Effects of Metabotropic Glutamate Receptor 3 Genotype on Phonetic Mismatch Negativity

Yuki Kawakubo,Yukiko Kano,Kiyoto Kasai,Tsukasa Sasaki,Motomu Suga,Mamoru Tochigi,Kenji Itoh,Masato Yumoto,Kenji Hashimoto

doi:10.1371/journal.pone.0024929

Yuki Kawakubo, Yukiko Kano + Show 7 more

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https://doi.org/10.1371/journal.pone.0024929

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Abstract

BackgroundThe genetic and molecular basis of glutamatergic dysfunction is one key to understand schizophrenia, with the identification of an intermediate phenotype being an essential step. Mismatch negativity (MMN) or its magnetic counterpart, magnetic mismatch field (MMF) is an index of preattentive change detection processes in the auditory cortex and is generated through glutamatergic neurotransmission. We have previously shown that MMN/MMF in response to phoneme change is markedly reduced in schizophrenia. Variations in metabotropic glutamate receptor (GRM3) may be associated with schizophrenia, and has been shown to affect cortical function. Here we investigated the effect of GRM3 genotypes on phonetic MMF in healthy men.MethodsMMF in response to phoneme change was recorded using magnetoencephalography in 41 right-handed healthy Japanese men. Based on previous genetic association studies in schizophrenia, 4 candidate SNPs (rs6465084, rs2299225, rs1468412, rs274622) were genotyped.Results GRM3 rs274622 genotype variations significantly predicted MMF strengths (p = 0.009), with C carriers exhibiting significantly larger MMF strengths in both hemispheres compared to the TT subjects.ConclusionsThese results suggest that variations in GRM3 genotype modulate the auditory cortical response to phoneme change in humans. MMN/MMF, particularly those in response to speech sounds, may be a promising and sensitive intermediate phenotype for clarifying glutamatergic dysfunction in schizophrenia.

Highlights

Synaptic pathology through glutamatergic dysfunction is a key to understand the pathophysiology of schizophrenia [1]
Observed reduction of mismatch negativity (MMN) event-related potentials or its magnetic counterpart, an index of auditory sensory memory with a major generator in the auditory cortex, has supported the hypothesis [5], since the generation of Mismatch negativity (MMN) is regulated through the N-methyl-D-aspartate (NMDA) receptor agonistic effect [6]
MMN/mismatch field (MMF) is elicited by change in speech sounds [7], which has been recognized as an index of language-specific speech-sound traces and learning-induced short-term plasticity

Summary

Introduction

Synaptic pathology through glutamatergic dysfunction is a key to understand the pathophysiology of schizophrenia [1]. MMN/MMF may be a useful intermediate phenotype to assess glutamatergic function in schizophrenia. The reduced MMF strengths were significantly associated with reduced left planum temporale gray matter volume reduction in patients with schizophrenia [10]. These results suggest that MMN/MMF in response to phoneme change may be a promising candidate as an intermediate phenotype of glutamate-related genes. Mismatch negativity (MMN) or its magnetic counterpart, magnetic mismatch field (MMF) is an index of preattentive change detection processes in the auditory cortex and is generated through glutamatergic neurotransmission. We have previously shown that MMN/MMF in response to phoneme change is markedly reduced in schizophrenia. We investigated the effect of GRM3 genotypes on phonetic MMF in healthy men

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Conclusion