GENETIC DISRUPTION OF THE AUTISM SPECTRUM DISORDER RISK GENE PLAUR INDUCES GABAA RECEPTOR SUBUNIT CHANGES

K. L. EAGLESON; M. C. GRAVIELLE; L. J. SCHLUETER MCFADYEN-KETCHUM; S. J. RUSSEK; D. H. FARB; P. LEVITT

NEUROSCIENCE

Elsevier

Lugar: New York; Año: 2010 vol. 168 p. 797 - 810

0306-4522

Disruption of the GABAergic system has been implicated in multiple developmental disorders, including epilepsy, autism spectrum disorder and schizophrenia. The uPAR-/- mouse has a regionally selective reduction in GABAergic interneurons in frontal and parietal regions of the cerebral cortex, as well as in the CA1 and dentate gyrus subfields of the hippocampus. Behaviorally, these mice exhibit an increased sensitivity to pharmacologically-induced convulsions, heightened anxiety and atypical social behavior. Recently, the human gene encoding uPAR (PLAUR), has been associated with autism risk. Here, we explored potential alterations in GABAergic circuitry that may occur in the context of altered interneuron development. Analysis of gene expression for 13 GABAA receptor subunits, using real-time PCR, indicated seven subunit mRNAs (a1, a2, a3, b2, b3,g 2S and g2L) of interest. Semi-quantitative in situ hybridization analysis focusing on these subunit mRNAs revealed a complex pattern of potential gene regulatory adaptations. The levels of a2 subunit mRNAs were increased in frontal cortex, CA1 and CA3, while those of a3 were decreased in frontal cortex and CA1. In contrast, a1 subunit mRNAs were unaltered in any region examined. There was an increase in the levels of b2 subunit mRNAs in frontal cortex, and reduced levels of b3 subunit mRNAs in parietal cortex. Finally, g2S subunit mRNAs were increased in parietal cortex, while g2L subunit mRNAs were increased in the dentate gyrus, thus potentially altering the g2s/g2L ratio in these two regions. For all subunits, no changes were observed in forebrain regions where GABAergic interneuron numbers are normal. We hypothesize that the potential changes in subunit composition occur as an adaptive response to decreased levels of GABA and establish a rationale for future electrophysiology studies to determine alterations in network activity in the cortex and hippocampus.