Dissertation/Thesis Abstract

The synaptic dynamics of working memory in a genetic model of psychosis
by Arguello, Paul Alexander, Ph.D., Columbia University, 2010, 109; 3400626
Abstract (Summary)

Psychiatric disorders are heterogeneous behavioral syndromes marked by significant cognitive impairments. These deficits are particularly prominent in psychotic disorders, are especially severe in schizophrenia and reflect underlying genetic liability. In light of recent successes and failures, psychiatric genetics is currently at a crossroads concerning how to efficiently identify causal genetic factors and how to translate these findings into meaningful insights for disease prevention and treatment. Clearly, teasing apart the contribution of genetic variants to neural development and function, and ultimately disease risk, necessitates the use of model systems.

We describe a mutant mouse model engineered to carry an allele mimicking a cytogenetic abnormality, t(1;11)(q42.1;q14.3), found to segregate with schizophrenia, major depression and bipolar disorder in a large family. This mutation disrupts DISC1, a protein involved in cellular proliferation, migration and signaling. Surprisingly, mutant Disc1 mice show selective behavioral deficits in tasks measuring working memory: the ability to transiently and flexible hold information in mind to guide behavior, a cognitive process closely linked to the functional integrity of prefrontal cortex. Synaptic transmission in prefrontal cortex is characterized by strongly facilitating synapses that may allow cortical networks to robustly maintain information during working memory. Recordings from prefrontal cortical slices of mutant animals reveal aberrant short-term changes in synaptic dynamics that are restricted to inputs from superficial layers, the target of top-down control underlying many higher-order cognitive process. Mathematical modeling indicates that in mutant animals these synapses do not readily maintain a transient facilitating state that occurs with each nerve impulse.

This model provides the opportunity to bridge the gap between a clear genetic risk factor and a disease relevant phenotype perhaps through the synaptic dynamics of prefrontal cortical circuits. Future work is needed to investigate whether such synaptic changes underlie the behavioral deficits observed in mutant animals and whether such changes might be common to other models of rare mutations associated with the disease. Such an approach in general will likely help weave together genetic, neural and cognitive elements of brain function into a better understanding of mental illness.

Indexing (document details)
Advisor: Gogos, Joseph
School: Columbia University
School Location: United States -- New York
Source: DAI-B 71/03, Dissertation Abstracts International
Subjects: Neurosciences, Mental health, Genetics
Keywords: Prefrontal cortex, Psychosis, Schizophrenia, Working memory
Publication Number: 3400626
ISBN: 978-1-109-67312-8
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