Alterations in GABAA-Receptor Trafficking and Synaptic Dysfunction in Brain Disorders

Abstract

GABA_A receptors (GABA_AR) are the major players in fast inhibitory neurotransmission in the central nervous system (CNS). Regulation of GABA_AR trafficking and the control of their surface expression play important roles in the modulation of the strength of synaptic inhibition. Different pieces of evidence show that alterations in the surface distribution of GABA_AR and dysregulation of their turnover impair the activity of inhibitory synapses. A diminished efficacy of inhibitory neurotransmission affects the excitatory/inhibitory balance and is a common feature of various disorders of the CNS characterized by an increased excitability of neuronal networks. The synaptic pool of GABA_AR is mainly controlled through regulation of internalization, recycling and lateral diffusion of the receptors. Under physiological condition these mechanisms are finely coordinated to define the strength of GABAergic synapses. In this review article, we focus on the alteration in GABA_AR trafficking with an impact on the function of inhibitory synapses in various disorders of the CNS. In particular we discuss how similar molecular mechanisms affecting the synaptic distribution of GABA_AR and consequently the excitatory/inhibitory balance may be associated with a wide diversity of pathologies of the CNS, from psychiatric disorders to acute alterations leading to neuronal death. A better understanding of the cellular and molecular mechanisms that contribute to the impairment of GABAergic neurotransmission in these disorders, in particular the alterations in GABA_AR trafficking and surface distribution, may lead to the identification of new pharmacological targets and to the development of novel therapeutic strategies.

Keywords: Alzheimer’s disease; GABAA receptor trafficking; Huntington’s disease; Parkinson’s disease; brain ischemia; epilepsy.

Figure 1

GABA_A receptor (GABA_AR) trafficking under physiologic condition. (1) GABA_AR are assembled in the ER. (2) In the ER, unassembled receptor subunits are subjected to poly-ubiquitination and targeted for proteasomal degradation. (3) GABA_AR transport to the Golgi is a process negatively regulated by Plic-1. Inside the Golgi, GABA_AR bind to GABA_AR associated protein (GABARAP)/N-ethylmaleimide-sensitive factor (NSF) complex that facilitates their transport to the plasma membrane. The delivery of GABA_AR to the plasma membrane is also regulated by GODZ, Big2, glutamate receptor-interacting protein (GRIP) and PRIP. (4) At the plasma membrane, GABA_AR quickly exchange between synaptic and extrasynaptic locations, and the accumulation of the receptor at the inhibitory synapses is regulated by its scaffold protein gephyrin. (5) The phosphorylation of β3 or γ2 GABA_AR subunits on their intracellular loop negatively regulates GABA_AR internalization. (6) The process of GABA_AR endocytosis is AP2/clathrin/dynamin-mediated. (7) Most internalized GABA_AR are rapidly recycled back to the plasma membrane by a mechanism dependent of the interaction with huntingtin-associated protein 1 (HAP1). (8) The non-recycled GABA_AR are targeted for lysosomal degradation.

Figure 2

Alterations of GABA_AR trafficking in brain disorders. Deficits in GABA_AR trafficking have been reported in different pathological conditions in the central nervous system (CNS). (1) Reduced synaptic clustering of GABA_AR has been observed in epilepsy, ischemia, autism spectrum disorders (ASDs) and Alzheimer’s disease (AD). (2) Increased dephosphorylation of GABA_AR β3 subunit on serine residues 408/9 (Ser^408/409) has been reported in epilepsy, ischemic condition and ASD. (3) An increase in AP2/clathrin/dynamin-mediated endocytosis of GABA_AR occurs in epileptic conditions, ischemia, ASD and AD. (4) Impairment in GABA_AR recycling has been shown in ischemic conditions and in Huntington’s disease (HD). (5) Enhanced lysosomal degradation of GABA_AR due to ubiquitination was detected after an ischemic insult.