Cognitive deficits are major disabling impairments associated with autism and schizophrenia. Because the underlying genetic and cellular mechanisms of such deficits are still poorly understood, mechanism-based therapeutic options do not exist, limiting the effective integration of patients into society. Previous clinical work has shown that executive functions such as working memory and cognitive flexibility start to lag behind from adolescence 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 identified two genes encoded in copy number variants (CNVs) at human chromosome 22q11.2, a high-risk factor for autism 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 to adulthood and that constitutively elevated activity of catechol-O-methyl-transferase (COMT) impairs the working memory of mice during adulthood, but not adolescence. During the previous funding period, we have further found that over-expression of COMT and the transcription factor TBX1, another 22q11.2 gene, in adult neural progenitor cells of the hippocampus recapitulates this age-dependent deficit in working memory capacity. The objective of the proposed project is to test our overarching hypothesis that dose alterations of CNV-encoded genes impair the developmental maturation of executive function through defective adult neurogenesis 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-associated CNV genes whose dose alterations affect adult neurogenesis and executive function. Our experimental readouts include executive function and adult neurogenesis. Upon completion of the proposed studies, these technically innovative experiments will, for the first time, establish a common cellular mechanism through which altered doses of autism- and schizophrenia-associated genes impair the developmental maturation of executive function. Identification of the developmental time window, neuroanatomical region(s), and cellular subtypes necessary for maturation of executive function will have a major impact on our understanding of the developmental mechanisms of executive function and its derailed trajectories. This proposal could lead to a better understanding of the neurobiological substrates for an important dimensional aspect of developmental neuropsychiatric disorders.

Public Health Relevance

Cognitive impairments are a major obstacle to integration into society for individuals with autism spectrum disorder and schizophrenia. The proposed studies will test the innovative concept that altered neurogenesis in the adolescent and adult brain impairs the developmental maturation of cognitive capacity. The outcome of the proposed studies will provide a solid foundation to more fully understand the mechanisms for developmental cognitive impairments seen in the neuropsychiatric disorders and to develop mechanism-based treatment options.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH099660-05
Application #
9386738
Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
Program Officer
Buhring, Bettina D
Project Start
2013-01-18
Project End
2021-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine, Inc
Department
Type
DUNS #
079783367
City
Bronx
State
NY
Country
United States
Zip Code
10461
Ó Broin, Pilib; Beckert, Michael V; Takahashi, Tomohisa et al. (2018) Computational Analysis of Neonatal Mouse Ultrasonic Vocalization. Curr Protoc Mouse Biol 8:e46
Hiroi, Noboru (2018) Critical reappraisal of mechanistic links of copy number variants to dimensional constructs of neuropsychiatric disorders in mouse models. Psychiatry Clin Neurosci 72:301-321
Boku, S; Izumi, T; Abe, S et al. (2018) Copy number elevation of 22q11.2 genes arrests the developmental maturation of working memory capacity and adult hippocampal neurogenesis. Mol Psychiatry 23:985-992
Solís, Oscar; García-Montes, Jose-Rubén; Garcia-Sanz, Patricia et al. (2017) Human COMT over-expression confers a heightened susceptibility to dyskinesia in mice. Neurobiol Dis 102:133-139
Esposito, Gianluca; Hiroi, Noboru; Scattoni, Maria Luisa (2017) Cry, baby, cry: Expression of Distress as a Biomarker and Modulator in Autism Spectrum Disorder. Int J Neuropsychopharmacol :
Kikusui, Takefumi; Hiroi, Noboru (2017) A Self-Generated Environmental Factor as a Potential Contributor to Atypical Early Social Communication in Autism. Neuropsychopharmacology 42:378
Takahashi, T; Okabe, S; Broin, P Ó et al. (2016) Structure and function of neonatal social communication in a genetic mouse model of autism. Mol Psychiatry 21:1208-14
Boku, Shuken; Toda, Hiroyuki; Nakagawa, Shin et al. (2015) Neonatal maternal separation alters the capacity of adult neural precursor cells to differentiate into neurons via methylation of retinoic acid receptor gene promoter. Biol Psychiatry 77:335-44
Hiroi, Noboru (2014) Small cracks in the dam: rare genetic variants provide opportunities to delve into mechanisms of neuropsychiatric disorders. Biol Psychiatry 76:91-2
Hiroi, N; Takahashi, T; Hishimoto, A et al. (2013) Copy number variation at 22q11.2: from rare variants to common mechanisms of developmental neuropsychiatric disorders. Mol Psychiatry 18:1153-65