Modulation of septal cell activity by extracellular zinc

ZINC released from axon terminals in the brain can interact with multiple membrane channels and receptors. However, the specific effects of these Zn²⁺dependent interactions on physiological processes remains unclear. Because Zn²⁺ -containing axon terminals are abundant in the septal region, we selected a septal cell line (SN56) to study the effects of Zn²⁺ on cell activity. Voltage-clamp recordings showed well-developed voltage- dependent Na⁺, Ca²⁺ and K⁺ currents. Micromolar concentrations of Zn²⁺ partially blocked Na⁺ and Ca²⁺ currents without affecting K⁺ currents. Current-clamp recordings showed that SN56 cells fire spontaneous and evoked action potentials. While most (≤83%) Na⁺ and Ca²⁺ currents were blocked with 1 μM tetrodotoxin (TTX) and 2 mM Co²⁺, action potentials persisted after either 1 μM TTX or 2 mM Co²⁺ application. In contrast, concentrations of Zn²⁺ (50-300 μM) that induced incomplete blockade (≤ 50%) of either Ca²⁺ and Na⁺ currents abolished action potential generation. These data show that simultaneous and partial blockade of Ca²⁺ and Na⁺ channels by Zn²⁺ inhibit SN56 cell activity. Because septal outputs extensively modulate the excitability of cortical and subcortical brain regions, Zn²⁺ inhibition of action potential generation in septal neurons could play an important physiological role in regulating brain activity.