Crucial Roles for SIRT2 and AMPA Receptor Acetylation in Synaptic Plasticity and Memory.

AMPA receptors (AMPARs) mediate fast excitatory synaptic transmission and are crucial for synaptic plasticity, learning, and memory. However, the molecular control of AMPAR stability and its neurophysiological significance remain unclear. Here, we report that AMPARs are subject to lysine acetylation at their C termini. Acetylation reduces AMPAR internalization and degradation, leading to increased cell-surface localization and prolonged receptor half-life. Through competition for the same lysine residues, acetylation intensity is inversely related to the levels of AMPAR ubiquitination. We find that sirtuin 2 (SIRT2) acts as an AMPAR deacetylase regulating AMPAR trafficking and proteostasis. SIRT2 knockout mice (Sirt2-/-) show marked upregulation in AMPAR acetylation and protein accumulation. Both Sirt2-/- mice and mice expressing acetylation mimetic GluA1 show aberrant synaptic plasticity, accompanied by impaired learning and memory. These findings establish SIRT2-regulated lysine acetylation as a form of AMPAR post-translational modification that regulates its turnover, as well as synaptic plasticity and cognitive function.

Soluble Aß oligomers impair hippocampal LTP by disrupting glutamatergic/GABAergic balance.

Epileptic activity may be more prevalent in early stage Alzheimer's disease (AD) than previously believed. Several studies report spontaneous seizures and interictal discharges in mouse models of AD undergoing age-related Aß accumulation. The mechanism by which Aß-induced neuronal excitability can trigger epileptiform activity remains unknown. Here, we systematically examined field excitatory postsynaptic potentials (fEPSP) in stratum radiatum and population spikes (PSs) in the adjacent stratum pyramidale of CA1 in wild-type mouse hippocampal slices. Soluble Aß oligomers (oAß) blocked hippocampal LTP and EPSP-spike (E-S) potentiation, and these effects were occluded by prior treatment with the glutamate uptake inhibitor TBOA. In accord, oAß elevated glutamate levels in the hippocampal slice medium. Recording the PS revealed that oAß increased PS frequency and reduced LTP, and this LTP deficit was occluded by pretreatment with the GABAA antagonist picrotoxin. Whole-cell recordings showed that oAß significantly increased spontaneous EPSC frequency. Decreasing neuronal activity by increasing GABA tone or partially blocking NMDAR activity prevented oAß impairment of hippocampal LTP. Finally, treating slices with two antiepileptic drugs rescued the LTP inhibition induced by oAß. We conclude that soluble Aß oligomers at the low nanomolar levels present in AD brain increase neuronal excitability by disrupting glutamatergic/GABAergic balance, thereby impairing synaptic plasticity.