Modulation of thalamocortical oscillations by TRIP8b, an auxiliary subunit for HCN channels

Zobeiri, Mehrnoush; Chaudhary, Rahul; Datunashvili, Maia; Heuermann, Robert J.; Lüttjohann, Annika; Narayanan, Venu; Balfanz, Sabine; Meuth, Patrick; Chetkovich, Dane M.; Pape, Hans‐Christian; Baumann, Arnd; Luijtelaar, Gilles van; Budde, Thomas

doi:10.1007/s00429-017-1559-z

Cited by 37 publications

(55 citation statements)

References 110 publications

(180 reference statements)

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“…Additionally, TRIP8b regulates trafficking and modulation of HCN isoforms in a TRIP8b splice variant‐dependent, highly compartment‐selective and even age‐dependent manner. Studies have shown direct interaction of TRIP8b and HCN4 as well as reduction of HCN4 expression due to TRIP8b knockout in thalamic tissue . Especially, the strong effect of TRIP8b on neuronal activity and behaviors in the thalamus suggests a direct functional effect of TRIP8b and HCN4 favored by the strong expression of HCN4 in thalamic tissue.…”

Section: Discussionmentioning

confidence: 99%

“…50 An essential contributor to HCN physiology is the auxiliary subunit TRIP8b, which affects trafficking as well as biophysical properties of HCN channels in several areas of the CNS. [51][52][53][54][55] In hippocampal neurons, downregulation of TRIP8b alters I h current density 54 and the resulting disruption of both synaptic and intrinsic plasticity of I h current during activity 51 results in antidepressant-like behaviors. 20 Notably, this effect is bidirectional as TRIP8b rescue can restore normal HCN channel trafficking and normal behaviors.…”

Section: Discussionmentioning

confidence: 99%

“…52 The integral role of TRIP8b in HCN channel regulation is further emphasized by its effect on the overall protein expression of HCN channels in different areas of the CNS 52,53,55 as well as on the basal cAMP levels in brain tissue. 55 Notably, the modulating effects of TRIP8b differ depending on the principal, channel-forming HCN isoform. It has been shown that binding of TRIP8b impairs cAMP effects on HCN2 and HCN4 but does not affect cAMP modulation of HCN1.…”

Section: Discussionmentioning

confidence: 99%

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HCN4 knockdown in dorsal hippocampus promotes anxiety‐like behavior in mice

Günther

Luczak

Gruteser

et al. 2019

Genes Brain and Behavior

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Hyperpolarization‐activated and cyclic nucleotide‐gated (HCN) channels mediate the I h current in the murine hippocampus. Disruption of the I h current by knockout of HCN1, HCN2 or tetratricopeptide repeat‐containing Rab8b‐interacting protein has been shown to affect physiological processes such as synaptic integration and maintenance of resting membrane potentials as well as several behaviors in mice, including depressive‐like and anxiety‐like behaviors. However, the potential involvement of the HCN4 isoform in these processes is unknown. Here, we assessed the contribution of the HCN4 isoform to neuronal processing and hippocampus‐based behaviors in mice. We show that HCN4 is expressed in various regions of the hippocampus, with distinct expression patterns that partially overlapped with other HCN isoforms. For behavioral analysis, we specifically modulated HCN4 expression by injecting recombinant adeno‐associated viral (rAAV) vectors mediating expression of short hairpin RNA against hcn4 (shHcn4) into the dorsal hippocampus of mice. HCN4 knockdown produced no effect on contextual fear conditioning or spatial memory. However, a pronounced anxiogenic effect was evident in mice treated with shHcn4 compared to control littermates. Our findings suggest that HCN4 specifically contributes to anxiety‐like behaviors in mice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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HCN4 knockdown in dorsal hippocampus promotes anxiety‐like behavior in mice

Günther

Luczak

Gruteser

et al. 2019

Genes Brain and Behavior

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“…Second, since HCN currents also play a role in the burst firing properties of thalamocortical neurons 74,75 , and Shox2 affects expression of both Hcn2 and Hcn4 mRNAs and proteins, we investigated the effect of Shox2 KO on HCN current by sequential hyperpolarizations in voltage-clamp mode. The amplitude of HCN current was measured as the difference between the end current of one-second hyperpolarization and the beginning instantaneous current at -150mV hyperpolarization (Fig.…”

Section: First We Determined the Physiological Properties Of T-type mentioning

confidence: 99%

The transcription factor Shox2 shapes thalamocortical neuron firing and synaptic properties

