The Role of MeCP2 in Regulating Synaptic Plasticity in the Context of Stress and Depression

Abstract

Methyl-CpG-binding protein 2 (MeCP2) is a transcriptional regulator that is highly abundant in the brain. It binds to methylated genomic DNA to regulate a range of physiological functions implicated in neuronal development and adult synaptic plasticity. MeCP2 has mainly been studied for its role in neurodevelopmental disorders, but alterations in MeCP2 are also present in stress-related disorders such as major depression. Impairments in both stress regulation and synaptic plasticity are associated with depression, but the specific mechanisms underlying these changes have not been identified. Here, we review the interplay between stress, synaptic plasticity, and MeCP2. We focus our attention on the transcriptional regulation of important neuronal plasticity genes such as BDNF and reelin (RELN). Moreover, we provide evidence from recent studies showing a link between chronic stress-induced depressive symptoms and dysregulation of MeCP2 expression, underscoring the role of this protein in stress-related pathology. We conclude that MeCP2 is a promising target for the development of novel, more efficacious therapeutics for the treatment of stress-related disorders such as depression.

Early life stress exacerbates behavioural and neuronal alterations in adolescent male mice lacking methyl-CpG binding protein 2 (Mecp2)

“…Since the effect of MS on the decrease of reelin does not seem to interact with the lack of Mecp2, we suggest that MS might downregulate its expression in a pathway independent of the levels of Mecp2. Although not assessed in the present study, MS could be inducing DNA methylation at the promoter region of reelin, as it has been previously observed in other models of autism-like disorders and schizophrenia (Sánchez-Lafuente et al, 2022).…”

“…In the adult brain, it persists in a subset of cortical, cerebellar and hippocampal interneurons, among others with functions related to synaptic plasticity ( Duveau et al, 2011 ). Notably, reelin expression is known to be under the epigenetic control of Mecp2 ( Sánchez-Lafuente et al, 2022 ). However, to our knowledge the expression of reelin has not been previously characterised in the Mecp2 -null mice, with the exception of a report showing an increase of Reln transcript in the cerebellum ( Jordan et al, 2007 ).…”

“…An increasing amount of evidence suggest that Mecp2 has a role on the susceptibility to early life environmental disturbances and thus on determining the coping strategies that animals develop later in life ( Abellán-Álvaro et al, 2021 ; Sánchez-Lafuente et al, 2022 ). Dosage-variation on functional MECP2 during human neurodevelopment have been described in RTT, predominantly affecting females ( Amir et al, 1999 ), but also affecting males in MDS ( D’Mello, 2021 ; Pascual-Alonso et al, 2021 ) and in cases of somatic mosaicism and intellectual disability associated with RTT ( Orrico et al, 2000 ; Kudo et al, 2002 ; Topçu et al, 2002 ; Venâncio et al, 2007 ).…”

Engeletin alleviates depression‐like phenotype by increasing synaptic plasticity via the BDNF‐TrkB‐mTORC1 signalling pathway

“…Much evidence suggests the synaptic plasticity dysregulation in depression aetiology, causing neuronal atrophy and synaptic weakening in critical brain regions (hippocampus and PFC). 20,21 Here, synaptic plasticity was assessed by PFC samples, western blotting and Golgi staining. which is essential for neuronal survival and brain neurogenesis and has been linked with current depression-related theories.…”

Caloric Restriction Can Ameliorate Postoperative Cognitive Dysfunction by Upregulating the Expression of Sirt1, MeCP2 and BDNF in the Hippocampal CA1 Region of Aged C57BL/6 Mice

“…By altering Sirt1 expression in the mouse hippocampus, CR can have neuroprotective effects [ 25 ]. MeCP2 is a transcriptional regulator that is highly abundant in the brain and can bind to methylated genomic DNA to regulate a range of physiological processes that are associated with adult synaptic plasticity and neuronal development [ 26 ]. Hippocampal MeCP2 knockdown has the opposite effects of overexpression, which could improve synaptic plasticity and cognitive function [ 27 ].…”