Laboratory of Biophysical Chemistry Department of Biology, Facultyof Sciences, Kyushu University

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Molecular asymmetry of hippocampal circuitry
 Asymmetrical hemispheric specialization is a fundamental concept of brain science and has been described mainly in higher-order functions of the brain. Recently we have found that synaptic distribution of NMDA receptor GluRε2 (NR2B) subunits in mouse hippocampus is asymmetrical between the left and right, and between the apical and basal dendrites of single neurons. These asymmetrical allocations of ε2 subunits differentiate the properties of NMDA receptors and synaptic plasticity between the left and right hippocampus. Our findings show asymmetries involved in a basic structure and function of simple neuronal network.
 Hippocampal CA1 pyramidal neurons receive major excitatory inputs from Schaffer collateral (sch) fibers from ipsilateral CA3 pyramidal neurons and commissural (com) fibers from contralateral CA3 pyramidal neurons. To characterize the NMDA receptors selectively in the sch-CA1 synapses, we have developed a method by which com fibers are denervated in live mice. Surprisingly, NMDA-EPSCs recorded in hippocampal slices prepared from the com fiber-denervated mice showed asymmetrical sensitivities to the ε2 subunit-selective antagonist Ro 25-6981 between the left and right hippocampus, and between the apical and basal dendrites of individual neurons. NMDA-EPSCs in the com-CA3 synapses, examined in naive mice, showed opposite asymmetry in Ro 25-6981 sensitivities to those in the sch-CA1 synapses. The difference in the properties of NMDA receptors was reflected in distinct properties of LTPs in the left and right hippocampus. Western blot analyses of PSD proteins purified from the com fiber-denervated mice hippocampi revealed that the functional asymmetries of hippocampal synapses can be explained by the asymmetrical allocation of ε2 subunits to these synapses.
 Our findings indicate that the ε2 subunit can be a key molecule to explore the unsettled problems in the field of brain asymmetry and suggest that the brain can involve asymmetries at each level of its structural hierarchy, namely neuron, synapse, neuronal network and left/right hemispheres of the brain.
 Left and right pyramidal neurons and their axons are colored red and blue, respectively. Closed and open circles represent ε2-dominant and ε2-non-dominant synapses, respectively. Straight and wavy lines represent inputs from the ipsilateral and contralateral CA3 pyramidal neurons, respectively. Apical; apical dendrites. Basal; basal dendrites.
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