Presynaptic HCN channels constrain GABAergic synaptic transmission in pyramidal cells of the medial prefrontal cortex

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are widely expressed in neurons in the central nervous system. It has been documented that HCN channels regulate the intrinsic excitability of pyramidal cells in the medial prefrontal cortex (mPFC) of rodents. Here, we report that HCN channels limited GABAergic transmission onto pyramidal cells in rat mPFC. The pharmacological blockade of HCN channels resulted in a significant increase in the frequency of both spontaneous and miniature inhibitory postsynaptic currents (IPSCs) in mPFC pyramidal cells, whereas potentiation of HCN channels reversely decreases the frequency of mIPSCs. Furthermore, such facilitation effect on mIPSC frequency required presynaptic Ca2+ influx. Immunofluorescence staining showed that HCN channels expressed in presynaptic GABAergic terminals, as well as in both soma and neurite of parvalbumin-expressing (PV-expressing) basket cells in mPFC. The present results indicate that HCN channels in GABAergic interneurons, most likely PV-expressing basket cells, constrain inhibitory control over layer 5-6 pyramidal cells by restricting presynaptic Ca2+ entry.

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Presynaptic HCN channels constrain GABAergic synaptic transmission in pyramidal cells of the medial prefrontal cortex

10.1101/2021.05.23.445332 ◽

2021 ◽

Author(s):

Wei Cai ◽

Shu-Su Liu ◽

Bao-Ming Li ◽

Xue-Han Zhang

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Pyramidal Cells ◽

Intrinsic Excitability ◽

High Dose ◽

Hcn Channels ◽

Gabaergic Interneurons ◽

Facilitation Effect ◽

Basket Cells ◽

The Central Nervous System

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are widely expressed in neurons in the central nervous system. It has been documented that HCN channels regulate the intrinsic excitability of pyramidal cells in the medial prefrontal cortex (mPFC) of rats. Here, we report that HCN channels limited GABAergic transmission onto pyramidal cells in the mPFC. Pharmacological block of HCN channels resulted in a significant increase in the frequency of both spontaneous and miniature inhibitory postsynaptic currents (IPSCs) in mPFC pyramidal cells. Such facilitation effect on mIPSCs required presynaptic Ca2+ influx and reversed by high-dose cAMP. Such facilitation did not exist in the presence of the T-type Ca2+ channel selective blockers. Immunofluorescence staining revealed that HCN channels expressed in presynaptic GABAergic terminals, as well as in both soma and neurite of parvalbumin-expressing (PV-expressing) basket cells in the mPFC. The present results indicate that HCN channels in GABAergic interneurons, most likely PV-expressing basket cells, constrain inhibitory control over layer 5-6 pyramidal cells through restricting presynaptic Ca2+ entry.

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The increase of intrinsic excitability of layer V pyramidal cells in the prelimbic medial prefrontal cortex of adult mice after peripheral inflammation

Neuroscience Letters ◽

10.1016/j.neulet.2015.11.030 ◽

2016 ◽

Vol 611 ◽

pp. 40-45 ◽

Cited By ~ 11

Author(s):

Xiao-Bo Wu ◽

Biao Liang ◽

Yong-Jing Gao

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Pyramidal Cells ◽

Intrinsic Excitability ◽

Peripheral Inflammation ◽

Adult Mice ◽

Layer V

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Dopamine D5 receptor immunoreactivity is differentially distributed in GABAergic interneurons and pyramidal cells in the rat medial prefrontal cortex

Neuroscience Research ◽

10.1016/j.neures.2010.07.1295 ◽

2010 ◽

Vol 68 ◽

pp. e291

Author(s):

Satoko Oda ◽

Hiromasa Funato ◽

Hiroaki Igarashi ◽

Junko Yokofujita ◽

Masaru Kuroda

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Pyramidal Cells ◽

Gabaergic Interneurons ◽

Dopamine D5 Receptor

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Dopamine D5 receptor immunoreactivity is differentially distributed in GABAergic interneurons and pyramidal cells in the rat medial prefrontal cortex

Brain Research ◽

10.1016/j.brainres.2010.03.011 ◽

2010 ◽

Vol 1329 ◽

pp. 89-102 ◽

Cited By ~ 18

Author(s):

Satoko Oda ◽

Hiromasa Funato ◽

Satomi Adachi-Akahane ◽

Masanori Ito ◽

Akiko Okada ◽

...

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Pyramidal Cells ◽

Gabaergic Interneurons ◽

Dopamine D5 Receptor

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A whole-brain map of long-range inputs to GABAergic interneurons in the mouse medial prefrontal cortex

Nature Neuroscience ◽

10.1038/s41593-019-0429-9 ◽

2019 ◽

Vol 22 (8) ◽

pp. 1357-1370 ◽

Cited By ~ 31

Author(s):

Qingtao Sun ◽

Xiangning Li ◽

Miao Ren ◽

Mengting Zhao ◽

Qiuyuan Zhong ◽

...

Keyword(s):

Prefrontal Cortex ◽

Long Range ◽

Medial Prefrontal Cortex ◽

Gabaergic Interneurons ◽

Whole Brain

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Constitutive Genetic Deletion of Hcn1 Increases Alcohol Preference during Adolescence

Brain Sciences ◽

10.3390/brainsci10110763 ◽

2020 ◽

Vol 10 (11) ◽

pp. 763

Author(s):

Michael C. Salling ◽

Neil L. Harrison

Keyword(s):

Prefrontal Cortex ◽

Alcohol Consumption ◽

Medial Prefrontal Cortex ◽

Neuronal Excitability ◽

Cell Types ◽

Brain Regions ◽

Alcohol Preference ◽

Hcn Channels ◽

Direct Role ◽

Genetic Deletion

The hyperpolarization-activated cyclic nucleotide-gated channel (HCN), which underlies the hyperpolarization-activated cation current (Ih), has diverse roles in regulating neuronal excitability across cell types and brain regions. Recently, HCN channels have been implicated in preclinical models of substance abuse including alcohol. In the prefrontal cortex of rodents, HCN expression and Ih magnitude are developmentally regulated during adolescence and may be vulnerable to alcohol’s effects. In mice, binge alcohol consumption during the adolescent period results in a sustained reduction in Ih that coincides with increased alcohol consumption in adulthood, yet the direct role HCN channels have on alcohol consumption are unknown. Here, we show that the genetic deletion of Hcn1 causes an increase in alcohol preference on intermittent 2-bottle choice task in homozygous null (HCN1−/−) male mice compared to wild-type littermates without affecting saccharine or quinine preference. The targeted viral deletion of HCN1 in pyramidal neurons of the medial prefrontal cortex resulted in a gradual loss of Hcn1 expression and a reduction in Ih magnitude during adolescence, however, this did not significantly affect alcohol consumption or preference. We conclude that while HCN1 regulates alcohol preference, the genetic deletion of Hcn1 in the medial prefrontal cortex does not appear to be the locus for this effect.

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