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Neuronal activity and subsequent calcium influx activates a signaling cascade that causes transcription factors in the nucleus to rapidly induce an early-response program of gene expression. This early-response program is composed of transcriptional regulators that in turn induce transcription of late-response genes, which are enriched for regulators of synaptic development and plasticity that act locally at the synapse.
Inhibition controls information flow through a neural circuit by modulating synaptic integration, restricting action potentials, and coordinating the activity of ensembles of neurons. These functions are mediated by a diverse array of inhibitory neuron subtypes that synapse on defined domains of a postsynaptic neuron. Activity-dependent transcription controls inhibitory synapse number and function, but how this transcription program affects the inhibitory inputs that form on distinct domains of a neuron remains unclear. We find that behaviorally-driven expression of the transcription factor NPAS4 orchestrates the redistribution of inhibitory synapses made onto a pyramidal neuron, simultaneously promoting inhibitory synapse formation onto the cell body while destabilizing inhibitory synapses formed on the dendrites. This rearrangement of inhibition across a neuron is mediated in part by the NPAS4 target gene brain derived neurotrophic factor (BDNF), which specifically regulates somatic inhibition. These findings suggest that sensory stimuli, by inducing NPAS4 and its target genes, differentially control spatial features of neuronal inhibition in a way that restricts the output of the neuron while creating a dendritic environment that is permissive for plasticity.
The ability of extrinsic environmental cues to modify the nervous system is critical both for the appropriate maturation of the nervous system, as well as for important adaptive functions of the mature brain, such as learning and memory. The discovery that, in response to sensory experience, neurotransmitter release at synapses and subsequent calcium influx into postsynaptic neurons lead to the synthesis of new gene products suggested a compelling mechanism by which long-lasting, use-dependent changes occur in the nervous system. Despite considerable progress in our understanding of the program of neuronal activity-regulated gene expression, direct evidence that the activity-dependent component of transcription per se is specifically important for nervous system development or function has been elusive. The first part of this thesis addresses this question through the development of a mutant mouse model in which the activity-dependent component of Bdnf expression is specifically disrupted. We find that mutation of the CaRE3/CRE (CREm) at endogenous Bdnf promoter IV by gene targeting results in an animal in which the neuronal activity-dependent component of Bdnf transcription in the cortex is selectively disrupted. CREm knock-in mice exhibit a reduction in the number of inhibitory synapses formed by cortical neurons in culture, a reduction in spontaneous inhibitory quantal transmission measured in acute brain slices, and a reduction in the level of inhibitory presynaptic markers in the cortex.
Regulation of gene transcription by neuronal activity is evident in a large number of neuronal processes ranging from neural development and refinement of neuronal connections to learning and response to injury. In the field of activity-dependent gene expression, rapid progress is being made that can impact these, and many other areas of neuroscience. This book offers an up-to-date picture of the field.
A new perspective on brain function depends upon an understanding of the interaction and integration of excitation and inhibition. A recent surge in research activity focused on inhibitory interneurons now makes a more balanced view possible. Technological advances such as improved imaging methods, visualized patch-clamp recording, multiplex single-cell PCR, and gene-targeted deletion or knock-in mice are some of the novel tools featured in this book. This book will provide an integrated view of neuron function, operating in a balanced regime of excitation and inhibition. It is a timely contribution emphasizing how this balance is established, maintained, and modified from the molecular to system levels. The broad spectrum of topics from molecular to cellular and system/computational neuroscience will appeal to a wide audience of advanced graduate students, post-docs, and faculty. Moreover, this book this book features active young researchers from around the world, who are currently educating the brain scientists of tomorrow.
The remarkable ability of the brain to convert transient experiences into enduring memories has long been attributed to activity-dependent changes in synaptic strength. Long-lasting changes in synaptic strength essential for learning and memory require neuronal gene expression, but the underlying mechanisms are unclear. In particular, the mechanisms by which synaptic activity triggers neuronal gene expression, and by which gene products act specifically at synapses that triggered their expression, are poorly understood. To gain insight into these mechanisms, we investigated the activity-dependent regulation of Arc, an immediate-early gene essential for synaptic plasticity. We found that neurons regulate Arc expression at multiple levels, and that pathways that control Arc transcription integrate signals from NMDA and AMPA receptors. A role for AMPA receptors in regulating Arc expression is particularly surprising in light of the prevailing view that AMPA receptors mediate fast excitatory synaptic transmission and effect short-term plasticity, but do not directly regulate neuronal gene expression. We examined the mechanism by which AMPA receptors control Arc transcription and identified a role for pertussis toxin-sensitive G-proteins. This finding adds to a growing body of evidence that AMPA receptors are cell-surface signal transducers, not just passive conduits for current flux. We also provide preliminary evidence that another molecule, protein kinase D (PKD), may play a critical role in activity-dependent neuronal gene expression. PKD regulates histone deacetylase (HDAC)-mediated gene expression in cardiomyocytes and lymphocytes, but virtually nothing is known about its role in neurons. We found that NMDA receptor stimulation induces PKD activation and dendritic translocation. NMDA receptors also regulate the nucleocytoplasmic distribution of HDACs, suggesting that PKD may mediate a novel synapse-to-nucleus signal transduction pathway. Indeed, protein microarray experiments identified neuronal substrates of PKD that are known to regulate synaptic function. Thus, our investigation of Arc and PKD uncovered novel mechanisms by which neuronal activity couples to gene expression. The diversity of mechanisms that regulate Arc and PKD likely reflects the complexity of neuronal adaptive responses to synaptic activity.
