Our understanding of many aspects of ASD biology has come from studying single gene disorders that have a high incidence of autism, such as Fragile X, Tuberous Sclerosis and Rett Syndrome (see also iPSC Top 10 story). Based on these types of studies, a current theory posits that autism is associated with over-excitation in the brain. The proper balance between excitation and inhibition in the brain is critical for normal function. Previous research has revealed that there is often too much of the excitatory neurotransmitter, glutamate, released between communicating neurons, causing overexcitation in local networks.
This November, in the journal Nature, Huda Zoghbi, M.D. and colleagues showed that a dearth of an inhibitory transmitter, GABA, in a new animal model also leads to over-excitability in neuron networks.1 Too little GABA in the network of neurons is somewhat like having faulty breaks in a car. In the mouse model, the over-excitability of the circuit leads to the repetitive behaviors associated with Rett syndrome. Obsessive hand-wringing behavior is a classic symptom of girls with Rett syndrome. In the mouse these symptoms include over-grooming and paw-clasping.
The traditional model for studying Rett syndrome is a mouse that is carrying an ineffective copy of the gene MeCP2. The Zoghbi lab research, led by postdoctoral fellow Hsiao-Tuan Chao, used a twist on this approach. Using molecular tools, the research team removed MeCP2 from specific cell types in the brain, in this case only cells that released GABA. The results were surprising. First, MeCP2 was found in great quantities in neurons that released GABA. Second, MeCP2 was shown to have a previously undiscovered role in producing GABA, as seen by a 30 percent drop in GABA measured when MeCP2 was “knocked-out”. Third, although the knock-out was restricted to only cells containing GABA, these mice mirrored most of the autism-like symptoms observed in girls with Rett syndrome.
The GABA-specific MeCP2 mutation was also made brain-region specific, so only parts of the brain would have the mutation. Although removing MeCP2 from all GABA-producing cells led to the late-stage breathing abnormalities and premature death that is unfortunately common in Rett syndrome, restriction of the MeCP2 knockout to GABA-producing cells in the front of brain resulted only in the types of behavioral symptoms familiar to autism.
The demonstration that MeCP2 is involved in the production of GABA is a new finding with great implications. “These findings reveal for perhaps the first time that subtle impairments in the function of GABA-releasing neurons, from any of a variety of causes, could lead to neuropsychiatric disorders like autism,” said Dr. Chao. Importantly, identification of a biological pathway opens the doors for treatment possibilities and drawing links to treatments that are already in the testing pipeline.