Patients with schizophrenia typically suffer from severe and disabling cognitive function, including disturbances in executive function and working memory. To clarify the neurobiology underlying these disturbances, we have studied cognitive function in mouse lines engineered to model a microdeletion on chromosome 22, an etiologically relevant mutation unequivocally associated with susceptibility to schizophrenia. Patients with schizophrenia, as well as subjects with these mutations, have pronounced disturbances in cognitive tasks that depend on the hippocampus and prefrontal cortex. Mice carrying the microdeletion perform poorly in tests of spatial working memory. We have recently shown that deficits in functional connectivity between the hippocampus and prefrontal cortex contribute to this spatial working memory dysfunction in these mice. Building on these findings, we propose to (1) examine the molecular basis of these effects by studying working memory and hippocampal-prefrontal connectivity in mice carrying mutations of single genes within the microdeletion region;(2) study the role of the ventral hippocampus in the behavioral and physiological phenotypes in the mutants, and (3) study the role of the thalamus in these phenotypes. The proposed experiments serve both basic and translational goals. Understanding of the neurobiological mechanisms of working memory in the mouse is an important step in determining the relevance of such models to cognitive tasks studied in humans. Exploring these mechanisms in mice carrying schizophrenia-predisposing mutations uses this understanding to identify the behaviorally relevant neural consequences of these mutations. The end goal of this work is to develop an integrative model of schizophrenia pathogenesis and pathophysiology that demonstrates how these genetic lesions alter neural cells, circuits and systems to disrupt cognitive function.

Public Health Relevance

This proposal is inherently translational in nature, aimed at elucidating the neurobiological substrates of psychiatric disease. It is aimed at identifying specific patterns of abnormal brain structure and function caused by schizophrenia predisposing genes. Identifying such patterns would set the stage for a novel approach to therapies aimed at reversing the underlying pathophysiology and restoring normal function.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Meinecke, Douglas L
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Columbia University (N.Y.)
Schools of Medicine
New York
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Tamura, Makoto; Mukai, Jun; Gordon, Joshua A et al. (2016) Developmental Inhibition of Gsk3 Rescues Behavioral and Neurophysiological Deficits in a Mouse Model of Schizophrenia Predisposition. Neuron 89:1100-9
Crabtree, Gregg W; Park, Alan J; Gordon, Joshua A et al. (2016) Cytosolic Accumulation of L-Proline Disrupts GABA-Ergic Transmission through GAD Blockade. Cell Rep 17:570-582
Padilla-Coreano, Nancy; Bolkan, Scott S; Pierce, Georgia M et al. (2016) Direct Ventral Hippocampal-Prefrontal Input Is Required for Anxiety-Related Neural Activity and Behavior. Neuron 89:857-66
Canetta, S; Bolkan, S; Padilla-Coreano, N et al. (2016) Maternal immune activation leads to selective functional deficits in offspring parvalbumin interneurons. Mol Psychiatry 21:956-68
Spellman, Timothy; Rigotti, Mattia; Ahmari, Susanne E et al. (2015) Hippocampal-prefrontal input supports spatial encoding in working memory. Nature 522:309-14
Stujenske, Joseph M; Spellman, Timothy; Gordon, Joshua A (2015) Modeling the Spatiotemporal Dynamics of Light and Heat Propagation for In Vivo Optogenetics. Cell Rep 12:525-34
Harris, Alexander Z; Gordon, Joshua A (2015) Long-range neural synchrony in behavior. Annu Rev Neurosci 38:171-94
Mukai, Jun; Tamura, Makoto; Fénelon, Karine et al. (2015) Molecular substrates of altered axonal growth and brain connectivity in a mouse model of schizophrenia. Neuron 86:680-95
Rosen, Andrew M; Spellman, Timothy; Gordon, Joshua A (2015) Electrophysiological endophenotypes in rodent models of schizophrenia and psychosis. Biol Psychiatry 77:1041-9
Spellman, Timothy J; Gordon, Joshua A (2015) Synchrony in schizophrenia: a window into circuit-level pathophysiology. Curr Opin Neurobiol 30:17-23

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