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Conditional Deletion of CC2D1A Reduces Hippocampal Synaptic Plasticity and Impairs Cognitive Function through Rac1 Hyperactivation
Ist Teil von
The Journal of neuroscience, 2019-06, Vol.39 (25), p.4959-4975
Ort / Verlag
United States: Society for Neuroscience
Erscheinungsjahr
2019
Link zum Volltext
Quelle
EZB Free E-Journals
Beschreibungen/Notizen
Coiled-coil and C2 domain containing 1A (CC2D1A) is an evolutionarily conserved protein, originally identified as a nuclear factor-κB activator through a large-scale screen of human genes. Mutations in the human
gene result in autosomal recessive nonsyndromic intellectual disability. It remains unclear, however, how
mutation leads to alterations in brain function. Here, we have taken advantage of Cre/loxP recombinase-based strategy to conditionally delete
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
(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.
deletion also resulted in decreased complexity of apical and basal dendritic arbors of CA1 pyramidal neurons. An enhanced basal Rac1 activity was observed following
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
cKO mice and reveal a novel role for CC2D1A in regulating hippocampal synaptic function.
CC2D1A is abundantly expressed in the brain, but there is little known about its physiological function. Taking advantage of
cKO mice, the present study highlights the importance of CC2D1A in the maintenance of LTP at Schaffer collateral-CA1 synapses and the formation of hippocampus-dependent long-term object location memory. Our findings establish a critical link between elevated Rac1 activity, structural and synaptic plasticity alterations, and cognitive impairment caused by
deletion. Moreover, partial blockade of Rac1 activity rescues synaptic plasticity and memory deficits in
cKO mice. Such insights may have implications for the utility of Rac1 inhibitors in the treatment of intellectual disability caused by
mutations in human patients.