Drebrin Isoforms Critically Regulate NMDAR- and mGluR-Dependent LTD Induction.

Hiroki Yasuda,Kenji Hanamura,Hiroyuki Yamazaki,Nobuhiko Kojima,Tomoaki Shirao,Kenji Sakimura

doi:10.3389/fncel.2018.00330

Hiroki Yasuda, Kenji Hanamura + Show 4 more

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https://doi.org/10.3389/fncel.2018.00330

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Abstract

Drebrin is an actin-binding protein that is preferentially expressed in the brain. It is highly localized in dendritic spines and regulates spine shapes. The embryonic-type (drebrin E) is expressed in the embryonic and early postnatal brain and is replaced by the adult-type (drebrin A) during development. In parallel, NMDA receptor (NMDAR)-dependent long-term depression (LTD) of synaptic transmission, induced by low-frequency stimulation (LFS), is dominant in the immature brain and decreases during development. Here, we report that drebrin regulates NMDAR-dependent and group 1 metabotropic glutamate receptor (mGluR)-dependent LTD induction in the hippocampus. While LFS induced NMDAR-dependent LTD in the developing hippocampus in wild-type (WT) mice, it did not induce LTD in developing drebrin E and A double knockout (DXKO) mice, indicating that drebrin is required for NMDAR-dependent LTD. On the other hand, LFS induced robust LTD dependent on mGluR5, one of group 1 mGluRs, in both developing and adult brains of drebrin A knockout (DAKO) mice, in which drebrin E is expressed throughout development and adulthood. Agonist-induced mGluR-dependent LTD was normal in WT and DXKO mice; however, it was enhanced in DAKO mice. Also, mGluR1, another group 1 mGluR, was involved in agonist-induced mGluR-dependent LTD in DAKO mice. These data suggest that abnormal drebrin E expression in adults promotes group 1 mGluR-dependent LTD induction. Therefore, while drebrin expression is critical for NMDAR-dependent LTD induction, developmental conversion from drebrin E to drebrin A prevents robust group 1 mGluR-dependent LTD.

Highlights

Synaptic plasticity is the change in efficacy of synaptic transmission induced by activity, which is hypothesized to be a molecular mechanism of learning and memory
We found that low-frequency stimulation (LFS) did not induce long-term depression (LTD) in P18–20 DXKO mice, but it did induce LTD in WT mice (Figures 1A–C; WT, 80.2 ± 4.5% of baseline 60 min after LFS, n = 14 from four mice; DXKO, 105.1 ± 4.1%, n = 12 from five mice; p < 0.0005, Student’s t-test)
LTD induced by LFS is NMDA receptor (NMDAR)-dependent in WT mice (Mulkey and Malenka, 1992; Dudek and Bear, 1993; Kemp et al, 2000; Malenka and Bear, 2004), suggesting that drebrin is necessary for the induction of NMDAR-dependent LTD in the P18–20 hippocampus

Summary

Introduction

Synaptic plasticity is the change in efficacy of synaptic transmission induced by activity, which is hypothesized to be a molecular mechanism of learning and memory. Drebrin A is neuronspecific, appears at nascent postsynaptic sites, and forms an F-actin platform for the molecular assembly of postsynaptic proteins, such as PSD-95, spikar and glutamate receptors (Takahashi et al, 2003; Aoki et al, 2005; Yamazaki et al, 2014). We have recently shown that long-term potentiation (LTP) and context-dependent fear memory are impaired in adult drebrin A knockout (DAKO) mice (Kojima et al, 2010, 2016), indicating that drebrin plays a pivotal role in synaptic plasticity (Sekino et al, 2017)

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