A new paper reports on research where they used genetic engineering to disrupt the function of GABA neurons, which resulted in the display of behaviors observed in numerous psychiatric disorders including Rett syndrome, bipolar disorder, autism, and juvenile-onset schizophrenia.
Note: Please see “Background” below for those desiring brief background information on neurons, GABA, and a few other key concepts.
The paper is titled “Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes” and was published November 11, 2010 in Nature.
Note: The paper is 7 pages long but has supplementary material that you must download separately. The supplementary material includes 66 pages of additional material contained in three pdf format files plus five movies.
Mutations in the MECP2 gene have been shown to cause behavior seen in psychiatric disorders including Rett syndrome, bipolar disorder, autism, and juvenile-onset schizophrenia. Among these, Rett syndrome is most commonly associated with this gene. Rett syndrome is characterized by apparently normal early development followed by regression, motor abnormalities, seizures and features of autism, especially stereotyped behaviors. Geneticly engineered mice that lack the MECP2 gene or have one of the mutations that have been shown to cause Rett syndrome show many of the same behaviors seen in humans with Rett syndrome.
The authors of the current paper explore the consequences of deleting the MECP2 gene from GABAergic neurons and demonstrate that subtle changes in the function of these neurons contributes to behavior changes seen in numerous psychiatric disorders and especially in Rett syndrome. Their geneticly engineered mice that lacked the MECP2 gene throughout the brain were indistinguishable from normal mice until they were about 5 weeks old. Then the mice began to exhibit repetitive behaviors reminiscent of mid-line hand-wringing that characterizes Rett syndrome. The authors also created mice that lacked the MECP2 gene in only a subset of forebrain GABAergic neurons. These mice showed repetitive behavior, impaired motor coordination, increased social interaction preference, reduced acoustic startle response, and enhanced prepulse inhibition.
Once the team demonstrated that their mice showed behaviors seen in humans diagnosed with Rett syndrome, they proceeded to investigate the biological mechanisms that may be causing the abnormal behaviors. They found that GABAergic neurons release smaller individual packets (quanta) of GABA neurotransmitter than normal. Everything else, including the number of packets released, appeared normal. This specific change in the function of GABAergic neurons seems to be the cause of the abnormal behaviors and also was shown by this team to impair a specific mechanism underlying learning and memory (long-term potentiation induced by theta-burst stimulation of Schaffer collateral synapses).
Background
Brain cells (neurons) send signals to and receive signals from other neurons. They communicate electrically by supporting electrical impulses known as action potentials. When an action potential reaches another neuron it sends a chemical to it through a special structure known as a synapse, which includes a very small space between the sending and receiving neurons. The chemical, known as a neurotransmitter, crosses the space in the synapse and binds to receptors on the receiving neuron where it influences electrical signaling. Some neurotransmitters increase the likelihood that the receiving neuron fires an action potential. These are known as excitatory neurotransmitters. Other neurotransmitters decrease the likelihood that the receiving neuron fires an action potential and are known as inhibitory neurotransmitters. GABA is an inhibitory neurotransmitter.
Other related blog posts:
Autism or Autism Trait in the Normal Population? The Crisis of Defining Normal
Genetics of Autism: Challenging Psychiatric Classifications
Schizophrenia and Bipolar Disorder Associated Differences in Brain Connections