Left−Right Asymmetry Defect in the Hippocampal Circuitry Impairs Spatial Learning and Working Memory in iv Mice

Kazuhiro Goto,Shigeru Watanabe,Ryo Kurashima,Isao Ito,Hayato Gokan,Naomi Inoue,Georges Chapouthier

doi:10.1371/journal.pone.0015468

Kazuhiro Goto, Shigeru Watanabe + Show 5 more

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https://doi.org/10.1371/journal.pone.0015468

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Abstract

Although left-right (L−R) asymmetry is a fundamental feature of higher-order brain function, little is known about how asymmetry defects of the brain affect animal behavior. Previously, we identified structural and functional asymmetries in the circuitry of the mouse hippocampus resulting from the asymmetrical distribution of NMDA receptor GluR ε2 (NR2B) subunits. We further examined the ε2 asymmetry in the inversus viscerum (iv) mouse, which has randomized laterality of internal organs, and found that the iv mouse hippocampus exhibits right isomerism (bilateral right-sidedness) in the synaptic distribution of theε2 subunit, irrespective of the laterality of visceral organs. To investigate the effects of hippocampal laterality defects on higher-order brain functions, we examined the capacity of reference and working memories of iv mice using a dry maze and a delayed nonmatching-to-position (DNMTP) task, respectively. The iv mice improved dry maze performance more slowly than control mice during acquisition, whereas the asymptotic level of performance was similar between the two groups. In the DNMTP task, the iv mice showed poorer accuracy than control mice as the retention interval became longer. These results suggest that the L−R asymmetry of hippocampal circuitry is critical for the acquisition of reference memory and the retention of working memory.

Highlights

The molecular basis of left-right (L2R) asymmetries in brain structure and function is one of the central issues to be elucidated in neuroscience
We have previously shown that the distribution of N-methyl-Daspartate receptor (NMDAR) e2 subunits in the mouse hippocampus is asymmetrical, both between synapses formed on the apical and basal dendrites of individual neurons and between synapses formed by inputs from the left and right pyramidal neurons (Figure 1, WT)[5,6]
Our results provide the first direct evidence that L2R asymmetry in hippocampal circuitry is critical for some aspects of higher-order brain functions

Summary

Introduction

The molecular basis of left-right (L2R) asymmetries in brain structure and function is one of the central issues to be elucidated in neuroscience. Conventional laterality research has mainly dealt with asymmetries in higher-order functions and in gross anatomical structures of the brain. We have previously shown that the distribution of N-methyl-Daspartate receptor (NMDAR) e2 subunits in the mouse hippocampus is asymmetrical, both between synapses formed on the apical and basal dendrites of individual neurons and between synapses formed by inputs from the left and right pyramidal neurons (Figure 1, WT)[5,6]. These asymmetrical allocations of e2 subunits affect the properties of NMDARs in hippocampal synapses and generate two populations of synapses with complementary properties. We hypothesized that the synaptic distribution of e2 subunits and the properties of NMDAR-mediated synaptic functions might be sensitive and quantitative indices for detecting abnormalities in the L2R asymmetry of the brain

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