Prenatal exposure to aluminum reduces expression of neuronal nitric oxide synthase and of soluble guanylate cyclase and impairs glutamatergic neurotransmission in rat cerebellum

Exposure to aluminum (Al) produces neurotoxic effects in humans. However, t he molecular mechanism of Al neurotoxicity remains unknown. Al interferes w ith glutamatergic neurotransmission and impairs the neuronal glutamate-nitr ic oxide-cyclic GMP (cGMP) pathway, especially in rats prenatally exposed t o Al. The aim of this work was to assess whether Al interferes with process es associated with activation of NMDA receptors and to study the molecular basis for the Al-induced impairment of the glutamate-nitric oxide-cGMP path way. We used primary cultures of cerebellar neurons prepared from control r ats or from rats prenatally exposed to Al. Prenatal exposure to Al prevente d glutamate-induced proteolysis of the microtubule-associated protein-2, di saggregation of microtubules, and neuronal death, indicating an impairment of NMDA receptor-associated signal transduction pathways. Prenatal exposure to Al reduced significantly the content of nitric oxide synthase and guany late cyclase and increased the content of calmodulin both in cultured neuro ns and in the whole cerebellum, This effect was selective for proteins of t he glutamate-nitric oxide-cGMP pathway as the content of mitogen-activated protein kinase and the synthesis of most proteins were not affected by pren atal exposure to Al. The alterations in the expression of proteins of the g lutamate-nitric oxide-cGMP pathway could be responsible for some of the neu rotoxic effects of Al.