Postnatal GAD67 ablation in a subset of corticolimbic interneurons confers a negative symptoms-like phenotype

Wednesday, October 26, 2011 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center	NIMH	NEURO/BEHAV/SENSYS-16

Authors

• S Kolata
• G Rompala
• Z Jiang
• K Nakao
• DA Paredes
• K Nakazawa

Abstract

Negative symptoms are characterized as a deficit in “normal” functioning, e.g. anhedonia, lack of motivation, and social withdrawal. These features, especially anhedonia, are shared by several neuropsychiatric disorders including major depression. While the underlying neurobiological dysfunctions are not well characterized, growing evidence suggest that a cortical/ subcortical imbalance of excitation and inhibition may be important. To that end, we generated and characterized a novel transgenic mouse line in which Gad67, the enzyme responsible for 95% of GABA production, was ablated following postnatal day 7 selectively in ~50% of cortical and hippocampal interneurons. In the homozygous mice, the number of cortical GABA-containing interneuron somas was significantly reduced. No behavioral abnormalities were detected in heterozygous Gad1 KO mutants. In contrast, in the homozygous mice this manipulation recapitulated a number of features common to negative symptoms including anhedonia, a lack of motivated behavior, and pronounced social withdrawal. However, there were no impairments in tests of behavioral despair. Perhaps consistent with this behavioral phenotype, in the nucleus accumbens baseline dopamine was elevated while amphetamine-evoked dopamine release was attenuated. In all, these results suggest that there is a strong relationship between negative-like symptoms and impaired subcortical dopamine regulation as a consequence of reduced corticolimibic GABA.

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