Effects of NALCN-Encoded Na⁺Leak Currents on the Repetitive Firing Properties of SCN Neurons Depend on K⁺-Driven Rhythmic Changes in Input Resistance

Jun 20, 2023The Journal of neuroscience : the official journal of the Society for Neuroscience

How Sodium Leak Currents Affect Repetitive Firing in Brain Clock Neurons Depends on Potassium-Controlled Rhythmic Changes in Input Resistance

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Abstract

NALCN-encoded sodium leak currents may differentially regulate daytime and nighttime firing rates of neurons in the suprachiasmatic nucleus.

Neurons in the suprachiasmatic nucleus generate daily rhythms in spontaneous action potential firing rates that influence physiology and behavior.
Firing rates are typically higher during the day compared to night, potentially due to subthreshold potassium conductance changes.
NALCN-encoded sodium leak currents appear to have a greater impact on daytime neurons compared to nighttime neurons.
Whole-cell recordings indicated that sodium leak current amplitudes are similar at both times, but their effects on membrane potential are more pronounced during the day.
Conditional knockout experiments showed that NALCN-encoded sodium currents selectively influence daytime repetitive firing rates.
The interaction between sodium leak currents and potassium current-driven changes in input resistance regulates the firing rates of SCN neurons.

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Neurons in the suprachiasmatic nucleus (SCN) generate circadian changes in the rates of spontaneous action potential firing that regulate and synchronize daily rhythms in physiology and behavior. Considerable evidence suggests that daily rhythms in the repetitive firing rates (higher during the day than at night) of SCN neurons are mediated by changes in subthreshold potassium (K) conductance(s). An alternative "bicycle" model for circadian regulation of membrane excitability in clock neurons, however, suggests that an increase in NALCN-encoded sodium (Na) leak conductance underlies daytime increases in firing rates. The experiments reported here explored the role of Naleak currents in regulating daytime and nighttime repetitive firing rates in identified adult male and female mouse SCN neurons: vasoactive intestinal peptide-expressing (VIP), neuromedin S-expressing (NMS) and gastrin-releasing peptide-expressing (GRP) cells. Whole-cell recordings from VIP, NMS, and GRPneurons in acute SCN slices revealed that Naleak current amplitudes/densities are similar during the day and at night, but have a larger impact on membrane potentials in daytime neurons. Additional experiments, using anconditional knockout approach, demonstrated that NALCN-encoded Nacurrents selectively regulate daytime repetitive firing rates of adult SCN neurons. Dynamic clamp-mediated manipulation revealed that the effects of NALCN-encoded Nacurrents on the repetitive firing rates of SCN neurons depend on Kcurrent-driven changes in input resistances. Together, these findings demonstrate that NALCN-encoded Naleak channels contribute to regulating daily rhythms in the excitability of SCN neurons by a mechanism that depends on Kcurrent-mediated rhythmic changes in intrinsic membrane properties.Elucidating the ionic mechanisms responsible for generating daily rhythms in the rates of spontaneous action potential firing of neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker in mammals, is an important step toward understanding how the molecular clock controls circadian rhythms in physiology and behavior. While numerous studies have focused on identifying subthreshold Kchannel(s) that mediate day-night changes in the firing rates of SCN neurons, a role for Naleak currents has also been suggested. The results of the experiments presented here demonstrate that NALCN-encoded Naleak currents differentially modulate daily rhythms in the daytime/nighttime repetitive firing rates of SCN neurons as a consequence of rhythmic changes in subthreshold Kcurrents. + + + + + + + + + + + + + + + + + + + in vivo SIGNIFICANCE STATEMENT

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Effects of NALCN-Encoded Na⁺Leak Currents on the Repetitive Firing Properties of SCN Neurons Depend on K⁺-Driven Rhythmic Changes in Input Resistance

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