Cognitive deficits are major disabling impairments associated with autism and schizophrenia. Because theunderlying genetic and cellular mechanisms of such deficits are still poorly understood, mechanism-basedtherapeutic options do not exist, limiting the effective integration of patients into society. Previous clinical workhas shown that executive functions such as working memory and cognitive flexibility start to lag behind fromadolescence to adulthood in individuals with autism and schizophrenia. However, the precise genetic,anatomical and cellular substrates through which this occurs are still poorly understood. We have identifiedtwo genes encoded in copy number variants (CNVs) at human chromosome 22q11.2, a high-risk factor forautism and schizophrenia, for which dose alterations impair the developmental maturation of working memory.Our published work shows that mice developmentally expand working memory capacity from adolescence toadulthood and that constitutively elevated activity of catechol-O-methyl-transferase (COMT) impairs theworking memory of mice during adulthood, but not adolescence. During the previous funding period, we havefurther found that over-expression of COMT and the transcription factor TBX1, another 22q11.2 gene, in adultneural progenitor cells of the hippocampus recapitulates this age-dependent deficit in working memorycapacity. The objective of the proposed project is to test our overarching hypothesis that dose alterations ofCNV-encoded genes impair the developmental maturation of executive function through defective adultneurogenesis in the hippocampus. To test this hypothesis, we developed experimental tools to regulate CNV-encoded genes in adult neural progenitor cells in the hippocampus at specific developmental time points.Moreover, we have established a screening system to identify other autism- and schizophrenia-associatedCNV genes whose dose alterations affect adult neurogenesis and executive function. Our experimentalreadouts include executive function and adult neurogenesis. Upon completion of the proposed studies, thesetechnically innovative experiments will, for the first time, establish a common cellular mechanism through whichaltered doses of autism- and schizophrenia-associated genes impair the developmental maturation ofexecutive function. Identification of the developmental time window, neuroanatomical region(s), and cellularsubtypes necessary for maturation of executive function will have a major impact on our understanding of thedevelopmental mechanisms of executive function and its derailed trajectories. This proposal could lead to abetter understanding of the neurobiological substrates for an important dimensional aspect of developmentalneuropsychiatric disorders.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
