Reliable Activation of Immature Neurons in the Adult Hippocampus

Abstract

Neurons born in the adult dentate gyrus develop, mature, and connect over a long interval that can last from six to eight weeks. It has been proposed that, during this period, developing neurons play a relevant role in hippocampal signal processing owing to their distinctive electrical properties. However, it has remained unknown whether immature neurons can be recruited into a network before synaptic and functional maturity have been achieved. To address this question, we used retroviral expression of green fluorescent protein to identify developing granule cells of the adult mouse hippocampus and investigate the balance of afferent excitation, intrinsic excitability, and firing behavior by patch clamp recordings in acute slices. We found that glutamatergic inputs onto young neurons are significantly weaker than those of mature cells, yet stimulation of cortical excitatory axons elicits a similar spiking probability in neurons at either developmental stage. Young neurons are highly efficient in transducing ionic currents into membrane depolarization due to their high input resistance, which decreases substantially in mature neurons as the inward rectifier potassium (Kir) conductance increases. Pharmacological blockade of Kir channels in mature neurons mimics the high excitability characteristic of young neurons. Conversely, Kir overexpression induces mature-like firing properties in young neurons. Therefore, the differences in excitatory drive of young and mature neurons are compensated by changes in membrane excitability that render an equalized firing activity. These observations demonstrate that the adult hippocampus continuously generates a population of highly excitable young neurons capable of information processing.

Reversal of hippocampal neuronal maturation by serotonergic antidepressants

“…In addition, the intact basal synaptic efficacy at both input and output synapses of the fluoxetine-treated GCs implies that the formation of synaptic connection itself was preserved. Young GCs generated during the fluoxetine treatment would be smaller and have higher input resistance than mature cells (12,14,16), and would have less synaptic contacts (16). Thus, these results are consistent with the idea that the immature-like GCs in fluoxetine-treated mice mostly originated from mature cells.…”

“…Our results suggest that the state of fluoxetine-treated GCs is comparable to that of 3-to 4-week-old adult-generated neurons (Fig. S9B), because (i) the calbindin expression and stimulus-induced c-Fos expression are established in 3-to 5-week-old GCs (17,25,28); (ii) whereas the number of calretinin-positive GCs was increased by fluoxetine, most cells were negative for this early postmitotic marker; and (iii) GCs less than 3 weeks old hardly generate repetitive action potentials (16), but fluoxetine-treated GCs did. In other words, fluoxetine reversed the late step of GC maturation.…”

“…The dentate gyrus is positioned at the entrance of the hippocampal excitatory trisynaptic circuit, and the mossy fiber (MF) from the DG plays a critical role in regulating associative synaptic plasticity in the hippocampal CA3 region (9,10). Because physiological properties of granule cells (GCs), the principal neurons of the DG, greatly change with development or neuronal maturation (11)(12)(13)(14)(15)(16), an increase in a proportion of relatively young GCs by facilitated neurogenesis may alter functional roles of the DG in the hippocampal circuit. However, the majority of the neuronal population in adult DG is composed of mature GCs.…”

Neurogenesis and Inflammation after Ischemic Stroke: What is Known and Where We Go from Here

“…Consequently, they fire more action potentials in a given time than their mature counterparts. [110][111][112] Thus, overall circuit excitation will be increased, which could help ameliorate some of the loss of excitation after cell death after ischemia. Therefore, in combination with other strategies such as stem cell transplantation, the use of endogenous neurogenesis mechanisms could prove to be extremely beneficial for brain repair.…”

Computational Modeling of Adult Neurogenesis

“…First, young neurons, particularly those ,2 -3 wk old, have a weaker and even depolarizing response to g-aminobutyric acid (GABA) (Ge et al 2006). Second, immature neurons maintain a distinct set of ion channels, contributing to both a higher overall resistance and a differential spiking response (Mongiat et al 2009). Finally, using a computational model far simpler than the multicompartmental GC models mentioned above, we have presented evidence that the reduced synaptic input, both inhibitory and excitatory, is sufficient to bias a typically silenced immature GC to fire more often than mature neurons (Li et al 2012).…”