Adult neurogenesis in the mammalian hippocampus: why the dentate gyrus?

Abstract

In the adult mammalian brain, newly generated neurons are continuously incorporated into two networks: interneurons born in the subventricular zone migrate to the olfactory bulb, whereas the dentate gyrus (DG) of the hippocampus integrates locally born principal neurons. That the rest of the mammalian brain loses significant neurogenic capacity after the perinatal period suggests that unique aspects of the structure and function of DG and olfactory bulb circuits allow them to benefit from the adult generation of neurons. In this review, we consider the distinctive features of the DG that may account for it being able to profit from this singular form of neural plasticity. Approaches to the problem of neurogenesis are grouped as "bottom-up," where the phenotype of adult-born granule cells is contrasted to that of mature developmentally born granule cells, and "top-down," where the impact of altering the amount of neurogenesis on behavior is examined. We end by considering the primary implications of these two approaches and future directions.

Figure 1.

Local circuitry of the DG. The dendrites of GCs (G) receive three primary bands of excitatory drive in the molecular layer (ML) from proximal to distal—mossy cell fibers (MCF), medial entorhinal cortical inputs via the medial perforant path (MPP), and lateral entorhinal cortex via the lateral perforant path (LPP). GCs also receive synaptic input from the hypothalamus, perirhinal cortex, and cholinergic neurons of the septum, and the region contains serotoninergic, noradrenergic, and dopaminergic projections. GCs innervate a number of cell types in the hilus, including glutamatergic mossy cells (M) and various GABAergic interneuron subtypes including basket cells (B), that express parvalbumin or cholecystokinin, and dendritic targeting neurons, many of which express somatostatin (S). Most of these cells project “back” to the GCL, as well as there being connections between hilar neurons. In CA3, each GC innervates a small number of pyramidal neurons (P) and numerous GABAergic interneurons (I) in the stratum lucidum region.

Figure 2.

Development of abGC intrinsic properties. Before 2–3 wk of age abGCs have substantial excitability (very high input resistances, low resting membrane potentials) but can fire only single blunted action potentials. Around the fourth week post-mitosis they have greater intrinsic excitability and fire trains of action potentials. (AP) Action potential.

Figure 3.

Development of abGC afferent innervation. abGCs undergo a complex program of afferent innervation over the first 4- to 6-wk post-mitosis. At early time points they respond to ambient neurotransmitters, then they are progressively innervated by GABAergic and glutamatergic inputs, first locally and then by distal inputs. Hence, at different ages abGCs differ significantly from matGCs in terms of synaptic drive; whether the two GC classes ultimately converge in terms of afferent connectivity or whether they differ qualitatively is currently under debate. matGCs are known to receive significant input from hypothalamic/supramammillary afferents and varied neuromodulatory systems, the development of which in abGCs has yet to be extensively studied. (NGF) Neurogliaform cell; (NA) noradrenalin; (DA) dopamine; (*) “fast” IPSCs are present but these synaptic inputs are still significantly slower than such events in matGCs (Marín-Burgin et al. 2012).

Figure 4.

Synaptic plasticity at abGC afferents. Convergent lines of evidence support the notion that excitatory synapses onto abGCs (nearly always studied via stimulation of the medial molecular layer, i.e., presumed medial perforant path afferents) have a lower threshold for LTP and potentiate to a great degree when the cell is 3–6 wk of age. This is due to a number of factors including less pronounced GABAergic inhibition and greater expression of the NR2B subunit of the NMDA receptor.

Figure 5.

Development of abGC efferent axons. abGCs appear to be well connected to their target cells in CA3 and the hilus by the time they are strongly afferently driven and capable of firing trains of action potentials. When precisely their large mossy terminals (LMTs) are mature, based on microscopy studies, is a matter of some debate. Functionally, CA3 pyramidal neurons (PNs) receive weak glutamatergic inputs from 2-wk post-mitosis and at 4-wk synapses are, at basal levels, of mature strength and potentiate to a greater degree than mature (8-wk-old) abGCs. The functional coupling of young abGCs to the local hilar network is apparent from morphological studies but is functionally uncharacterized. (*) See Figure 1 for matGC connectivity.