Extracellular sodium modulates the excitability of cultured hippocampal pyramidal cells.

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.

Capillary endothelial Na(+), K(+), ATPase transporter homeostasis and a new theory for migraine pathophysiology.

BACKGROUND: Cerebrospinal fluid sodium concentration ([Na(+)](csf)) increases during migraine, but the cause of the increase is not known. OBJECTIVE: Analyze biochemical pathways that influence [Na(+)](csf) to identify mechanisms that are consistent with migraine. METHOD: We reviewed sodium physiology and biochemistry publications for links to migraine and pain. RESULTS: Increased capillary endothelial cell (CEC) Na(+), K(+), -ATPase transporter (NKAT) activity is probably the primary cause of increased [Na(+)](csf). Physiological fluctuations of all NKAT regulators in blood, many known to be involved in migraine, are monitored by receptors on the luminal wall of brain CECs; signals are then transduced to their abluminal NKATs that alter brain extracellular sodium ([Na(+)](e)) and potassium ([K(+)](e)). CONCLUSIONS: We propose a theoretical mechanism for aura and migraine when NKAT activity shifts outside normal limits: (1) CEC NKAT activity below a lower limit increases [K(+)](e), facilitates cortical spreading depression, and causes aura; (2) CEC NKAT activity above an upper limit elevates [Na(+)](e), increases neuronal excitability, and causes migraine; (3) migraine-without-aura may arise from CEC NKAT over-activity without requiring a prior decrease in activity and its consequent spreading depression; (4) migraine triggers disturb, and treatments improve, CEC NKAT homeostasis; (5) CEC NKAT-induced regulation of neural and vasomotor excitability coordinates vascular and neuronal activities, and includes occasional pathology from CEC NKAT-induced apoptosis or cerebral infarction.