Epigenetics, hippocampal neurogenesis, and neuropsychiatric disorders: unraveling the genome to understand the mind

Abstract

In mature, differentiated neurons in the central nervous system (CNS), epigenetic mechanisms--including DNA methylation, histone modification, and regulatory noncoding RNAs--play critical roles in encoding experience and environmental stimuli into stable, behaviorally meaningful changes in gene expression. For example, epigenetic changes in mature hippocampal neurons have been implicated in learning and memory and in a variety of neuropsychiatric disorders, including depression. With all the recent (and warranted) attention given to epigenetic modifications in mature neurons, it is easy to forget that epigenetic mechanisms were initially described for their ability to promote differentiation and drive cell fate in embryonic and early postnatal development, including neurogenesis. Given the discovery of ongoing neurogenesis in the adult brain and the intriguing links among adult hippocampal neurogenesis, hippocampal function, and neuropsychiatric disorders, it is timely to complement the ongoing discussions on the role of epigenetics in mature neurons with a review on what is currently known about the role of epigenetics in adult hippocampal neurogenesis. The process of adult hippocampal neurogenesis is complex, with neural stem cells (NSCs) giving rise to fate-restricted progenitors and eventually mature dentate gyrus granule cells. Notably, neurogenesis occurs within an increasingly well-defined "neurogenic niche", where mature cellular elements like vasculature, astrocytes, and neurons release signals that can dynamically regulate neurogenesis. Here we review the evidence that key stages and aspects of adult neurogenesis are driven by epigenetic mechanisms. We discuss the intrinsic changes occurring within NSCs and their progeny that are critical for neurogenesis. We also discuss how extrinsic changes occurring in cellular components in the niche can result in altered neurogenesis. Finally we describe the potential relevance of epigenetics for understanding the relationship between hippocampal neurogenesis in neuropsychiatric disorders. We propose that a more thorough understanding of the molecular and genetic mechanisms that control the complex process of neurogenesis, including the proliferation and differentiation of NSCs, will lead to novel therapeutics for the treatment of neuropsychiatric disorders.

Figure 1. Ongoing neurogenesis occurs in two discrete regions in the adult mammalian brain

(a) Progenitor cells (A–C) in the anterior subventricular zone (SVZ) lie adjacent to the ependymal cell (D) layer lining the lateral ventricles and interact with basal lamina extending from the vasculature. SVZ progenitors differentiate and migrate through the rostral migratory stream before they reach the olfactory bulb (OB) and integrate as granule neurons in the granule cell layer and as periglomerular neurons (not shown). (b) Type 1 and Type 2 progenitor cells in the subgranular zone (SGZ) proliferate and go through several stages of morphological and physiological changes as they differentiate into newborn neurons in the dentate gyrus of the hippocampus. Abbreviations are as follows: GCL, granule cell layer; Mol, molecular layer.

Figure 2. Environmental factors signal to the neural stem cell genome to regulate cell fate decisions and neurogenesis

Sequence-specific transcription factors work in concert with the chromatin machinery to direct the neuronal lineage program within neural stem cells. In the stem cell state, repressive chromatin remodeling machinery maintains neuronal gene repression (OFF) through one set of histone modifications, such as histone H3 lysine K9 methylation and DNA cytosine methylation. Stimulation by environmental factors and/or stress signals (during disease) can induce adult neurogenesis and survival/maturation of newborn neurons by de-repressing or activating neuronal gene expression (ON) through the hyperacetylation and/or switch in histone modification to histone H3 lysine K4 methylation. The emergence of noncoding RNAs adds another layer of regulatory complexity to help fine-tune gene expression. Abbreviations are as follows: Me: methylation, Ac: acetylation, K: lysine, ncRNAs: noncoding RNAs, TF: transcription factor.

Figure 3. Hypothetical relationship among animal models of psychiatric disorders, epigenetic regulation in SGZ stem cells, and altered adult hippocampal neurogenesis

Environmental/physiological stimuli, such as drug-induced seizure activity or chronic exposure to antidepressant agents or drugs of abuse, lead to complex neuroadaptations in discrete brain regions including altered neurogenesis. We hypothesize that these stimuli may also produce cell-intrinsic changes in chromatin remodeling that contributes to altered neurogenesis and ultimately altered neuronal genome structure. Recent advances in understanding epigenetic regulation and technical advances in determining and independently regulating chromatin modifications now make it possible to test these hypothetical relationships.