion of CC2D1A or CC2D1B genes alone does not induce developmental defects (Drusenheimer et al., 2015, Zamarbide et al., 2018). However, non-redundant roles of these proteins are indicated by the perinatal death of CC2D1A-deficient mice (Al-Tawashi et al., 2012, Drusenheimer et al., 2015, Zamarbide et al., 2018).…”

Conditional Deletion of CC2D1A Reduces Hippocampal Synaptic Plasticity and Impairs Cognitive Function through Rac1 Hyperactivation

“…Two recent studies have further shown that forebrain-specific Cc2d1a cKO mice display reduced memory retention in the novel object recognition and delayed learning in remembering the location of the platform once it was learned in the Morris water maze (Oaks et al, 2017;Zamarbide et al, 2018). In addition to cognitive deficits, we provide further evidence that cKO mice display altered anxiety-like behavior, as evidenced by measuring performance in the OF, EPM, and LDB tests, confirming that CC2D1A is critically involved in regulating anxious behavioral characteristics (Oaks et al, 2017;Zamarbide et al, 2018).…”

Gastrodin Rescues Autistic-Like Phenotypes in Valproic Acid-Induced Animal Model

“…Autism spectrum disorder (ASD) represents a neurodevelopmental disorder that is characterized by impaired social interaction, repetitive conduct and anxiety-like behaviors (1). Several brain structures and function have been suggested to underlie behavioral abnormalities of ASD including the basolateral amygdala (BLA) (2).…”