Synaptic integration and plasticity of new neurons in the adult hippocampus

Abstract

Adult neurogenesis, a developmental process encompassing the birth of new neurons from adult neural stem cells and their integration into the existing neuronal circuitry, highlights the plasticity and regenerative capacity of the adult mammalian brain. Substantial evidence suggests essential roles of newborn neurons in specific brain functions; yet it remains unclear how these new neurons make their unique contribution. Recently, a series of studies have delineated the basic steps of the adult neurogenesis process and shown that many of the distinct steps are dynamically regulated by the activity of the existing circuitry. Here we review recent findings on the synaptic integration and plasticity of newborn neurons in the adult hippocampus, including the basic biological process, unique characteristics, critical periods, and activity-dependent regulation by the neurotransmitters GABA and glutamate. We propose that adult neurogenesis represents not merely a replacement mechanism for lost neurons, but also an ongoing developmental process in the adult brain that offers an expanded capacity for plasticity for shaping the existing circuitry in response to experience throughout life.

Figure 1. Synaptic integration of new granule cells in the dentate gyrus of the adult mouse hippocampus

Shown is a schematic summary of the synaptic integration and maturation process of newborn dentate granule cells in the adult mouse hippocampus. Adult neurogenesis is a developmental process consisting of proliferation and fate specification of adult neural progenitors, and migration and integration of new neurons into the existing circuitry. New neurons also follow a stereotypic process to establish different types of synaptic inputs. For GABA signalling, tonic GABA activation occurs first, followed by formation of GABAergic dendritic synaptic inputs and finally perisomatic GABAergic inputs. New neurons exhibit a gradual change in the expression of different chloride transporters. As a consequence, new neurons are initially depolarized by GABA and gradually become hyperpolarized by GABA during their maturation. For glutamate signalling, glutamatergic synapse formation starts after initial synaptogenesis of GABAergic dendritic synaptic inputs and before synaptogenesis of perisomatic GABAergic synaptic inputs. During the maturation stages, there are two critical periods when new neurons are particularly sensitive to glutamatergic signalling, the first involving NR1-dependent competitive survival of new neurons and the second involving NR2B-dependent enhanced synaptic plasticity. The images shown in the top panel were adapted from Ge et al. (2006, 2007b).

Figure 2. Differential modulation of glutamateric synaptic plasticity of adult-born dentate granule cells by GABA

LTP recorded from GFP⁺ adult-born dentate granule cells in acute slices prepared at 4 weeks (A) or 8 weeks (B) after retrovirus-mediated birth-dating and expression of GFP as in Ge et al. (2007b). Evoked postsynaptic potentials (EPSPs) were recorded from GFP⁺ dentate granule cells under the whole-cell current-clamp at 32–34°C and LTP was induced with a physiologically relevant theta burst stimulation (TBS) protocol consisting of four repeated episodes (at 0.1 Hz) of 10 stimuli at 100 Hz, repeated 10 times at 5 Hz and paired with a 100 pA postsynaptic current injection (as in Ge et al. 2007b). Based on the intracellular/extracellular solutions for cells recorded at both time points ([Cl⁻]_i= 19 mm; [Cl⁻]_o= 134.1 mm), the expected chloride reversal potential is −51 mV. Shown in the top row is an example of LTP of EPSPs recorded under the whole-cell current-clamp. Representative EPSPs averaged from five consecutive stimuli were taken before and after LTP induction by a physiologically relevant TBS (arrow) at the time points (1 and 2) indicated in the graph. Scale bars: 5 mV and 50 ms. Shown at the bottom are the summaries of LTP recorded in the presence or absence of bicuculline (10 μm) in the recording bath (artificial cerebrospinal fluid; ACSF). Normalized EPSP amplitudes are shown. Values represent means ±s.e.m. The summary plot for neurons recorded in the presence of bicucculline was adapted from Ge et al. (2007b).