The genes implicated in autism thus far support the hypothesis that impaired neuronal connectivity may underlie autism pathogenesis. They also suggest that an imbalance between excitatory and inhibitory synapses — the junctions between neurons — during development may play a role in the disorder. Further knowledge of the protein and pathway interactions for the implicated genes is needed for a better understanding of the underlying pathogenic mechanisms of autism.

Individuals with autism have deficits in social and emotional learning. The amygdala, a region of the brain involved in orchestrating emotion and emotional memory, is affected in individuals with autism. The nature of the dysfunction is not well characterized, however. Eric Kandel, Yun-Beom Choi, Craig Bailey and their colleagues at Columbia University Medical Center aim to examine the role of an autism-implicated protein, neurexin, at synapses in the amygdala. They also plan to investigate how neurexin is involved in fear memory, a function that is associated with the amygdala.

Modifications in inhibition mediated by gamma-aminobutyric acid type A receptors (GABAAR) are continually implicated in the etiology of autism. GABAAR receptors mediate both phasic (transient) and tonic inhibition  (sustained) forms of chloride-ion-mediated neuronal inhibition. Duplications of and mutations within the receptor’s beta-3 subunit are strongly linked to autism. The functional expression of GABAARs is subject to regulation via phosphorylation of serine residues 408 and 409 within the beta-3 subunit, a covalent modification of protein structure that plays a key role in regulating GABAAR activity.

In most cases of autism, the cause is unknown. However, a number of rare syndromes caused by known genetic abnormalities include features of autism, and understanding the mechanism by which these syndromic forms develop may provide insight into autism more generally.

Although the clinical manifestations of autism spectrum disorders are highly variable and their underlying causes are still largely unknown, accumulating evidence implicates variations in genes encoding synaptic proteins, which function at the connections between brain cells. Altered synaptic proteins can lead to faulty wiring in the developing brain.

The development of brain cell connections, or synapses, occurs during the third trimester of gestation and throughout the first few years of life. Proper synaptic formation and brain wiring require a complex interaction between brain activity, usually driven by sensory experience, and genes.

The development of brain cell connections, or synapses, in humans occurs during the third trimester of prenatal life and throughout the first few years of life. Proper synaptic formation and brain wiring requires a complex interaction between brain activity, usually driven by sensory experience, and genes. Many of the genes whose mutations are linked to autism play a role in synapse formation or pruning during brain development. Some people with autism show an excess of synapses, consistent with a deficit in synaptic pruning. Synaptic pruning is a normal developmental process that results in the elimination of inappropriate or unused synapses.

CNTNAP2 is a gene that encodes a member of the neurexin family of proteins and has been implicated in autism spectrum disorders. Neurexins function in the vertebrate nervous system as cell adhesion molecules and receptors. CNTNAP2 is expressed in the region where precursor cells of the neocortex (the outer layer of the brain) originate during embryogenesis, suggesting that it has a role in regulating neural stem cells.

Autism is a syndrome with many causes. David Sulzer and his colleagues at Columbia University examined their new hypothesis that some of these processes converge during a developmental period from early childhood through adolescence when cortical synapses — the connections that provide for communication between neurons — lose approximately half of their overall density, a phenomenon known as ‘synaptic pruning.’