Recent studies demonstrated a photophobia mechanism with modulation of nociceptive, cortico-thalamic neurons by retinal ganglion cell projections; however, little is known about how their neuronal homeostasis is disrupted. Since we have found that lumbar cerebrospinal fluid (CSF) sodium increases during migraine and that cranial sodium increases in a rat migraine model, the purpose of this study was to examine the effects of extracellular sodium ([Na(+)](o)) on the intrinsic excitability of hippocampal pyramidal neurons. We monitored excitability by whole cell patch using a multiplex micropipette with a common outlet to change artificial CSF (ACSF) [Na(+)](o) at cultured neurons accurately (SD<7 mM) and rapidly (<5s) as determined by a sodium-selective micro-electrode of the same size and at the same location as a neuronal soma. Changing [Na(+)](o) in ACSF from 100 to 160 mM, choline-balanced at 310-320 mOsm, increased the action potential (AP) amplitude, decreased AP width, and augmented firing rate by 28%. These effects were reversed on returning the ACSF [Na(+)](o) to 100mM. Testing up to 180 mM [Na(+)](o) required ACSF with higher osmolarity (345-355 mOsm), at which the firing rate increased by 36% between 100 and 180 mM [Na(+)](o), with higher amplitude and narrower APs. In voltage clamp mode, the sodium and potassium currents increased significantly at higher [Na(+)](o). These results demonstrate that fluctuations in [Na(+)](o) modulate neuronal excitability by a sodium current mechanism and that excessively altered neuronal excitability may contribute to hypersensitivity symptoms.
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