Regulation of Glutamatergic Synaptic Transmission and Plasticity by MHC class I

Disruption of glutamatergic synaptic transmission is a consistent finding in autism, and alterations in ionotropic glutamate receptors have also been reported in related disorders, including Rett syndrome and tuberous sclerosis, but the cause of these changes remains unknown. Maternal viral infection is a risk factor for autism, and recent studies in animal models implicate the immune response, not the virus itself, in disruption of fetal brain development. Here we report that changes in the levels of specific immune proteins, members of the major histocompatibility class I (MHCI), are sufficient to induce abnormalities in glutamatergic synaptic transmission and synaptic plasticity in developing and adult hippocampal neurons.

In mice genetically deficient for cell surface MHCI, hippocampal synaptic plasticity driven by activation of NMDA-type glutamate receptors (NMDARs) is selectively shifted in favor of potentiation. Concomitantly, trafficking of AMPA-type glutamate receptors (AMPARs), which is thought to underlie changes in synaptic strength in the adult hippocampus, is altered in these transgenics. In particular, LTD induction protocols, which normally decrease cell surface AMPARs, instead increase cell surface AMPARs in MHCI-deficient animals, paralleling the observed shift in plasticity. In these same animals, activity-dependent remodeling of developing projections is disrupted. Together, these results suggest that changes in MHCI levels may mechanistically link maternal immune challenge, a risk factor for autism, with glutamatergic dysfunction and altered synaptic connectivity, common symptomatic correlates of this disorder. Clarifying this link could lead to novel, immune-based strategies for the diagnosis, treatment, and prevention of autism.