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Review
. 2016 Feb 23:8:31.
doi: 10.3389/fnagi.2016.00031. eCollection 2016.

Implications of GABAergic Neurotransmission in Alzheimer's Disease

Yanfang Li  1 , Hao Sun  1 , Zhicai Chen  1 , Huaxi Xu  2 , Guojun Bu  3 , Hui Zheng  4
Affiliations
Review

Implications of GABAergic Neurotransmission in Alzheimer's Disease

Yanfang Li et al. Front Aging Neurosci. .

Abstract

Alzheimer's disease (AD) is characterized pathologically by the deposition of β-amyloid peptides (Aβ) and the accumulation of neurofibrillary tangles (NFTs) composed of hyper-phosphorylated tau. Regardless of the pathological hallmarks, synaptic dysfunction is widely accepted as a causal event in AD. Of the two major types of synapses in the central nervous system (CNS): glutamatergic and GABAergic, which provide excitatory and inhibitory outputs respectively, abundant data implicate an impaired glutamatergic system during disease progression. However, emerging evidence supports the notion that disrupted default neuronal network underlies impaired memory, and that alterations of GABAergic circuits, either plays a primary role or as a compensatory response to excitotoxicity, may also contribute to AD by disrupting the overall network function. The goal of this review is to provide an overview of the involvement of Aβ, tau and apolipoprotein E4 (apoE4), the major genetic risk factor in late-onset AD (LOAD), in GABAergic neurotransmission and the potential of modulating the GABAergic function as AD therapy.

Keywords: GABAergic neurotransmission; amyloid beta-peptides; apolipoproteins E; neuronal inhibition; tau proteins.

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Figures

Figure 1
Figure 1
Proposed model of GABAergic signaling in AD pathogenesis. Calcium enters the presynaptic terminal via Aβ formed pores on cell membrane. The increased calcium concentration triggers presynaptic glutamate neurotransmitter release and activates postsynaptic receptors. The activated NMDA receptors further enhance the GABAA receptor activation to dampen the overexcitation. In astrocytes, GABA could be synthesized from putresine or glutamate and released via GAT3/4 or Best1 channel. The release of GABA from astrocytes may be enhanced under AD conditions to activate the extrasynaptic GABAA and GABAB receptors, resulting in suppressed long-term potentiation (LTP) and impaired cognition. The activation of GABAA receptors by anesthetics reduces PP2A binding with tau protein, resulting in tau hyperphosphorylation, which feeds back and enhances the activation of GABAergic interneurons and GABA release. ApoE4 secreted from GABAergic interneurons results in reduced interneuron number and reduced GABAergic innervation to other neurons, eventually leading to the disruption of neuronal circuitry and impaired cognition.
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