Session 4: Neurotransmitters Systems in Autism

Timothy M. DeLorey, Ph.D.
Molecular Research Institute, Mountain View CA

¡-Aminobutyric acid type A (GABAA) receptors are ligand-gated chloride channels that mediate rapid inhibitory neurotransmission. These receptors are heteromeric structures assembled from a repertoire of approximately 20 subunit isoforms. Recently, chromosome 15q11-13 has been implicated as one of the regions potentially associated with autism. This region contains a cluster of GABAA receptor subunit genes including gabrb3, gabra5 and gabrg3 (encoding the subunits ß₃, a₅, and ¡₃ respectively). Targeted disruption of one of these genes in mouse, the gabrb3 gene, results in homozygous knockout mice with approximately 50% reduction in GABAA receptor binding in neonatal and adult brain. Consequently, these mice exhibit impaired GABA function in isolated dorsal root ganglia (Homanics et al., 1997), cultured hippocampal neurons (Krasowski et al., 1998), and the thalamic reticular nucleus (Huntsman et al., 1999). Interestingly, these knockout mice exhibit behavioral features common to autism including seizures, learning and memory deficits, repetitive behavior, hyperactivity, and a disturbed rest-activity cycle (DeLorey et al., 1998). The above findings taken together suggest that the gabrb3 knockout mouse could share common etiological elements with autism. Further investigation into this potential association is clearly warranted.

Homanics et al., (1997) PNAS 94:4143-4148.
Krasowski et al., (1998) Neurosci.Lett 240:81-84.
DeLorey et al., (1998) J.Neurosci., 18:8505-8514.
Huntsman et al., (1999) Science 283:541-3.

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