Cortical Interneuronal Subtypes in Autism

Thursday, May 15, 2014
Atrium Ballroom (Marriott Marquis Atlanta)
V. Martinez Cerdeno, E. Hashemi and J. Ariza Torres, University of California, Davis, Sacramento, CA

Patients with autism exhibit altered cognitive function that is revealed in EEG recordings as an imbalance of excitation to inhibition in the cerebral cortex. The concept that increased excitation / inhibition underlies the autistic cognitive phenotype is supported by the high prevalence of epilepsy in patients with autism. In addition, mouse models with misexpression of Fmr1, MeCP2 or Neuroligin 3 genes exhibit cortical interneuron defects. Furthermore, mice lacking the Dlx1 gene have fewer cortical interneurons and have age-dependent seizures and deficits in fear conditioning that resemble those seen in autism. Imbalanced excitation / inhibition could result from multiple alterations of brain structure and/or function, including an alteration in the number or ratio of specific interneuron subtypes in the cerebral cortex. The majority of interneurons in the cerebral cortex can be classified in three major subtypes: parvalbumin+ (PV), calbindin+ (CB), or calretinin+ (CR) interneurons. These interneuron subtypes have distinct morphologies, physiological properties, and connectivity patterns. 


We hypothesize that an alteration in the number of interneurons within each interneuronal subtype in the cerebral cortex could explain, at least in part, the altered cognition phenotype in autism. 


To test this hypothesis we collected cortical tissue from subjects with autism and typically developed control subjects, and analyzed cortical areas that are affected in autism: the prefrontal and temporal cortex. We optimized a method for triple immunostaining together with Nissl in human cortical tissue, quantified the number of interneurons that express CB, CR, or PV, and calculated ratios for the number of interneurons expressing each marker. Determining whether the ratio in the number of specific interneurons is altered in autism will address one of the mechanisms that could alter the excitation / inhibition balance in the cerebral cortex.


We are collecting data on this project. Our preliminary data suggests that the ratio of interneurons that express CB, CR, and PV changes across ages.  We predict that there will be an alteration in the ratio of interneurons that express CB, CR or PV in the cerebral cortex of subjects with autism. 


Determining whether the ratio of interneuron subtypes is altered in the autistic brain will address one potential mechanism that could alter the excitation / inhibition balance in the cerebral cortex. Altering the ratio or number of cortical interneuron subtypes would impact the functioning of cortical circuitry.