Direct and indirect enhancement of GABAergic neurotransmission by ammonia: implications for the pathogenesis of hyperammonemic syndromes

Experimental evidence indicates that ammonia causes neuroexcitation and seizures. This contrasts with the lethargy, confusion and other manifestations of global CNS depression commonly considered to be major components of hyperammonemic encephalopathies. Substantial data now indicates that ammonia can modulate GABAergic neurotransmission through direct and indirect mechanisms. This modulation consists of an enhancement of GABAergic neurotransmission at concentrations commonly encountered in hyperammonemic states and precedes the suppression of inhibitory neuronal function observed at higher (>1 mM) ammonia concentrations. Not only is this increase in GABAergic neurotransmission consistent with the clinical picture of lethargy, ataxia and cognitive deficits associated with liver failure and congenital hyperammonemia, but it also provides a mechanism for testing new therapeutic modalities for the treatment of hyperammonemic encephalopathy. (C) 2002 Published by Elsevier Science Ltd.