Neuronal major histocompatibility complex class I molecules are implicated in the generation of asymmetries in hippocampal circuitry

Left-right asymmetry is a fundamental feature of higher-order brain function; however, the molecular basis of brain asymmetry has remained unclear. We have recently demonstrated asymmetries in hippocampal circuitry resulting from the asymmetrical allocation of NMDA receptor (NMDAR) subunit GluRe{open}2 (NR2B) in pyramidal cell synapses. This asymmetrical allocation of e{open}2 subunits affects the properties of NMDARs and generates two populations of synapses, 'e{open}2-dominant' and 'e{open}2-non-dominant' synapses, according to the hemispheric origin of presynaptic inputs and cell polarity of the postsynaptic neurone. To identify key regulators for generating asymmetries, we analysed the hippocampus of β2-microglobulin (β2m)-deficient mice lacking cell surface expression of major histocompatibility complex class I (MHCI). Although MHCI proteins are well known in the immune system, accumulating evidence indicates that MHCI proteins are expressed in the brain and are required for activity-dependent refinement of neuronal connections and normal synaptic plasticity. We found that β2m proteins were localised in hippocampal synapses in wild-type mice. NMDA EPSCs in β2m-deficient hippocampal synapses receiving inputs from both hemispheres showed similar sensitivity to Ro 25-6981, an e{open}2 subunit-selective antagonist, with those in 'e{open}2-dominant' synapses for both the apical and basal synapses of pyramidal neurones. The structural features of the β2m-deficient synapse in addition to the relationship between the stimulation frequency and synaptic plasticity were also comparable to those of 'e{open}2-dominant' synapses. These observations indicate that the β2m-deficient hippocampus lacks 'e{open}2-non-dominant' synapses and circuit asymmetries. Our findings provide evidence supporting a critical role of MHCI molecules for generating asymmetries in hippocampal circuitry.