AUTHOR=Kawasaki Yasuhiro , Saito Mitsuru , Won Jonghwa , Bae Jin Young , Sato Hajime , Toyoda Hiroki , Kuramoto Eriko , Kogo Mikihiko , Tanaka Takuma , Kaneko Takeshi , Oh Seog Bae , Bae Yong Chul , Kang Youngnam 

TITLE=Inhibition of GluR Current in Microvilli of Sensory Neurons via Na+-Microdomain Coupling Among GluR, HCN Channel, and Na+/K+ Pump

JOURNAL=Frontiers in Cellular Neuroscience

VOLUME=12

YEAR=2018

URL=https://www.frontiersin.org/journals/cellular-neuroscience/articles/10.3389/fncel.2018.00113

DOI=10.3389/fncel.2018.00113

ISSN=1662-5102

ABSTRACT=<p>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 (<italic>I</italic><sub>h</sub>) on input resistance or <italic>I</italic><sub>h</sub> 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 <italic>I</italic><sub>h</sub> enhancement apparently diminished the glutamate receptor (GluR) current (<italic>I</italic><sub>GluR</sub>) evoked by puff application of glutamate/AMPA and enhanced a transient outward current following <italic>I</italic><sub>GluR</sub> (OT-<italic>I</italic><sub>GluR</sub>). This suggests that some outward current opposes inward <italic>I</italic><sub>GluR</sub>. The <italic>I</italic><sub>GluR</sub> inhibition displayed a U-shaped voltage-dependence with a minimal inhibition around the resting membrane potential, suggesting that simple shunting effects or deactivation of <italic>I</italic><sub>h</sub> cannot explain the U-shaped voltage-dependence. Confocal imaging of Na<sup>+</sup> revealed that GluR activation caused an accumulation of Na<sup>+</sup> in the microvilli, which can cause a negative shift of the reversal potential for <italic>I</italic><sub>h</sub> (<italic>E</italic><sub>h</sub>). Taken together, it was suggested that <italic>I</italic><sub>GluR</sub> evoked in MTN neurons is opposed by a transient decrease or increase in standing inward or outward <italic>I</italic><sub>h</sub>, respectively, both of which can be caused by negative shifts of <italic>E</italic><sub>h</sub>, as consistent with the U-shaped voltage-dependence of the <italic>I</italic><sub>GluR</sub> inhibition and the OT-<italic>I</italic><sub>GluR</sub> 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 <italic>I</italic><sub>h</sub> deactivation and/or shunting effect and supported the negative shift of <italic>E</italic><sub>h</sub> which causes the U-shaped voltage-dependent inhibition of <italic>I</italic><sub>GluR</sub>.</p>