Epigenetic and Transcriptional Regulation of Spontaneous and Sensory Activity Dependent Programs During Neuronal Circuit Development

Abstract

Spontaneous activity generated before the onset of sensory transduction has a key role in wiring developing sensory circuits. From axonal targeting, to synapse formation and elimination, to the balanced integration of neurons into developing circuits, this type of activity is implicated in a variety of cellular processes. However, little is known about its molecular mechanisms of action, especially at the level of genome regulation. Conversely, sensory experience-dependent activity implements well-characterized transcriptional and epigenetic chromatin programs that underlie heterogeneous but specific genomic responses that shape both postnatal circuit development and neuroplasticity in the adult. In this review, we focus on our knowledge of the developmental processes regulated by spontaneous activity and the underlying transcriptional mechanisms. We also review novel findings on how chromatin regulates the specificity and developmental induction of the experience-dependent program, and speculate their relevance for our understanding of how spontaneous activity may act at the genomic level to instruct circuit assembly and prepare developing neurons for sensory-dependent connectivity refinement and processing.

Homophilic wiring principles underpin neuronal network topologyin vitro

“…Here, the role of individual neurons can be determined by a combination of factors, such as their laminar location, connectivity, neurochemical sensitivities and morphology 14 . During embryonic development, a series of spatiotemporally defined genetic and activity-dependent programs 15 regulate the expression of cell-type specific recognition molecules to initiate axonal and dendritic outgrowth, which ultimately leads to the formation of synapses [16][17][18] . Although there is now a large body of evidence on the mechanisms of specific guidance cues during circuit formation 19 , linking this knowledge to explain the emergence of complex topological features remains challenging.…”

Bioelectronic Medicine: a multidisciplinary roadmap from biophysics to precision therapies

“…It achieves this through coupling to cell metabolism (e.g., gene expression, protein synthesis). Spontaneous activity is essential during development to regulate neurogenesis, neuronal differentiation, programmed cell death, migration, myelination, establishment of proper connectivity, and synaptic pruning ( Luhmann et al, 2016 ; Faust et al, 2021 ; Pumo et al, 2022 ). In the adult brain, electrical activity maintains and regulates the number, shape, and receptor composition of synapses, as well as neurotransmitter identity in behaviorally relevant circuits ( Spitzer, 2017 ; Pan and Monje, 2020 ).…”

Immediate-Early Genes as Influencers in Genetic Networks and their Role in Alzheimer’s Disease

“…Neuronal activity elevation induces the expression of several activity-regulated genes (ARGs) 1 . Activity-dependent regulation of gene expression has emerged as a prevailing explanatory mechanism of how molecular-level activity translates to neuron-level functions pertinent to neuronal connectivity and synaptic plasticity 2 . ARGs can be divided into two groups based on their response time, namely primary response genes (PRGs) and secondary response genes (SRGs) 3 .…”

“…Beyond their key role in neuronal circuits, IEGs are also involved in critical roles in other tissues 11 and are thus considered less amenable as pharmacological targets for the treatment of brain diseases. A possible mitigation has been proposed to uncover upstream modulators and downstream targets of IEGs that could be more amenable to manipulation by pharmacological or other means 2 . To that end, an extended outstanding question is to pinpoint the targets/modulators of IEGs in specific neuronal cell types and specific brain circuits 12 .…”

“…This paper is organized as follows, as illustrated in the workflow in Figure 1: (1) We use a mouse ARG data set and its mapped human genes to investigate whether IEGs also share key topological properties beyond their gene-induction mode that separate them from other ARGs (Figure 1A and 1B). (2) We investigate the role of ARGs in biological pathways, diseases and in terms of their mutational constraint profile (Figure 1C). (3) With AD as a case study, we explore in detail the role of variants in or close to ARGs with genome-wide association study (GWAS) summary statistics and functional investigation (Figure 1D), ( 4) by combining the network approach and the GWAS annotated ARGs in AD, we highlight genes close to ARGs as potential drug targets for AD, with a focus on MARK4, using a combination of network theory approach and GWAS summary statistics analysis (Figure 1E).…”