Altered calcium currents and axonal growth in Nf1 haploinsufficient mice

Abstract

Mutations of the neurofibromin gene (NF1) cause neurofibromatosis type 1 (NF1), a disease in which learning disabilities are common. Learning deficits also are observed in mice with a heterozygous mutation of Nf1 (Nf1(+/-)). Dysregulation of regulated neurotransmitter release has been observed in Nf1(+/-) mice. However, the role of presynaptic voltage-gated Ca(2+) channels mediating this release has not been investigated. We investigated whether Ca(2+) currents and transmitter release were affected by reduced neurofibromin in Nf1(+/-) mice. Hippocampal Ca(2+) current density was greater in neurons from Nf1(+/-) mice and a greater fraction of Ca(2+) currents was activated at less depolarized potentials. In addition, release of the excitatory neurotransmitter, glutamate, was increased in neuronal cortical cultures from Nf1(+/-) mice. Dendritic complexity and axonal length were also increased in neurons Nf1(+/-) mice compared to wild-type neurons, linking loss of neurofibromin to developmental changes in hippocampal axonal/cytoskeletal dynamics. Collectively, these results show that altered Ca(2+) channel density and transmitter release, along with increased axonal growth may account for the abnormal nervous system functioning in NF1.