Adult Neurogenesis, Glia, and the Extracellular Matrix

Abstract

In the adult mammalian hippocampus, new neurons arise from stem and progenitor cell division, in a process known as adult neurogenesis. Adult-generated neurons are sensitive to experience and may participate in hippocampal functions, including learning and memory, anxiety and stress regulation, and social behavior. Increasing evidence emphasizes the importance of new neuron connectivity within hippocampal circuitry for understanding the impact of adult neurogenesis on brain function. In this Review, we discuss how the functional consequences of new neurons arise from the collective interactions of presynaptic and postsynaptic neurons, glial cells, and the extracellular matrix, which together form the "tetrapartite synapse."

Keywords: adult neurogenesis; astrocytes; extracellular matrix; hippocampus; immature neuron; microglia; perineuronal nets; progenitor cell; stem cell.

Figure 1.. Overview of adult neurogenesis in the hippocampus, the circuitry into which the new cells are incorporated, and their involvement in behavior.

(A) Different stages of adult neurogenesis in the dentate gyrus (DG) of the hippocampus. New granule neurons originate from radial glial stem cells residing in the subgranular zone. These stem cells give rise to amplifying progenitor cells that in turn produce neuroblasts. The neuroblasts migrate into the granule cell layer and develop into immature granule neurons with a single dendritic tree extending toward the molecular layer and an axon (mossy fiber, mf) extending through the hilus toward the CA3 and CA2 subfields. (B) Schematic diagram of new neuron projections, showing the different hippocampal subfields (DG, CA3, CA2, and CA1) which serve as new neuron targets. Mossy fibers from new granule neurons form connections with hilar mossy cells, pyramidal cells in the CA3 and CA2, as well as with inhibitory interneurons in the DG, hilus, and CA3. (C) New granule neurons have been linked to behaviors associated with the hippocampus, such as spatial navigation learning, anxiety/stress regulation, and social cognition. Compared to rodents with typical numbers of new neurons (left), rodents with reduced adult neurogenesis (right) are impaired on some cognitive tests (for example, unable to locate the location of a hidden platform in the Morris water maze), have atypical responses in anxiety tests (for example, different latencies to approach food in the novelty suppressed feeding task), and impaired social cognition (for example, inability to recognize previously encountered mice in a social interaction test).

Figure 2.. Glia influence adult neurogenesis and synaptic connections formed by new neurons.

(A) Mechanisms of glial influences on adult neurogenesis. Through their secretion of growth factors and anti-inflammatory cytokines, astrocytes and microglia promote adult neurogenesis. Under pathological conditions, reactive microglia produce inflammatory cytokines that impair adult neurogenesis. Microglia also participate in adult neurogenesis by phagocytosing new neurons after they have died. (B) Mechanisms of glial influence on new neuron synapses. Astrocytes and microglia participate in regulating synapse number by secreting growth factors, cytokines, and ECM molecules. Astrocytes and microglia also shape neural circuits by engulfing weak synapses through phagocytosis. Glia modulate synaptic transmission by sensing changes in synaptic activity and releasing growth factors, cytokines, and/or gliotransmitters which, in turn, increase or decrease neural activity.

Figure 3.. The extracellular matrix influences adult neurogenesis and the synaptic connections formed by new neurons.

(A) Extracellular matrix (ECM) molecules such as tenascins, reelin, and chondroitin sulfate proteoglycans promote adult neurogenesis. (B) ECM influences new neuron connections and synaptic transmission. ECM molecules participate in the formation and stability of synapses, and through their interactions with cell surface receptors, influence synaptic activity by increasing neurotransmitter receptor activity, which increases intracellular calcium levels and enhances neural activity. (C) Specialized ECM structures, perineuronal nets (PNNs), which enwrap the cell body and proximal dendrites of hippocampal inhibitory interneurons and CA2 pyramidal cells, may attract or repel mossy fibers from new neurons.

Figure 4.. Models of new neuron connectivity under optimal, suboptimal, and pathologically dysfunctional states.

(A) Long-term physical exercise improves cognitive function and reduces anxiety. Optimization of hippocampus function may be achieved through the stimulation of adult neurogenesis, with the production of more new granule cells, each with more extensive dendritic trees and increased numbers of dendritic spines. New granule neurons form more connections with their targets, including inhibitory interneurons and CA2/CA3 pyramidal cells. Reduced PNNs along with healthy glial cells surrounding new synapses promote healthy new granule neuron connections to their target cells. (B) Chronic stress diminishes cognitive function and increases anxiety. Suboptimal function of the hippocampus occurs as a result of suppressed adult neurogenesis, with the production of fewer new granule cells, each with stunted dendritic trees and reduced numbers of dendritic spines. Stress-induced increases in PNNs along with alterations in glial cells (fewer astrocytes and reactive microglia) prevent healthy new granule neuron connections to their target cells. (C) Seizures significantly impair cognitive function and increase anxiety. Pathological function of the hippocampus results from the paradoxical production of more new granule neurons, each with with more extensive dendritic branching and increased numbers of dendritic spines. These new neurons are in ectopic locations and often have an aberrant basal dendritic tree extending into the hilus. These abnormalities impair integration by causing recurrent excitatory connections with other new granule neurons. Reduced PNNs along with reactive astrocytes and reactive microglia prevent the formation of healthy connections between new neurons and their target cells.