Brief Communications Amyloid- Impairs Synaptic Inhibition via GABAA Receptor Endocytosis

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 GABAA 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 GABAA receptor agonist isoguvacine. The A -induced IPSC decline could be prevented with intracellular applications of p4, a blocker of GABAA receptor internalization. It is concluded that A weakens synaptic inhibition via downregulation of GABAA receptors.