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

J Physiol. 2013 Oct 1;591(19):4777-91. doi: 10.1113/jphysiol.2013.252122. Epub 2013 Jul 22.


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 GluR2 (NR2B) in pyramidal cell synapses. This asymmetrical allocation of 2 subunits affects the properties of NMDARs and generates two populations of synapses, '2-dominant' and '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 2 subunit-selective antagonist, with those in '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 '2-dominant' synapses. These observations indicate that the β2m-deficient hippocampus lacks '2-non-dominant' synapses and circuit asymmetries. Our findings provide evidence supporting a critical role of MHCI molecules for generating asymmetries in hippocampal circuitry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Excitatory Postsynaptic Potentials
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Hippocampus / physiology*
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Neuronal Plasticity
  • Phenols / pharmacology
  • Piperidines / pharmacology
  • Protein Transport
  • Pyramidal Cells / metabolism*
  • Pyramidal Cells / physiology
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synapses / metabolism
  • Synapses / physiology*
  • beta 2-Microglobulin / genetics
  • beta 2-Microglobulin / metabolism


  • Histocompatibility Antigens Class I
  • NR2B NMDA receptor
  • Phenols
  • Piperidines
  • Receptors, N-Methyl-D-Aspartate
  • Ro 25-6981
  • beta 2-Microglobulin