Nav1.6 Sodium Channels Are Critical to Pacemaking and Fast Spiking in Globus Pallidus Neurons

Abstract

Neurons in the external segment of the globus pallidus (GPe) are autonomous pacemakers that are capable of sustained fast spiking. The cellular and molecular determinants of pacemaking and fast spiking in GPe neurons are not fully understood, but voltage-dependent Na ϩ channels must play an important role. Electrophysiological studies of these neurons revealed that macroscopic activation and inactivation kinetics of their Na ϩ channels were similar to those found in neurons lacking either autonomous activity or the capacity for fast spiking. What was distinctive about GPe Na ϩ channels was a prominent resurgent gating mode. This mode was significantly reduced in GPe neurons lacking functional Nav1.6 channels. In these Nav1.6 null neurons, pacemaking and the capacity for fast spiking were impaired, as was the ability to follow stimulation frequencies used to treat Parkinson's disease (PD). Simulations incorporating Na ϩ channel models with and without prominent resurgent gating suggested that resurgence was critical to fast spiking but not to pacemaking, which appeared to be dependent on the positioning of Na ϩ channels in spike-initiating regions of the cell. These studies not only shed new light on the mechanisms underlying spiking in GPe neurons but also suggest that electrical stimulation therapies in PD are unlikely to functionally inactivate neurons possessing Nav1.6 Na ϩ channels with prominent resurgent gating.

CaV1.3-Driven SK Channel Activation Regulates Pacemaking and Spike Frequency Adaptation in Mouse Chromaffin Cells

“…SK channels preserve the high rate of Na v channel recovery at rest A reduced availability of transient Na v channels supporting the spike upstroke is generally reflected in a depolarization of the spike threshold (V thresh ) and a gradual decay of dV/dt max (Gettes and Reuter, 1974;Colbert et al, 1997;Mercer et al, 2007;Deister et al, 2009). This information can be easily obtained by displaying the membrane voltage (V ) against its first time derivative (dV/dt), resulting in a "phase plane" plot (Jenerick, 1963) for control (black) and apamin (red) (Fig.…”

Molecular and functional differences in voltage-activated sodium currents between GABA projection neurons and dopamine neurons in the substantia nigra

“…Na V 1.6 (␣6) and Na V ␤4 (␤4) are critical for I NaR generation (Bant and Raman 2010;Do and Bean 2004;Grieco and Raman 2004;Grieco et al 2005). In cerebellar Purkinje neurons and granule neurons and the GABA neurons in the globus pallidus, the Na v channels containing Na V 1.6 and/or Na v ␤4 have a resurgent property that generates a I NaR after the inactivation of the I NaT and upon repolarization (Bant and Raman 2010;Khaliq et al 2003;Mercer et al 2007;. I NaR has been suggested to facilitate fast spiking.…”

“…G/G max , normalized conductance; I/I max , normalized current. (Aman and Raman 2007;Bant and Raman 2010;Grieco et al 2004;Mercer et al 2007;Rush et al 2005).…”

“…For example, I NaT in hippocampal fast-spiking interneurons recovers rapidly from inactivation and thus promotes fast spiking (Martina & Jonas 1997). Na V channels containing Na V 1.6 and/or Na V ␤4 may have a resurgent property that generates a resurgent Na current (I NaR ) after the inactivation of the I NaT and upon repolarization that may facilitate fast spiking (Bant and Raman 2010;Khaliq et al 2003;Mercer et al 2007;. Additionally, Na V channels also conduct a small but long-lasting or persistent Na current (I NaP ) that increases neuronal excitability and promotes pacemaking firing (Bean 2007;Crill 1996).…”

Do gap junctions regulate synchrony in the Parkinsonian basal ganglia?

“…Intrinsic properties of GPe neurons are determined by more than 10 voltage-gated ion channel types [Mercer et al, 2007, Günay et al, 2008, Jaeger and Kita, 2011. Changes in the expression or function of these channels can contribute to changes in activity dynamics and influence synchrony in vivo.…”