Autism, the Brain’s Frontal Lobes, and the CNTNAP2 Gene

Recent studies on the genetics of childhood psychiatric diseases have resulted in a long list of candidate genes that may contribute to the risk of autism spectrum disorders (see my earlier blog post “Genetics of Autism: Challenging Psychiatric Classifications“). A common genetic variation in the contactin-associated protein-like 2 (CNTNAP2) gene is a strong candidate for risk of autism and other disorders including Tourette syndrome, obsessive compulsive disorder, and epilepsy. CNTNAP2 has been shown to affect language ability and is associated in autism with specific language impairment.

Anatomical studies have shown that CNTNAP2 messenger RNA (mRNA) is significantly enriched in the frontal and temporal lobes of the developing human brain. CNTNAP2 is involved in clustering voltage-gated potassium channels (Kv1.1) at the nodes of Ranvier. During development, Caspr2, the protein encoded by CNTNAP2, is thought to assist in interactions important for cellular migration and subsequent laminar organization, indicating a role for CNTNAP2 in the construction of neural circuits.

The authors of the new paper “Altered Functional Connectivity in Frontal Lobe Circuits Is Associated with Variation in the Autism Risk Gene CNTNAP2” published November 3, 2010 in Science Translational Medicine set out to test if a variation at the CNTNAP2 gene would predispose a person to cognitive dysfunction due to changes in typical frontal lobe neural activity and functional connectivity.

The research team scanned the brains of 32 children using functional magnetic resonance imaging (fMRI). Half of the participants were diagnosed with autism and the other half had no known psychiatric disorders. The participants performed a learning task during the brain scans.

The researchers investigated the brain areas and connections affected by the rs2710102 allele (in the CNTNAP2 gene), which is known to confer the risk of autism on carriers. Interestingly, the frequency of the risk genotype was similar between the typically developing and the autism groups so they collapsed the data across groups and investigated the appearance of the risk variant and associated differences in brain function.

Those without the risk allele showed stronger long-range anterior-posterior connectivity between the medial prefrontal cortex and the medial occipital and ventral temporal cortices. Brain imaging studies have shown that robust short range functional connections in the maturing human brain get progressively weaker and the sparser long range functional connections get progressively stronger (see my earlier blog post “Predicting Individual Brain Maturity from Functional Imaging“). These data suggest that those carrying the risk allele retain a more immature functional connectivity in certain areas of the cerebral cortex associated with language, sociability, and other cognitive skills.

The team also showed significantly reduced activity in the medial prefrontal cortex during the learning task in the group not carrying the risk allele. The medial prefrontal cortex is typically more active during rest than during externally directed attention. The team’s findings suggest that those carrying the risk allele process externally directed attention differently than those without the allele.

Other related blog posts:

Predicting Individual Brain Maturity from Functional Imaging

Genetics of Autism: Challenging Psychiatric Classifications

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