Imbalance between GABAergic and Glutamatergic Transmission Impairs Adult Neurogenesis in an Animal Model of Alzheimer's Disease

Abstract

SUMMARY Adult neurogenesis regulates plasticity and function in the hippocampus, which is critical for memory and vulnerable to Alzheimer’s disease (AD). Promoting neurogenesis may improve hippocampal function in AD brains. However, how amyloid β (Aβ), the key AD pathogen, affects the development and function of adult-born neurons remains unknown. Adult-born granule cells (GCs) in human amyloid precursor protein (hAPP) transgenic mice, an AD model, showed greater dendritic length, spine density, and functional responses than controls early in development, but were impaired morphologically and functionally during later maturation. Early inhibition of GABAA receptors to suppress GABAergic signaling or late inhibition of calcineurin to enhance glutamatergic signaling normalized the development of adult-born GCs in hAPP mice with high Aβ levels. Aβ-induced increases in GABAergic neurotransmission or an imbalance between GABAergic and glutamatergic neurotransmission may contribute to impaired neurogenesis in AD.

Adult Neurogenesis in Neurodegenerative Diseases: Figure 1.

“…In particular, Ab-mediated alterations of the GABAergic neurotransmission or an imbalance between hippocampal GABAergic and glutamatergic neurotransmission result in an impaired hippocampal neurogenesis in AD. Specifically, Ab modifies the balance between excitatory and inhibitory inputs on adult-born neurons (Sun et al 2009). Furthermore, risk genes for AD, such as the apolipopotein E, may have a detrimental effect on adult hippocampal neurogenesis as a result of altered signaling that promotes glial differentiation at the expense of neurogenesis (Li et al 2009).…”

Adult Neurogenesis and Mental Illness

“…In fact, the anxiolytic-like effects of running are blocked by GABA receptor antagonists in mice , suggesting that running and anxiolytic drugs may share the same mechanism. Little is known about the effects of anxiolytic medications on granule neuron maturation, but pentobarbital increases dendritic length in young granule neurons, whereas the GABA-A receptor antagonist picrotoxin inhibits maturation, decreasing both spine density and dendritic length (Sun et al, 2009). In addition to any effects on maturation, the finding that running increases GABAergic signaling in the dentate gyrus and decreases the activation of new granule neurons by stress suggests that anxiolytic medications may alter the functioning of new neurons in stressful situations.…”

GABA Is Depolarizing in Hippocampal Dentate Granule Cells of the Adolescent and Adult Rats

“…However, measurements of V rest and E GABA appeared to be nontrivial (see Glickfeld et al, 2009). Recent studies (Ge et al, 2006;Sun et al, 2009) have reported that GABAergic action switches from depolarizing to hyperpolarizing during maturation of DGCs. In their studies, V rest of DGCs remains at ϳϪ60 mV throughout all developmental stages, whereas E GABA shifts from ϳϪ40 to ϳϪ70 mV during development.…”

“…In contrast, the action of GABAergic inputs onto dentate granule cells (DGCs), a key relay station that controls information transfer from the entorhinal cortex into the hippocampus proper (Amaral et al, 2007), remains inconclusive. Recent studies showed that GABAergic action switches from "depolarizing" to "hyperpolarizing" during maturation of DGCs (Ge et al, 2006;Sun et al, 2009;Ming and Song, 2011). Yet these findings contrast with a previous report that GABAergic inputs onto DGCs are depolarizing (Staley and Mody, 1992) and are contradictory to the relatively hyperpolarized resting potential (V rest ) of DGCs, which is negative to the reversal potential for GABAergic currents (E GABA ) (Staley and Mody, 1992;Kraushaar and Jonas, 2000).…”