title: Amyloid-β Impairs Synaptic Inhibition via GABA(A) Receptor Endocytosis.
abstract: Amyloid β (Aβ) is thought to play an important role in the pathogenesis of Alzheimer's disease. Aβ 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 Aβ effects at inhibitory synapses. This study investigates the impact of acute Aβ1-42 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 Aβ (1 μm) 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 GABAA receptor agonist isoguvacine. The Aβ-induced IPSC decline could be prevented with intracellular applications of p4, a blocker of GABA(A) receptor internalization. It is concluded that Aβ weakens synaptic inhibition via downregulation of GABA(A) receptors.
authors.affiliation: Department Physiology & Institute of Neuroscience, Trinity College, Dublin 2, Ireland ulrichd@tcd.ie.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ulrich
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D005260:Female; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011963:Receptors, GABA-A; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer; GABA; IPSP; amyloid-β; cortex; plasticity