TY - JOUR

T1 - The Role of Stress-Induced Changes of Homer1 Expression in Stress Susceptibility

AU - Reshetnikov, Vasiliy V.

AU - Bondar, Natalia P.

N1 - Funding Information: This work was financially supported by the Russian Science Foundation (grant no. 16-15-10131). Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/6

Y1 - 2021/6

N2 - Stress negatively affects processes of synaptic plasticity and is a major risk factor of various psychopathologies such as depression and anxiety. HOMER1 is an important component of the postsynaptic density: constitutively expressed long isoforms HOMER1b and HOMER1c bind to group I metabotropic glutamate receptors MGLUR1 (GRM1) and MGLUR5 and to other effector proteins, thereby forming a postsynaptic protein scaffold. Activation of the GLUR1–HOMER1b,c and/or GLUR5–HOMER1b,c complex regulates activity of the NMDA and AMPA receptors and Ca2+ homeostasis, thus modulating various types of synaptic plasticity. Dominant negative transcript Homer1a is formed as a result of activity-induced alternative termination of transcription. Expression of this truncated isoform in response to neuronal activation impairs interactions of HOMER1b,c with adaptor proteins, triggers ligand-independent signal transduction through MGLUR1 and/or MGLUR5, leads to suppression of the AMPA- and NMDA-mediated signal transmission, and thereby launches remodeling of the postsynaptic protein scaffold and inhibits long-term potentiation. The studies on animal models confirm that the HOMER1a-dependent remodeling most likely plays an important part in the stress susceptibility, whereas HOMER1a itself can be regarded as a neuroprotector. In this review article, we consider the effects of different stressors in various animal models on HOMER1 expression as well as impact of different HOMER1 variants on human behavior as well as structural and functional characteristics of the brain.

AB - Stress negatively affects processes of synaptic plasticity and is a major risk factor of various psychopathologies such as depression and anxiety. HOMER1 is an important component of the postsynaptic density: constitutively expressed long isoforms HOMER1b and HOMER1c bind to group I metabotropic glutamate receptors MGLUR1 (GRM1) and MGLUR5 and to other effector proteins, thereby forming a postsynaptic protein scaffold. Activation of the GLUR1–HOMER1b,c and/or GLUR5–HOMER1b,c complex regulates activity of the NMDA and AMPA receptors and Ca2+ homeostasis, thus modulating various types of synaptic plasticity. Dominant negative transcript Homer1a is formed as a result of activity-induced alternative termination of transcription. Expression of this truncated isoform in response to neuronal activation impairs interactions of HOMER1b,c with adaptor proteins, triggers ligand-independent signal transduction through MGLUR1 and/or MGLUR5, leads to suppression of the AMPA- and NMDA-mediated signal transmission, and thereby launches remodeling of the postsynaptic protein scaffold and inhibits long-term potentiation. The studies on animal models confirm that the HOMER1a-dependent remodeling most likely plays an important part in the stress susceptibility, whereas HOMER1a itself can be regarded as a neuroprotector. In this review article, we consider the effects of different stressors in various animal models on HOMER1 expression as well as impact of different HOMER1 variants on human behavior as well as structural and functional characteristics of the brain.

KW - depression

KW - Homer1

KW - metabotropic glutamate receptors

KW - stress

KW - synaptic plasticity

UR - http://www.scopus.com/inward/record.url?scp=85107434762&partnerID=8YFLogxK

U2 - 10.1134/S0006297921060018

DO - 10.1134/S0006297921060018

M3 - Review article

C2 - 34225586

AN - SCOPUS:85107434762

VL - 86

SP - 613

EP - 626

JO - Biochemistry (Moscow)

JF - Biochemistry (Moscow)

SN - 0006-2979

IS - 6

ER -