Amyloid-β Impairs Synaptic Inhibition via GABAA Receptor Endocytosis

Amyloid beta (A beta) is thought to play an important role in the pathogenesis of Alzheimer's disease. A beta 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 beta effects at inhibitory synapses. This study investigates the impact of acute A beta 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 beta (1 mu 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 beta-induced IPSC decline could be prevented with intracellular applications of p4, a blocker of GABA(A) receptor internalization. It is concluded that A beta weakens synaptic inhibition via downregulation of GABA(A) receptors.