Glutamatergic postsynaptic density in early life stress programming: Topographic gene expression of mGlu5 receptors and Homer proteins

Buonaguro, Elisabetta Filomena; Morley‐Fletcher, Sara; Avagliano, Camilla; Vellucci, Licia; Iasevoli, Felice; Bouwalerh, Hammou; Camp, Gilles Van; Nicoletti, Ferdinando; Maccari, Stefania; Bartolomeis, Andrea de

doi:10.1016/j.pnpbp.2019.109725

Cited by 13 publications

(10 citation statements)

References 66 publications

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“…Another recent study parallels these findings, showing that early life stress in rats causes these animals to spend less time in the light area of a light-dark box and to exhibit lower mGlu5 gene expression within the amygdala. This study also showed that time spent in the light area is positively correlated with mGlu5 gene expression within the amygdala (Buonaguro et al, 2020). One question that remains is whether such mGlu5-mediated neuroimmune mechanisms are therapeutic in cases of comorbid PTSD and SUDs.…”

Section: Posttraumatic Stress Disordersupporting

confidence: 60%

Neuroimmune Mechanisms as Novel Treatment Targets for Substance Use Disorders and Associated Comorbidities

et al. 2021

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Recent studies examining the neurobiology of substance abuse have revealed a significant role of neuroimmune signaling as a mechanism through which drugs of abuse induce aberrant changes in synaptic plasticity and contribute to substance abuse-related behaviors. Immune signaling within the brain and the periphery critically regulates homeostasis of the nervous system. Perturbations in immune signaling can induce neuroinflammation or immunosuppression, which dysregulate nervous system function including neural processes associated with substance use disorders (SUDs). In this review, we discuss the literature that demonstrates a role of neuroimmune signaling in regulating learning, memory, and synaptic plasticity, emphasizing specific cytokine signaling within the central nervous system. We then highlight recent preclinical studies, within the last 5 years when possible, that have identified immune mechanisms within the brain and the periphery associated with addiction-related behaviors. Findings thus far underscore the need for future investigations into the clinical potential of immunopharmacology as a novel approach toward treating SUDs. Considering the high prevalence rate of comorbidities among those with SUDs, we also discuss neuroimmune mechanisms of common comorbidities associated with SUDs and highlight potentially novel treatment targets for these comorbid conditions. We argue that immunopharmacology represents a novel frontier in the development of new pharmacotherapies that promote long-term abstinence from drug use and minimize the detrimental impact of SUD comorbidities on patient health and treatment outcomes.

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Section: Posttraumatic Stress Disordersupporting

confidence: 60%

Neuroimmune Mechanisms as Novel Treatment Targets for Substance Use Disorders and Associated Comorbidities

et al. 2021

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“…mGlu5 and NMDA receptors are physically linked by a chain of scaffolding proteins and functionally interact in the induction of activity-dependent synaptic plasticity [ 59 , 60 ]. Changes in mGlu5 and NMDA receptors found in this study are in agreement with previous data observed in adult PRS male rats [ 61 ] and suggest that PRS impairs the receptor substrates of synaptic plasticity in aged male rats. Interestingly, the lowering effect of PRS on mGlu2/3 receptor protein levels in the ventral hippocampus and prefrontal cortex of aged rats was not sex-dependent, whereas it was sex-dependent in non-stressed control rats, with control females showing reduced mGlu2/3 protein levels as compared to control males.…”

Section: Discussionsupporting

confidence: 93%

Maternal stress programs a demasculinization of glutamatergic transmission in stress-related brain regions of aged rats

et al. 2021

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Brain aging may be programmed by early-life stress. Aging affects males and females differently, but how perinatal stress (PRS) affects brain aging between sexes is unknown. We showed behavioral and neurobiological sex differences in non-stressed control rats that were strongly reduced or inverted in PRS rats. In particular, PRS decreased risk-taking behavior, spatial memory, exploratory behavior, and fine motor behavior in male aged rats. In contrast, female aged PRS rats displayed only increased risk-taking behavior and reduced exploratory behavior. PRS induced large reductions in the expression of glutamate receptors in the ventral and dorsal hippocampus and prefrontal cortex only in male rats. PRS also reduced the expression of synaptic vesicle-associated proteins, glucocorticoid receptors (GR), and mineralocorticoid receptors (MR) in the ventral hippocampus of aged male rats. In contrast, in female aged rats, PRS enhanced the expression of MRs and brain-derived neurotrophic factor (BDNF) in the ventral hippocampus and the expression of glial fibrillary acidic protein (GFAP) and BDNF in the prefrontal cortex. A common PRS effect in both sexes was a reduction in exploratory behavior and metabotropic glutamate (mGlu2/3) receptors in the ventral hippocampus and prefrontal cortex. A multidimensional analysis revealed that PRS induced a demasculinization profile in glutamate-related proteins in the ventral and dorsal hippocampus and prefrontal cortex, as well as a demasculinization profile of stress markers only in the dorsal hippocampus. In contrast, defeminization was observed only in the ventral hippocampus. Measurements of testosterone and 17-β-estradiol in the plasma and aromatase in the dorsal hippocampus were consistent with a demasculinizing action of PRS. These findings confirm that the brains of males and females differentially respond to PRS and aging suggesting that females might be more protected against early stress and age-related inflammation and neurodegeneration. Taken together, these results may contribute to understanding how early environmental factors shape vulnerability to brain aging in both sexes and may lay the groundwork for future studies aimed at identifying new treatment strategies to improve the quality of life of older individuals, which is of particular interest given that there is a high growth of aging in populations around the world.

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“…This process coincides with the period of intense reorga nization of synapses and establishment of the stable synaptic networks. In a study on rats, it was found that chronic stress during prenatal period increased mRNA and protein expression of Homer1a in the amygdala in the juvenile and adult animals [21,73]. By contrast, the level of Homer1a in hippocampus and prefrontal cortex was high in the juvenile animals [73] and low in adults [21].…”

Section: Delayed Effects Of Stress On Homer1 Expressionmentioning

confidence: 99%

“…Because the impaired glutamate transmission is observed in a variety of stress induced psychopathologies, we have hypothesized that HOMER1 can be considered as an important component of stress susceptibility/resistance. Research in the last two decades indicates that changes in the expression of HOMER1 or its dominant negative isoform HOMER1a are observed in animals after restraint stress [19], social defeat stress [20], and in adult animals subjected to pre natal stress [21]. In addition, it has been shown that the expression of HOMER1 changes after treatment with anxiolytics or antidepressants [22].…”

Section: Introductionmentioning

confidence: 99%

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

Reshetnikov

Bondar

2021

Biochemistry Moscow

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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.

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Glutamatergic postsynaptic density in early life stress programming: Topographic gene expression of mGlu5 receptors and Homer proteins

Cited by 13 publications

References 66 publications

Neuroimmune Mechanisms as Novel Treatment Targets for Substance Use Disorders and Associated Comorbidities

Neuroimmune Mechanisms as Novel Treatment Targets for Substance Use Disorders and Associated Comorbidities

Maternal stress programs a demasculinization of glutamatergic transmission in stress-related brain regions of aged rats

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

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