Ammonia-mediated LTP inhibition: Effects of NMDA receptor antagonists and L-carnitine

Because hyperammonemia is thought to contribute to the pathogenesis of hepatic encephalopathy, we examined the effects of ammonia on ATP levels, neuronal morphology, and synaptic function in rat hippocampal slices. Although ammonia did not alter ATP levels supported by 10 mM glucose, ammonia significantly depressed ATP levels in the presence of 3.3 mM glucose or 10 mM pyruvate, suggesting effects on respiratory energy metabolism. Ammonia also impaired synaptic function and neuronal integrity sustained by pyruvate. In 10 mM glucose, ammonia inhibited the induction and maintenance of long-term potentiation (LTP) in a concentration-dependent fashion. These inhibitory effects of ammonia were overcome by l-carnitine. DL-APV, an antagonist of NMDA receptors, also diminished the effects of ammonia on ATP levels and LTP induction, indicating that ammonia impairs neuronal function via altered metabolism and untimely NMDA receptor activation. These results suggest that l-carnitine and NMDA receptor antagonists have the potential to preserve neuronal function during hyperammonemia.