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

Abstract

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.

HOMER1A restores sevoflurane-induced cognitive dysfunction by regulating microglia's activation through activating the AMPK/TXNIP axis

“…AMP-activated protein kinase (AMPK) affects cell growth, the balance energy metabolism and other processes [11]. On the one side, AMPK activation can alleviate cognitive impairment mediated by neuronal apoptosis.…”

“…HOMER1A is a member of the postsynaptic density protein family, which exhibits crucial roles in neuronal synaptic activity and is widely involved in neurological diseases [10,11]. HOMER1A has been revealed to possess neuroprotective effects, and its upregulation can reduce cell apoptosis caused by traumatic neuronal injury and enhance protective autophagy, thereby alleviating brain injury [12].…”

Social stress under binge-like alcohol withdrawal in adolescence: evidence of cannabidiol effect on maladaptive plasticity in rats

“…On the other hand, HOM1 is critical in postsynaptic density remodelling, by affecting synaptic architecture and facilitating glutamate signal transduction (Yoon et al, 2021). Fluctuations in HOM1 are observed in animals after restraint-, social defeat-, prenatal-stress and alcohol consumption (Brancato et al, 2021; Castelli, Brancato, Cavallaro, Lavanco, & Cannizzaro, 2017; Reshetnikov & Bondar, 2021). Interestingly, deletion of HOM1 has been correlated with stress susceptibility and HPA dysfunction (Reshetnikov & Bondar, 2021) indicating a prominent role in the feedback regulation of the HPA axis and stress coping.…”

“…Fluctuations in HOM1 are observed in animals after restraint-, social defeat-, prenatal-stress and alcohol consumption (Brancato et al, 2021; Castelli, Brancato, Cavallaro, Lavanco, & Cannizzaro, 2017; Reshetnikov & Bondar, 2021). Interestingly, deletion of HOM1 has been correlated with stress susceptibility and HPA dysfunction (Reshetnikov & Bondar, 2021) indicating a prominent role in the feedback regulation of the HPA axis and stress coping. In line with our previous data on alterations of the effector systems regulating the expression of specific markers of synaptic remodelling in the NAc of BAW rats (Brancato et al, 2021), the consistent reduction of PSD95 and HOM1 scaffolding currently observed is associated with the suppression of both ARC and FOXP1 expression.…”

“…dysfunction (Reshetnikov & Bondar, 2021) indicating a prominent role in the feedback regulation of the HPA axis and stress coping. In line with our previous data on alterations of the effector systems regulating the expression of specific markers of synaptic remodelling in the NAc of BAW rats (Brancato et al, 2021), the consistent reduction of PSD95 and HOM1 scaffolding currently observed is associated with the suppression of both ARC and FOXP1 expression.…”