The limited regenerative capacity of the adult mammalian brain following neuronal injury has encouraged researchers to explore neuronal replacement strategies to repair neural circuits and to recover compromised behavioural functions. One strategy uses retroviruses that target proliferating glia cells to induce ectopic overexpression of neuronal transcription factors (TFs), leading to glia-to-neuron reprogramming. Although these induced neurons (iNs) have been shown to acquire a neuronal morphology and neuron-specific functional features, it is not known to which extent their molecular phenotype resembles that of endogenous neurons (eNs) and whether they display homeostatic synaptic plasticity, a feature that would allow them to functionally integrate into a pre-existing neuronal network. These two aims were addressed in this work by overexpressing the TF Neurog2 in postnatal cortical glia and coculturing these with cortical eNs that have already established a network in vitro to allow integration of newly generated iNs. After a period of two weeks, network activity was either pharmacologically inhibited or left unperturbed and single-nucleus (sn) RNA-sequencing was performed. Interestingly, the subsequent molecular characterization of the iN population pointed to two distinct sources of diversity among the iN population: molecular subtype identities, comprising a broad range of inferred cortical subtypes and distinct developmental stages. To assess if iNs undergo HSP, I investigated the transcriptional dynamics in response to activity inhibition and how these compare to the ones elicited in eNs. While eNs displayed regulation of gene signatures indicative of HSP, iNs displayed downregulation of dendritic and postsynaptic genes that correlated with a reduced morphological complexity following activity inhibition. Interestingly, a set of synapserelated genes that was upregulated by eNs in response to activity inhibition was found to be highly expressed in iNs under control condition. Furthermore, pharmacological network activity disinhibition resulted in minimal c-Fos upregulation in iNs compared to eNs, pointing to limited integration into the network and suggesting that the high basal expression of synaptic genes in iNs may reflect ongoing competition for synaptic input. Immunocytochemical stainings showed that GABAergic, but not glutamatergic synapses decorate iNs. Taken together, these data suggest that iNs are not yet functionally integrated into the network, despite wide expression of synaptic machinery-related genes. Lack of synaptic input may be constraining iN maturation, while their high basal expression of synapse-related genes may indicate an increased competition for synaptic input. In sum, this work provides the first snRNA-seq study comparing the molecular phenotype and activity-dependent transcriptome of glia-derived iNs and cortical eNs, and suggests avenues for refining the iN differentiation process towards a functionally more mature and responsive phenotype.
This book provides the reader with background information on neurotransmitter release. Emphasis is placed on the rationale by which proteins are assigned specific functions rather than just providing facts about function.
Offers an up-to-date account of the latest research findings concerned with the regulatory mechanisms of gene expression in neuronal and glial cells under different conditions. The book explores the cellular and neurobiological aspects of important phenomena of the nervous system and its role in health, disease and injury. Contributions from prominent scientists in the field address a variety of specific topics concerned with gene expression in the nervous system--from growth, hormonal and trophic factors to neural tissue reactions in injury or aging.
To characterize the mechanisms by which MEF2 regulates synapse development, we perform a series of genome-wide analyses that identify the full complement of activity-regulated MEF2 target genes. The MEF2 targets identified in this context encode proteins with diverse functions at synapses, suggesting a broad role for MEF2 in synapse development and remodeling. Moreover, several MEF2 targets are mutated in human neurological disorders including epilepsy and autism-spectrum disorders. These analyses also reveal that neuronal activity leads to alternative polyadenylation site usage at many of the MEF2 target genes, resulting in the activity-dependent production of truncated mRNAs that may function to antagonize the activity of their full-length counterparts. Together, these experiments identify and characterize a MEF2-regulated program of gene expression that provides a link between neuronal activity and synapse development.