Gene Expression Deficits in Pyramidal Neurons From the Anterior Cingulate Cortex in Males With Autism

Background: Altered brain morphology was one of the first pathobiological findings associated with autism spectrum disorder. These gross abnormalities, documented in both white and gray matter areas in autistic brains, are postulated to contribute to disrupted neuronal communication. For example, glutamatergic pyramidal neurons in the anterior cingulate cortex (ACC) have decreased size and increased cell density in autism. Objectives: We sought to determine whether autism-related gene expression abnormalities exist in the ACC that might underlie previously observed cell morphological alterations found in this brain region. Specifically, levels of expression of genes associated with glutamatergic neurotransmission were measured in pyramidal neurons and surrounding astrocytes in the ACC of postmortem brain tissues from autism donors and matched developmentally normal control donors. Methods: Postmortem brain tissues were obtained from 6-8 age-matched pairs of male subjects who had autism and developmentally normal control males (age range 6-37). Laser-guided microdissection was used to capture pure populations of pyramidal neurons and astrocytes from layer III of the ACC. The expression of glutamate-related genes was measured in RNA isolates by reverse transcription followed by end-point PCR using three stable reference genes to normalize expression levels. Results: ACC pyramidal neurons from autism subjects demonstrated significantly reduced gene expressions of the obligatory glutamatergic NMDA receptor subunit NR1, a glutamate transporter SLC1A1, and the glutamate receptor anchoring protein GRIP1. There was also a robust reduction in the gene expression of the brain-derived neurotrophic factor (BDNF) receptor NTRK2 in autism pyramidal neurons, with gene expression levels of BDNF itself unaffected. No gene expression abnormalities were observed in ACC astrocytes surrounding the pyramidal neurons from autistic subjects. Conclusions: Autism spectrum disorder is associated with a reduction in the expression of genes associated with glutamatergic neurotransmission and downstream BDNF signaling in pyramidal neurons of the ACC. These findings suggest that glutamatergic signaling is compromised in these excitatory neurons in autism and raise hope that drugs or other treatments may be developed to overcome these pathobiological deficits