TY - JOUR
T1 - Ammonia inhibits long-term potentiation via neurosteroid synthesis in hippocampal pyramidal neurons
AU - Izumi, Y.
AU - Svrakic, N.
AU - O'Dell, K.
AU - Zorumski, C. F.
N1 - Funding Information:
This work was supported by NIH Grants MH077791 , GM47969 and AA017413 and the Bantly Foundation . We thank Dr. Barry A. Hong, Department of Psychiatry of the Washington University of School of Medicine for thoughtful suggestions to initiate this study. We also thank the late Robert Purdy, a pioneer in neurosteroid research, for the neurosteroid antibody and helpful advice.
PY - 2013/3/3
Y1 - 2013/3/3
N2 - 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 5α-reduced neurosteroids, we found that 100 μM 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 5α-reductase, a key enzyme required for alloP synthesis. Finasteride also overcame LTP inhibition by 100 μM 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.
AB - 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 5α-reduced neurosteroids, we found that 100 μM 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 5α-reductase, a key enzyme required for alloP synthesis. Finasteride also overcame LTP inhibition by 100 μM 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.
KW - Allopregnanolone
KW - Finasteride
KW - Hepatic encephalopathy
KW - LTP
KW - Neurosteroid
KW - Tetrahydrodeoxycorticosterone
UR - http://www.scopus.com/inward/record.url?scp=84873748944&partnerID=8YFLogxK
U2 - 10.1016/j.neuroscience.2012.12.035
DO - 10.1016/j.neuroscience.2012.12.035
M3 - Article
C2 - 23276672
AN - SCOPUS:84873748944
VL - 233
SP - 166
EP - 173
JO - Neuroscience
JF - Neuroscience
SN - 0306-4522
ER -