Neuroscience 2005 Abstract
| Presentation Number: | 1021.2 |
|---|---|
| Abstract Title: | Overexpression of Gαs in mice leads to biochemical, structural, and cognitive deficits associated with Schizophrenia and Tourette's syndrome. |
| Authors: |
Kelly, M. P.*1,2
; Esposito, M. F.1
; Tokarczyk, J.2
; Siegel, S. J.2
; Kanes, S. J.2
; Abel, T.1
1Dept Biol, Univ. of Pennsylvania, Philadelphia, PA 2Dept Psychiatry, Univ. of Pennsylvania, Philadelphia, PA |
| Primary Theme and Topics |
Disorders of the Nervous System - Cognitive, Emotional and Behavioral State Disorders -- Schizophrenia: Animal models |
| Secondary Theme and Topics | Cognition and Behavior<br />- Animal Cognition and Behavior<br />-- Cognitive learning and memory systems |
| Session: |
1021. Schizophrenia: Genetic Models Poster |
| Presentation Time: | Wednesday, November 16, 2005 2:00 PM-3:00 PM |
| Location: | Washington Convention Center - Hall A-C, Board # UU10 |
| Keywords: | CYCLIC AMP, PREPULSE INHIBITION, G PROTEIN, CORTEX |
Several neurotransmitter systems, including dopamine, serotonin, and glutamate, have been implicated in the etiology of schizophrenia and Tourette’s Syndrome, suggesting that a downstream mechanism common to each of these neurotransmitters may ultimately underlie these psychiatric disorders. We have developed mice in which the tetracycline system drives overexpression (within postnatal forebrain neurons) of the G-protein subunit Gαs, which couples receptors to stimulation of the cAMP cascade. Gαs mice show increased cAMP levels in striatum, but decreased cAMP in cortex and hippocampus. Gαs mice also exhibit enlarged ventricles (see MF Esposito et al., 2005, SFN abstract). Behaviorally, Gαs mice exhibit intact procedural learning but reduced sensorimotor gating, impaired hippocampus-dependent learning/memory, and hyperlocomotion. Importantly, cAMP and behavioral deficits of these mice reverse with suppression of transgene expression by doxycycline. Further, the phosphodiesterase inhibitor rolipram (0.66 mg/kg), which increases cAMP levels, or the antipsychotic haloperidol (1.0 mg/kg) rescues the sensorimotor gating deficits of these mice, the latter of which is due to a selective rescue of cAMP levels in temporal cortex. Future experiments will determine whether the decrease in cortical cAMP levels is due to decreased synthesis or increased degradation, whether the memory deficits are due to impaired acquisition and/or retrieval, and if these mice show alterations in expression of the immediate-early gene Arc (activity-regulated cytoskeleton-associated protein), which is key to plasticity and memory. In summary, our data suggest that deficits in cAMP signaling may contribute to endophenotypes associated with schizophrenia and Tourette’s Syndrome and that drugs that increase cAMP intracellularly may prove valuable as a novel class of antipsychotics.
Supported by NIH; Tourette’s Syndrome Association; Merck, Whitehall, and Packard Foundations
Sample Citation:
[Authors]. [Abstract Title]. Program No. XXX.XX. 2005 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2005. Online.
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