Variations in GABA-Related Genes Increase Brain Excitability in Autism Spectrum Disorders
People with Autism Spectrum Disorders (ASDs) often also have epilepsy, a neurological condition featuring uncontrollable, spontaneous seizures. This provides a clue that genes associated with ASD are likely to encode proteins important for maintaining brain stability. In fact, scientists have discovered a strong association between ASD and one such family of proteins: receptors for GABA (gamma-amino butyric acid), an inhibitory neurotransmitter that usually keeps brain excitation in check.
Most synapses in the brain are excitatory, inducing a positive electrical charge in another neuron. However, if every synapse in the brain were excitatory, brain activity would escalate to uncontrollable levels, as in seizures. To prevent this, a fraction of synapses in the brain are inhibitory, meaning that they induce a negative electrical charge in another neuron.
GABA is the major inhibitory neurotransmitter in the brain. It essentially acts as a brake for brain activation. Several aspects of GABA regulation have been linked to ASD, from early brain development to adult brain function.
Variations in GABA receptor subunits have been strongly associated with ASD. GABA receptors come in two major forms: fast, “ionotropic” GABAA receptors let negatively charged chloride ions flow into the neuron, and slow, “metabotropic” GABAB receptors produce chemical messages inside the neuron. GABAA receptors, the most common form in the brain, contain five subunits that shape their properties. Genome-wide association studies have linked the GABAA receptor subunit genes GABRA4 (α4 subunit), GABRB1 (β1 subunit), and GABRB3 (β3 subunit) to autism. In addition, deletion of a chromosomal region that contains a cluster of a variety of GABA receptor genes (region 15q11-13) causes Angelman Syndrome.
Genes controlling the development of GABA-releasing neurons have also been associated with ASD. Autism-linked variations in the ARX and DLX family of transcription factors interfere with proper expression of GABA. Absence of such GABA-releasing neurons would negatively affect early brain development as well as adult brain stability.
Notably, variations in other ASD-linked genes affect GABA signaling. New evidence shows that the gene MECP2, the mutation of which causes Rett Syndrome, is critical for normal function of GABA-releasing neurons. When MECP2 expression was blocked in GABAergic neurons of mice, GABA expression and release were reduced and the mice exhibited autistic behaviors.
ASD is a complex disorder that is likely to be caused by a combination of mutations in a variety of genes. GABA receptors are a promising therapeutic target because of their important role in monitoring brain excitation. Identification and exploration of autism-linked mutations in other GABA-related genes could shed light on the pathogenesis of autism.
Catherine Croft Swanwick, Ph.D.
Originally written June 23, 2010 Last updated September 29, 2011 by Catherine Croft Swanwick, Ph.D.