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

Abstract

Coiled-coil and C2 domain containing 1A (CC2D1A) is an evolutionarily conserved protein, originally identified as a nuclear factor-B activator through a large-scale screen of human genes. Mutations in the human Cc2d1a gene result in autosomal recessive nonsyndromic intellectual disability. It remains unclear, however, how Cc2d1a mutation leads to alterations in brain function. Here, we have taken advantage of Cre/loxP recombinase-based strategy to conditionally delete Cc2d1a exclusively from excitatory neurons of male mouse forebrain to examine its role in hippocampal synaptic plasticity and cognitive function. We confirmed the expression of CC2D1A protein and mRNA in the mouse hippocampus. Double immunofluorescence staining showed that CC2D1A is expressed in both excitatory and inhibitory neurons of the adult hippocampus. Conditional deletion of Cc2d1a (cKO) from excitatory neurons leads to impaired performance in object location memory test and altered anxiety-like behavior. Consistently, cKO mice displayed a deficit in the maintenance of LTP in the CA1 region of hippocampal slices. Cc2d1a deletion also resulted in decreased complexity of apical and basal dendritic arbors of CA1 pyramidal neurons. An enhanced basal Rac1 activity was observed following Cc2d1a deletion, and this enhancement was mediated by reduced SUMO-specific protease 1 (SENP1) and SENP3 expression, thus increasing the amount of Rac1 SUMOylation. Furthermore, partial blockade of Rac1 activity rescued impairments in LTP and object location memory performance in cKO mice. Together, our results implicate Rac1 hyperactivity in synaptic plasticity and cognitive deficits observed in Cc2d1a cKO mice and reveal a novel role for CC2D1A in regulating hippocampal synaptic function.

Ubiquitin and Ubiquitin-Like Proteins in the Critical Equilibrium between Synapse Physiology and Intellectual Disability

“…Since RAC1 activity is enhanced by sumoylation, hyperactived RAC1 results in abnormal dendritic morphology and synaptic dysfunction. Remarkably, pharmacological blockade of RAC1 activity partially rescues deficits in synaptic plasticity and memory observed in Cc2d1a-cKO mice (Yang et al, 2019). In conclusion, this work provides further experimental evidence supporting the hypothesis that aberrant sumoylation is a key molecular determinant underlying ID etiology.…”

“…Mutations in the Coiled-coil and C2 domain containing 1A (CC2D1A) gene are associated with non-syndromic ID (OMIM 608443). This gene codes for CC2D1A, a DNA binding protein that regulates multiple cellular signaling pathways, including serotonin and dopamine receptors, dendritic arborization, synapse maturation, and plasticity (Zhao et al, 2011;Al-Tawashi et al, 2012;Manzini et al, 2014;Oaks et al, 2017;Yang et al, 2019). Consistent with these roles, the loss of CC2D1A in vivo determines the appearance of cognitive and social deficits (Oaks et al, 2017).…”

“…Very recently, it was shown that conditional deletion of Cc2d1a in excitatory neurons of the forebrain leads to decreased levels of SENP1 and SENP3. As a consequence, the desumoylation of the small GTPase RAC1, one of the major targets of SENP1 and SENP3, is suppressed (Yang et al, 2019). Since RAC1 activity is enhanced by sumoylation, hyperactived RAC1 results in abnormal dendritic morphology and synaptic dysfunction.…”

Digging behavior discrimination test to probe burrowing and exploratory digging in male and female mice

“…The impetus for developing a novel digging paradigm originated from previous studies of a mouse model for ID and ASD, where the Cc2d1a gene is conditionally removed in the cortex and hippocampus, the Cc2d1a cKO (Oaks et al, 2017;Yang et al, 2019). While these mice showed hyperactivity and obsessive grooming in addition to cognitive and social deficits (Oaks et al, 2017;Yang et al, 2019), reduced digging activity was identified in the marble burying test with no change in marble number (Oaks et al, 2017). We found the DBD test to be more sensitive in defining digging changes with a decrease in burrowing and a trend towards increased exploratory digging in male cKO mice.…”

Molecular causes of sex‐specific deficits in rodent models of neurodevelopmental disorders

“…Global loss of Cc2d1a in the mouse does not appear to grossly affect development, but causes early postnatal lethality through respiratory and swallowing deficits (Oaks et al, 2017;Zhao, Li, & Chen, 2010;Zhao, Raingo, Chen, & Kavalali, 2011). Postnatal removal of Cc2d1a in the forebrain, bypasses early lethality and behavioral analysis in male mice recapitulates several features of ASD and ID including cognitive and social deficits, hyperactivity, increased anxiety-like behaviors and obsessive grooming (Oaks et al, 2017;Yang, Yu, Wen, Ling, & Hsu, 2019 -Tawashi et al, 2012) and cAMP response element-binding protein (CREB), a transcription factor critical for spatial memory formation ( Figure 3) (Alberini, 2009;Kandel, 2012;Ortega-Martínez, 2015;Sekeres, Neve, Frankland, & Josselyn, 2010).…”