5HT1A, Benzodiazepine and NMDA Receptor Binding in Broca's Area in Autism

Background: Language and communication deficits are often the first presenting symptoms in individuals with autism.  Language functioning in these individuals presents as a phenotypically diverse spectrum of linguistic abilities and deficits—in semantic, syntactic, pragmatic and phonologic linguistic categories. These linguistic deficits may be related to disturbed functioning and connectivity of language related brain regions. One of the primary functions of Broca’s area, the opercular (BA44) and triangular (BA45) premotor regions of the inferior frontal gyrus, is speech production. Neuroimaging studies of individuals with autism engaged in language tasks report abnormal asymmetry and activation patterns in Broca’s area as well as evidence of altered connectivity between Broca’s area and other language related brain regions. It is likely that receptor/synaptic-level deficits in part underlie this reported malfunctioning of Broca’s area in autism.  Previously, our laboratory found alterations of GABA and serotonin (5HT) receptor subtypes in brain regions involved with social communication. GABA, serotonin and glutamate are suggested to be influential in the etiology, symptoms and treatment of autism. Understanding the neurochemical profile of these receptor subtypes in Broca’s area in autistic individuals may help identify some of the key neural substrates underlying these abnormalities and may direct future studies aimed at treating core neural impairments related to language deficits in the disorder.

Objectives: To determine the density of 5HT1A, benzodiazepine, and NMDA receptor binding sites in superficial (I-IV) and deep layers (V-VI) of Broca's area (BA44-45) in adult autism and matched control cases.   

Methods: In Broca’s area, single concentration receptor binding studies were completed for 5HT1A (³H-8-OH-DPAT), benzodiazepine (³H-Flunitrazepam), and NMDA (³H-MK-801) receptors in autism (n= 4-6) and control (n= 8-9) fresh frozen human postmortem 20 µm thick tissue sections from the left hemisphere matched for age and post-mortem interval. Optical densities were measured in superficial and deep layers of Broca’s area using the Inquiry program. Student t-tests compared superficial layers, deep layers, and superficial and deep layers combined in Broca’s area by group.

Results: There was a significant overall reduction in the density of NMDA receptors (p=0.03) in the combined superficial and deep layers of Broca’s area in autism. Also, there was a trend toward a reduction in the density of NMDA (p=0.09) and 5-HT1a (p=0.07) receptors in the superficial layers in the autistic group. In contrast, there were no significant findings or trends in benzodiazepine binding site densities in Broca’s area.

Conclusions: The significant overall reduction in NMDA receptor density in superficial and deep layers combined and a trend toward a reduction of NMDA and 5HT1A receptors in superficial layers suggest that these specific receptor subtypes may contribute to the underlying synaptic connectivity disturbances in Broca’s area in autism.

Acknowledgements: We gratefully acknowledge a grant from the Nancy Lurie Marks Family Foundation. Tissue specimens were obtained from the Harvard Brain and Tissue Resource Center, the NICHD Brain and Tissue Bank for Developmental Disorders and The Autism Research Foundation.