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Cc2d1a Loss of Function Disrupts Functional and Morphological Development in Forebrain Neurons Leading to Cognitive
Adam W Oaks1, Marta Zamarbide1, Dimira E Tambunan2,3
1Department of Pharmacology and Physiology and Integrative Systems Biology, The George Washington University School of Medicine and Health Sciences, Washington, DC 20037, USA.
Abstract:
Loss-of-function (LOF) mutations in CC2D1A cause a spectrum of neurodevelopmental disorders, including intellectual disability, autism spectrum disorder, and seizures, identifying a critical role for this gene in cognitive and social development. CC2D1A regulates intracellular signaling processes that are critical for neuronal function, but previous attempts to model the human LOF phenotypes have been prevented by perinatal lethality in Cc2d1a-deficient mice. To overcome this challenge, we generated a floxed Cc2d1a allele for conditional removal of Cc2d1a in the brain using Cre recombinase. While removal of Cc2d1a in neuronal progenitors using Cre expressed from the Nestin promoter still causes death at birth, conditional postnatal removal of Cc2d1a in the forebrain via calcium/calmodulin-dependent protein kinase II-alpha (CamKIIa) promoter-driven Cre generates animals that are viable and fertile with grossly normal anatomy. Analysis of neuronal morphology identified abnormal cortical dendrite organization and a reduction in dendritic spine density. These animals display deficits in neuronal plasticity and in spatial learning and memory that are accompanied by reduced sociability, hyperactivity, anxiety, and excessive grooming. Cc2d1a conditional knockout mice therefore recapitulate features of both cognitive and social impairment caused by human CC2D1A mutation, and represent a model that could provide much needed insights into the developmental mechanisms underlying nonsyndromic neurodevelopmental disorders.
Insights
Loss-of-function mutations in CC2D1A cause neurodevelopmental disorders. Conditional knockout mice lacking CC2D1A in the forebrain exhibit cognitive and social deficits, providing a new model for studying these conditions.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Loss-of-function (LOF) mutations in CC2D1A are linked to neurodevelopmental disorders, including intellectual disability and autism spectrum disorder.
- CC2D1A plays a crucial role in neuronal function and cognitive and social development.
- Previous mouse models of CC2D1A LOF were lethal perinatally, hindering study of its role in adult brain function.
Purpose of the Study:
- To develop a conditional mouse model for studying CC2D1A's role in neurodevelopment.
- To investigate the impact of CC2D1A deficiency in the adult brain on cognitive and social behaviors.
Main Methods:
- Generated a floxed Cc2d1a allele for conditional gene knockout.
- Utilized Cre-lox system with CamKIIa promoter for postnatal forebrain-specific deletion of Cc2d1a.
- Assessed neuronal morphology, plasticity, spatial learning, memory, sociability, hyperactivity, and anxiety in knockout mice.
Main Results:
- Conditional postnatal deletion of Cc2d1a in the forebrain resulted in viable and fertile mice.
- Mice exhibited abnormal cortical dendrite organization and reduced dendritic spine density.
- Deficits in neuronal plasticity, spatial learning, and memory were observed, alongside reduced sociability, hyperactivity, anxiety, and excessive grooming.
Conclusions:
- Conditional knockout mice lacking Cc2d1a in the forebrain successfully model key features of human CC2D1A-associated neurodevelopmental disorders.
- This model provides a valuable tool for understanding the mechanisms underlying cognitive and social impairments in nonsyndromic neurodevelopmental disorders.
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