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 Ca2+ channels mediating this release has not been investigated. We investigated whether Ca2+ currents and transmitter release were affected by reduced neurofibromin in Nf1+/- mice. Hippocampal Ca2+ current density was greater in neurons from Nf1+/- mice and a greater fraction of Ca2+ 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 Ca2+ channel density and transmitter release, along with increased axonal growth may account for the abnormal nervous system functioning in NF1.
- Axonal growth
- Glutamate release
- N-type calcium channels/CaV2.2
- Sholl analysis
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