Neural Stem Cell of the Hippocampus

Abstract

The formation of the hippocampus is generated during embryonic development, but most neurons within the structure are produced after birth. The hippocampus is a primary region of neurogenesis within the adult mammalian brain. Adult-born neurons have to integrate into the established neural circuitry throughout life. Although the function of neurogenesis in the adult hippocampus, particularly in humans, remains unclear, experimental data suggest that adult-born neurons are involved in some forms of memory, as well as in diseases. Adult hippocampal neurogenesis is dynamic, responding to physiological and pathological stimuli that may promote brain function or contribute to diseases such as epilepsy. Here, we review some of the mechanisms and signaling pathways involved in the development of the hippocampus, as well as in adult neurogenesis. We discuss some recent findings suggesting heterogeneity within the hippocampal stem cell pool and the regulation of activation of quiescent stem cells. Finally, we discuss some of the issues relating neurogenesis to pathophysiology and aging.

Introduction

Formation of the central nervous system (CNS) requires a precise control of proliferation, cell fate determination, and differentiation. Here we review some aspects of development of the hippocampus and regulation of adult neurogenesis from adult neural stem cells (aNSCs) in the dentate gyrus (DG). Following determination of the neural ectoderm and formation of the neural tube, a process known as neurulation, neuroectodermal (neuroepithelial) cells make up the entire neural tube. Neuroepithelial cells are patterned along the dorsoventral and anterior–posterior axis. This patterning defines the regions of the CNS and spinal cord. As neurogenesis commences, neuroepithelial cells, which span the entire thickness of the neural tube, transform into radial glial cells (RGCs). Although a few neurons are generated directly from the neuroepithelium, RGCs continue to act as primary progenitors for both neurons and glial cells (Anthony et al., 2004, Malatesta et al., 2003). Most neurons are generated during embryogenesis by RGCs that undergo self-renewing asymmetric cell divisions. The generation of neurons from RGCs usually progresses through an intermediate progenitor stage, which expands the number of cells generated. RGCs transform into parenchymal astrocytes and ependymal cells in the peri- and postnatal period, or continue to act as aNSCs in the walls of the lateral ventricles (subventricular zone, SVZ) and the subgranular zone (SGZ) of the hippocampal DG (Kriegstein & Alvarez-Buylla, 2009). Under physiological conditions, aNSCs display the structural and antigenic features of astrocytes (Doetsch et al., 1999, Garcia et al., 2004a, Seri et al., 2004, Seri et al., 2001). They retain the ability to self-renew throughout life and continue to generate actively dividing cell intermediates that function as transit-amplifying progenitors (TAPs). The aNSCs and TAPs of the SVZ and SGZ have distinct features, fates and functions (Kriegstein and Alvarez-Buylla, 2009, Ming and Song, 2011). In the SVZ, the immature neuroblasts migrate in chains to the olfactory bulb and differentiate into multiple distinct neuronal subtypes (Doetsch, 2003, Kriegstein and Alvarez-Buylla, 2009, Merkle et al., 2007). In the hippocampus, a single neuron-type is generated, DG granule neurons (Seri et al., 2004). In addition, the growth factor requirements and the response of the aNSCs in the SVZ and DG differ markedly.

In this review, we focus on NSCs in the hippocampal DG. The hippocampus is part of the limbic system and plays important roles in the consolidation of information, as well as long and short term memory, and spatial navigation. The DG is the primary input into the hippocampal formation receiving connections from the entorhinal cortex. Neurogenesis in the DG of the hippocampus is prominent in adult rodents as well as primates and humans (Bergmann et al., 2012, Eriksson et al., 1998, Spalding et al., 2013). Adult neurogenesis in the DG is critical for some forms of learning and memory and is modulated by pathological conditions (Zhao, Deng, & Gage, 2008). NSC identity in the adult DG has not been fully elucidated. However, embryonic RGCs and NSCs of the adult DG do share some features that suggest similarities between these two populations. Here we discuss formation of the hippocampal DG and some of the molecular pathways involved in the formation of this brain region. We then review some of the mechanisms controlling neurogenesis in the adult DG, the effects of physiological stimuli, and pathological insults including epilepsy and depression, as well as during aging.