Amyloid-  Impairs Synaptic Inhibition via GABAA Receptor Endocytosis

Abstract

Amyloid ␤ (A␤) is thought to play an important role in the pathogenesis of Alzheimer's disease. A␤ may exert its neurotoxic effects via multiple mechanisms and in particular through degradation of excitatory synaptic transmission associated with impaired synaptic plasticity. In contrast, much less is known about A␤ effects at inhibitory synapses. This study investigates the impact of acute A␤1-42 application on GABAergic synaptic transmission in rat somatosensory cortex in vitro. Whole-cell voltage-clamp recordings were obtained from layer V pyramidal cells, and monosynaptic GABA A receptor-mediated IPSCs were elicited. Bath-applied A␤ (1 M) depressed the IPSCs on average to 60% of control, whereas a reversed sequence control peptide was ineffective. Paired-pulse stimuli indicated a postsynaptic site of action. This was further corroborated by a decreased postsynaptic responsiveness to local puffs of the GABA A receptor agonist isoguvacine. The A␤-induced IPSC decline could be prevented with intracellular applications of p4, a blocker of GABA A receptor internalization. It is concluded that A␤ weakens synaptic inhibition via downregulation of GABA A receptors.

Sleep: A Novel Mechanistic Pathway, Biomarker, and Treatment Target in the Pathology of Alzheimer's Disease?

“…For example, the precise mechanism(s) through which Aβ disrupts NREM sleep physiology, specifically within slow oscillation frequency range (<1Hz), is unknown. One tenable candidate that we offer is Aβ-disruption of frontal NMDA and GABA A receptor function that underlies NREM slow oscillation expression in cortical regions known to accumulate Aβ early 43–45 . The low frequency (<1Hz) slow oscillations of NREM sleep are governed by NMDA and GABA A receptor activity, the former dictating a cellular UP state of cortical excitation, the latter the DOWN state involving prolonged hyperpolarization 44 .…”

Therapeutics of Neurotransmitters in Alzheimer’s Disease

“…These two studies have shown that the β2/3 subunits are relatively resistant to alteration in AD patients [126]. Ulrich [127] investigated the effect of Aβ peptides on synaptic transmission through the GABA (A) receptor-mediated endocytosis mechanism and found that Aβ may weaken synaptic inhibition through downregulation of GABA (A) receptors and reversed in the presence of GABA (A) receptor agonist (isoguvacine).…”

Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease

“…In a separate study of the fimbria-CA3 complex postsynaptic response, Aβ also induces a significant decrease in late inhibitory postsynaptic currents (IPSCs) (Nava-Mesa et al, 2013). Treatment of somatosensory neurons with soluble Aβ as much as 1 µM has also been found to decrease agonist-evoked GABA A responses and to depress monosynaptic GABA A receptor-mediated IPSCs to 60% of control levels on average, whereas a reversed sequence control peptide is ineffective (Ulrich, 2015). The downregulated GABA A receptors for Aβ-mediated synaptic inhibition are due to increased endocytosis of GABA A receptors, because the induced IPSC decline was prevented by intracellular applications of p4, a peptide inhibitor to block the dynamin-mediated removal of GABA A receptors from the plasma membrane.…”