AMMONIA INHIBITS LONG-TERM POTENTIATION VIA NEUROSTEROID SYNTHESIS IN HIPPOCAMPAL PYRAMIDAL NEURONS

作者：Izumi Y^*; Svrakic N; O'Dell K; Zorumski C F

来源：Neuroscience, 2013, 233: 166-173.

DOI：10.1016/j.neuroscience.2012.12.035

• hepatic encephalopathy
• finasteride
• allopregnanolone
• tetrahydrodeoxycorticosterone
• LTP
• neurosteroid

Neurosteroids are a class of endogenous steroids synthesized in the brain that are believed to be involved in the pathogenesis of neuropsychiatric disorders and memory impairment. Ammonia impairs long-term potentiation (LTP), a synaptic model of learning, in the hippocampus, a brain region involved in memory acquisition. Although mechanisms underlying ammonia-mediated LTP inhibition are not fully understood, we previously found that the activation of N-methyl-D-aspartate receptors (NMDARs) is important. Based on this, we hypothesize that metabolic stressors, including hyperammonemia, promote untimely NMDAR activation and result in neural adaptations that include the synthesis of allopregnanolone (alloP) and other GABA-potentiating neurosteroids that dampen neuronal activity and impair LTP and memory formation. Using an antibody against 5 alpha-reduced neurosteroids, we found that 100 mu M ammonia acutely enhanced neurosteroid immunostaining in pyramidal neurons in the CA1 region of rat hippocampal slices. The enhanced staining was blocked by finasteride, a selective inhibitor of 5 alpha-reductase, a key enzyme required for alloP synthesis. Finasteride also over-came LTP inhibition by 100 mu M ammonia, as did picrotoxin, an inhibitor of GABA-A receptors. These results indicate that GABA-enhancing neurosteroids, synthesized locally within pyramidal neurons, contribute significantly to ammonia-mediated synaptic dysfunction. These results suggest that the manipulation of neurosteroid synthesis could provide a strategy to improve cognitive function in individuals with hyperammonemia.

• 出版日期2013-3-13