Cc2d1a Loss of Function Disrupts Functional and Morphological Development in Forebrain Neurons Leading to Cognitive and Social Deficits

Adam W. Oaks, Marta Zamarbide, Dimira E. Tambunan, Emanuela Santini, Stefania Di Costanzo, Heather L. Pond, Mark W. Johnson, Jeff Lin, Dilenny M. Gonzalez, Jessica F. Boehler, Guangying K. Wu, Eric Klann, Christopher A. Walsh, M. Chiara Manzini

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1670-1685
Number of pages16
JournalCerebral cortex (New York, N.Y. : 1991)
Volume27
Issue number2
DOIs
StatePublished - Feb 1 2017

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Calcium-Calmodulin-Dependent Protein Kinase Type 2
Prosencephalon
Neurons
Nestin
Grooming
Dendritic Spines
Calcium-Calmodulin-Dependent Protein Kinases
Mutation
Neuronal Plasticity
Dendrites
Knockout Mice
Intellectual Disability
Cause of Death
Anatomy
Seizures
Anxiety
Alleles
Parturition
Organizations
Phenotype

Keywords

  • autism
  • cognitive development
  • dendritic spines
  • intellectual disability
  • long-term plasticity

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience

Cite this

Cc2d1a Loss of Function Disrupts Functional and Morphological Development in Forebrain Neurons Leading to Cognitive and Social Deficits. / Oaks, Adam W.; Zamarbide, Marta; Tambunan, Dimira E.; Santini, Emanuela; Di Costanzo, Stefania; Pond, Heather L.; Johnson, Mark W.; Lin, Jeff; Gonzalez, Dilenny M.; Boehler, Jessica F.; Wu, Guangying K.; Klann, Eric; Walsh, Christopher A.; Manzini, M. Chiara.

In: Cerebral cortex (New York, N.Y. : 1991), Vol. 27, No. 2, 01.02.2017, p. 1670-1685.

Research output: Contribution to journalArticle

Oaks, AW, Zamarbide, M, Tambunan, DE, Santini, E, Di Costanzo, S, Pond, HL, Johnson, MW, Lin, J, Gonzalez, DM, Boehler, JF, Wu, GK, Klann, E, Walsh, CA & Manzini, MC 2017, 'Cc2d1a Loss of Function Disrupts Functional and Morphological Development in Forebrain Neurons Leading to Cognitive and Social Deficits', Cerebral cortex (New York, N.Y. : 1991), vol. 27, no. 2, pp. 1670-1685. https://doi.org/10.1093/cercor/bhw009
Oaks, Adam W. ; Zamarbide, Marta ; Tambunan, Dimira E. ; Santini, Emanuela ; Di Costanzo, Stefania ; Pond, Heather L. ; Johnson, Mark W. ; Lin, Jeff ; Gonzalez, Dilenny M. ; Boehler, Jessica F. ; Wu, Guangying K. ; Klann, Eric ; Walsh, Christopher A. ; Manzini, M. Chiara. / Cc2d1a Loss of Function Disrupts Functional and Morphological Development in Forebrain Neurons Leading to Cognitive and Social Deficits. In: Cerebral cortex (New York, N.Y. : 1991). 2017 ; Vol. 27, No. 2. pp. 1670-1685.
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