Thyroid hormone (triiodo-L-thyronine, T3) increases voltage-gated Na⁺current density (Nav-D) in postnatal rat hippocampal neurons, thereby accelerating action potential upstroke velocity and firing rates (Hoffmann and Dietzel, Neurosci 125: 369–379, 2004). This upregulation of the Nav-D could underlie increases in cortical excitability induced by thyroid hormone (Rizzo et al., J Neurol Sci 266: 38–43, 2008).

To determine whether T3 acts directly on neurons or via intermediate factors we investigated changes of the Nav-D following T3-treatments under various culture conditions. Our experiments revealed that a preincubation with T3 for 4 days in vitro only regulated Nav-D if glial cells were present or after incubation of neuron enriched cultures with T3- treated conditioned media from astrocyte cultures. The effect could be abolished by heating the conditioned media to 95°, indicating that the upregulation of the Nav-D is caused by a protein. The regulation of the Nav-D was mimicked by the addition of basic fibroblast growth factor (bFGF), known to be released from cerebellar glial cells by T3-treatment (Lima et al., J Endocrinol 154: 167–175, 1997) to the culture medium. Preincubation of the cultures with monoclonal antibodies against bFGF inhibited the upregulation of Nav-D, both in cultures pretreated with bFGF or with T3- preincubated astrocyte conditioned medium. These observations were corroborated by recordings using reversed Na⁺gradients that allow the isolation of soma-near Na⁺currents under improved space clamp conditions.

Our results indicate, that T3 stimulated glial cells upregulate the Nav-D in neurons by a signal cascade involving the release of bFGF.