Abstract
Glutamatergic dendritic EPSPs evoked in cortical pyramidal neurons are depressed by activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels expressed in dendritic spines. This depression has been attributed to shunting effects of HCN current (Ih) on input resistance or Ih deactivation. Primary sensory neurons in the rat mesencephalic trigeminal nucleus (MTN) have the somata covered by spine-like microvilli that express HCN channels. In rat MTN neurons, we demonstrated that Ih enhancement apparently diminished the glutamate receptor (GluR) current (IGluR) evoked by puff application of glutamate/AMPA and enhanced a transient outward current following IGluR (OT-IGluR). This suggests that some outward current opposes inward IGluR. The IGluR inhibition displayed a U-shaped voltage-dependence with a minimal inhibition around the resting membrane potential, suggesting that simple shunting effects or deactivation of Ih cannot explain the U-shaped voltage-dependence. Confocal imaging of Na+ revealed that GluR activation caused an accumulation of Na+ in the microvilli, which can cause a negative shift of the reversal potential for Ih (Eh). Taken together, it was suggested that IGluR evoked in MTN neurons is opposed by a transient decrease or increase in standing inward or outward Ih, respectively, both of which can be caused by negative shifts of Eh, as consistent with the U-shaped voltage-dependence of the IGluR inhibition and the OT-IGluR generation. An electron-microscopic immunohistochemical study revealed the colocalization of HCN channels and glutamatergic synapses in microvilli of MTN neurons, which would provide a morphological basis for the functional interaction between HCN and GluR channels. Mathematical modeling eliminated the possibilities of the involvements of Ih deactivation and/or shunting effect and supported the negative shift of Eh which causes the U-shaped voltage-dependent inhibition of IGluR.
Highlights
To investigate the possible functional interactions between hyperpolarization-activated cyclic nucleotide-gated (HCN) and glutamate receptor (GluR) channels during spike firing in mesencephalic trigeminal nucleus (MTN) neurons, we first examined the effects of 8-Br-cAMP on the firing activities caused by a puff application (100 ms duration) of amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrate (AMPA) and current-pulse injections at a resting and a hyperpolarized membrane potentials (−70 and −90 mV, respectively) under the current-clamp condition
Given the activation of current mediated by HCN channels (Ih) by 8-Br-cAMP, these observations strongly suggest that, at least in MTN neurons, the shunting effects of Ih were not involved in the inhibition of the bursting by the activation of GluR, and the bursts appeared to be suppressed by a functional interaction between GluR and HCN channels
By taking advantages of the morphological structure of MTN neurons that have round shaped somata from which short spine-like microvilli of 1.0–1.5 μm length directly protruded (Figure 7; see Kang et al, 2004), wholecell voltage-clamp recordings of GluR responses and Ih were obtained from MTN neurons with little space-clamp errors (Figures 2–5) while we showed current-clamp recordings (Figure 1)
Summary
Many studies have reported that, in cortical pyramidal cells and in various other neurons, the activation of hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels can decrease the amplitude and/or duration of EPSPs or depolarizations evoked by current pulses (Magee, 1998, 1999; Yamada et al, 2005; Carr et al, 2007; Ying et al, 2007; Harnett et al, 2015). The peak level of the EPSP observed following the blockade of Ih with ZD7288 was not higher than that of the control due to the hyperpolarization of the baseline potential, while this was not necessarily the case for that of summated EPSPs (Carr et al, 2007), indicating that the shunting effect is not always effective It has been proposed in a mathematical simulation study that, in CA1 hippocampal pyramidal neurons, HCN-mediated depolarization can secondarily activate M-type K+ channels or some other K+ channels, which can produce a real shunting conductance with a more negative reversal potential (George et al, 2009; Migliore and Migliore, 2012). It remains unclear and controversial how Ih diminishes EPSPs despite its crucial involvement in various brain functions
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