Selective Participation of Somatodendritic HCN Channels in Inhibitory But Not Excitatory Synaptic Integration in Neurons of the Subthalamic Nucleus

Abstract

The activity patterns of subthalamic nucleus (STN) neurons are intimately linked to motor function and dysfunction and arise through the complex interaction of intrinsic properties and inhibitory and excitatory synaptic inputs. In many neurons, hyperpolarizationactivated cyclic nucleotide-gated (HCN) channels play key roles in intrinsic excitability and synaptic integration both under normal conditions and in disease states. However, in STN neurons, which strongly express HCN channels, their roles remain relatively obscure. To address this deficit, complementary molecular and cellular electrophysiological, imaging, and computational approaches were applied to the rat STN. Molecular profiling demonstrated that individual STN neurons express mRNA encoding several HCN subunits, with HCN2 and 3 being the most abundant. Light and electron microscopic analysis showed that HCN2 subunits are strongly expressed and distributed throughout the somatodendritic plasma membrane. Voltage-, current-, and dynamic-clamp analysis, two-photon Ca 2ϩ imaging, and computational modeling revealed that HCN channels are activated by GABA A receptor-mediated inputs and thus limit synaptic hyperpolarization and deinactivation of low-voltage-activated Ca 2ϩ channels. Although HCN channels also limited the temporal summation of EPSPs, generated through two-photon uncaging of glutamate, this action was largely shunted by GABAergic inhibition that was necessary for HCN channel activation. Together the data demonstrate that HCN channels in STN neurons selectively counteract GABA A receptor-mediated inhibition arising from the globus pallidus and thus promote single-spike activity rather than rebound burst firing.

Biophysical basis of the phase response curve of subthalamic neurons with generalization to other cell types

“…STN cells express high-voltage-activated (HVA) Ca 2ϩ channels (Bevan and Wilson 1999;Hallworth et al 2003;Song et al 2000) that are evidently the primary source for the Ca 2ϩ that activates SK currents (Bevan and Wilson 1999;Hallworth et al 2003). Finally, subthalamic neurons express hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels and T-type Ca 2ϩ channels (Atherton et al 2010;Beurrier et al 1999;Bevan and Wilson 1999;Nakanishi et al 1987). We omit HCN and T-type Ca 2ϩ currents from our model, as they are largely deactivated or inactivated, respectively, over the voltage range encountered during autonomous oscillations or during excitatory synaptic input (Atherton et al 2010;Bevan et al 2002a).…”

“…Finally, subthalamic neurons express hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels and T-type Ca 2ϩ channels (Atherton et al 2010;Beurrier et al 1999;Bevan and Wilson 1999;Nakanishi et al 1987). We omit HCN and T-type Ca 2ϩ currents from our model, as they are largely deactivated or inactivated, respectively, over the voltage range encountered during autonomous oscillations or during excitatory synaptic input (Atherton et al 2010;Bevan et al 2002a). This model differs from our past subthalamic model (Terman et al 2002) in several ways, incorporating several new experimental findings on the nature of the subthalamic AHP (Hallworth et al 2003;Teagarden et al 2008), the overall current-voltage (I-V) curve (Farries et al 2010), and the limited role of HCN and T currents in ongoing spontaneous activity (Atherton et al 2010;Bevan et al 2002a).…”

Regulation of neuronal chloride homeostasis by neuromodulators

“…Because HCN channels are sensitive to the level of hyperpolarization (Atherton et al . 2010), increases in KCC2 function that strengthen hyperpolarizing inhibition should amplify HCN‐mediated neurophysiologic effects. Strong hyperpolarizing inhibitory postsynaptic potentials (IPSPs) due to strong inward Cl − gradients activate I h , which when combined with T‐type calcium currents (hyperpolarization removes these channels from the inactivated state), can drive action potential firing.…”

PIP2-Mediated HCN3 Channel Gating Is Crucial for Rhythmic Burst Firing in Thalamic Intergeniculate Leaflet Neurons

“…Here, we examined burst firing and its regulation by I h during hyperpolarization in HCN2 Ϫ/Ϫ IGL neurons. We used the specific M-channel inhibitor XE991 (10 M) to block the delayed-rectifier M-type potassium conductance (Hu et al, 2002), and CNQX (10 M) and gabazine (10 M) to block fast synaptic transmission, since these conductances are known to affect I h -induced voltage responses (Magee, 1999;Ying et al, 2007b;George et al, 2009;Atherton et al, 2010). In normal ACSF, IGL neurons exhibited a resting membrane potential of Ϫ72.6 Ϯ 2.4 mV (n ϭ 14), and superfusion of the three blockers produced an insignificant depolarization in the membrane potential (3.5 Ϯ 2.8 mV, p Ͼ 0.05, n ϭ 14).…”