Abstracts

Rationale: Autism spectrum disorders (ASDs), characterized by impaired social interactions, impaired communication and stereotyped behaviors, are highly associated with epilepsy (up to 38%). A shift in cortical excitatory/inhibitory balance towards increased excitation and/or decreased inhibition may play a key role in the pathophysiology of both ASDs and epilepsy. We hypothesized that differences in AMPA receptor (AMPAR) and NMDA receptor (NMDAR) subunit expression in ASD and epilepsy patients may represent a basis for distinct clinical neurological manifestations. Identifying specific synaptic mechanisms for autism and epilepsy will allow development of targeted therapies. Methods: Brain specimens from treatment-resistant temporal lobe epilepsy cases were collected prospectively during resective surgery at NYULMC (n=5; ages 21-37 years). Autopsy temporal and frontal lobe samples from ASD patients (n=5; ages 4-22 years) and region-matched control specimens from cases with normal neurological history (n=10; ages 5-48 years) were obtained from Maryland Brain and Tissue Bank. All ASD cases met the standard diagnostic criteria (Autism Diagnostic Interview-Revised) and had no evidence of epilepsy, while none of the epilepsy patients were diagnosed with autism. The levels of the NMDAR and AMPAR subunits (NR1, NR2A, NR2B, GluR1 and GluR2) were quantified by Western blot and compared among groups (one-way ANOVA and t-tests). Results: Temporal lobe cortex analysis demonstrated a significant increase in NR1 expression in autism patients (288% of control; p<0.0001), but no significant change in epilepsy cases (96% of control; p>0.05). In both groups, NR2A was significantly decreased (ca. 40% of control; p<0.0001), while NR2B demonstrated a significant upregulation (255% of control in autism and 511% of control in epilepsy; p<0.0001). NR2B levels were significantly higher in epilepsy, relative to autism patients (p<0.001). GluR1 expression was increased in both autism (388% of control; p<0.0001) and epilepsy specimens (514% of control; p<0.0001), in contrast to GluR2 which was significantly reduced (40% of control in autism and 32% of control in epilepsy; p<0.0001), consistent with the presence of Ca2+- permeable AMPARs. There were no significant differences (p>0.05) in NMDAR and AMPAR subunits between temporal and frontal lobe specimens from autism cases. Conclusions: Our results suggest increased NMDAR function in ASD patients (increased NR1) and provide a basis for novel therapeutic strategies targeting these receptors. Enhanced intracellular Ca2+ signaling due to altered NMDAR and AMPAR subunit composition (increased NR2B and decreased GluR2) may impair synaptic function and operate as a feed-forward loop for both autism and epilepsy. Therefore, drugs specifically targeting Ca2+- permeable AMPARs or NR2B- containing NMDARs may be beneficial for both ASD and epilepsy patients. Acknowledgments: FACES, NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD, contract HHSN275200900011C.