Maroteaux

Song

et al. 2019

Preprint

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Thalamocortical neurons (TCNs) transmit information about sensory stimuli from the thalamus to the cortex. In response to different physiological states and demands TCNs can fire in tonic and/or phasic burst modes. These firing properties of TCNs are supported by precisely timed inhibitory synaptic inputs from the thalamic reticular nucleus and intrinsic currents, including T-type Ca 2+ and HCN currents. These intrinsic currents are mediated by Cav3.1 and HCN channel subunits, and alterations in expression or modulation of these channels can have dramatic implications on thalamus function. The factors that regulate these currents controlling the firing patterns important for integration of the sensory stimuli and the consequences resulting from the disruption of these firing patterns are not well understood. Shox2 is a transcription factor known to be important for pacemaker activity in the heart. We show here that Shox2 is also expressed in adult mouse thalamus. We hypothesized that genes regulated by Shox2's transcriptional activity may be important for physiological properties of TCNs. In this study, we used RNA sequencing on control and Shox2 knockout mice to determine Shox2-affected genes and revealed a network of ion channel genes important for neuronal firing properties. Quantitative PCR confirmed that expression of Hcn2, 4 and Cav3.1 genes were affected by Shox2 KO. Western blotting showed expression of the proteins for these channels was decreased in the thalamus, and electrophysiological recordings showed that Shox2 KO impacted the firing and synaptic properties of TCNs. Finally, behavioral studies revealed that Shox2 expression in TCNs play a role in somatosensory function and object recognition memory. Overall, these results reveal Shox2 as a transcription factor important for TCN firing properties and thalamic function. 1 Processing of sensory information is mediated by precise circuitry that senses stimuli in 2 the periphery and transforms the information through a network of synaptic connections to 3 ultimately allow perception and cognitive processing of the surrounding world. Rhythmic 4 oscillations of brain activity crucial to cognitive function emerge from neuronal network 5 interactions that consist of reciprocal connections between the thalamus, the inhibitory 6 thalamic reticular nucleus and the cortex 1 . Dysfunction of these oscillations caused by 7 aberrant activity in the thalamic circuit is thought to play a role in many neuropathological 8 conditions, including epilepsy 2-4 , autism 5-7 , and schizophrenia [8][9][10][11] . Furthermore, damage to 9 thalamic nuclei, especially medial and anterior nuclei, causes severe memory deficits known 10 as diencephalic amnesia 12-17 . 11 The intrinsic properties that shape action potential firing and contribute to rhythmic 12 oscillations of the thalamocortical neurons (TCNs) are important for efficient transfer of 13 information from the thalamus to the cortex. Notably, TCNs switch their firing states between 14 2 modes, burst and tonic fi...

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“…In thalamic and central neurons, HCN channel activation by cAMP depolarizes resting membrane potential, reduces membrane resistance, and increases tonic firing (3,9). Conversely, reduction of HCN channel currents via genetic knockout, pharmacological blockers, or inhibitory regulators leads to reduced action potential firing rate and dysrhythmia in the SAN (10)(11)(12) and altered ratios of tonic and burst firing in thalamocortical neurons, which are associated with transitions between sleep and wakefulness (3,9,13).…”

Section: Introductionmentioning

confidence: 99%

Isoform-specific regulation of HCN4 channels by a family of endoplasmic reticulum proteins

Peters

Myers

Juchno

et al. 2020

Preprint

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The pore-forming subunits of ion channels are regulated by auxiliary interacting proteins.Hyperpolarization-activated cyclic nucleotide-sensitive isoform 4 (HCN4) channels are critical determinants of electrical excitability in many types of cells including neurons and cardiac pacemaker cells. Here we report the discovery of two novel HCN4 regulatory proteins. Despite their homology, the two proteinslymphoid-restricted membrane protein (LRMP) and inositol trisphosphate receptor-associated guanylate kinase substrate (IRAG)have opposing effects on HCN4, causing loss-and gain-of-function, respectively. LRMP and IRAG are expected to play critical roles in regulation of physiological processes ranging from wakefulness to heart rate through their modulation of HCN4 channel function.

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Modulation of thalamocortical oscillations by TRIP8b, an auxiliary subunit for HCN channels

Cited by 37 publications

References 110 publications

HCN4 knockdown in dorsal hippocampus promotes anxiety‐like behavior in mice

HCN4 knockdown in dorsal hippocampus promotes anxiety‐like behavior in mice

The transcription factor Shox2 shapes thalamocortical neuron firing and synaptic properties

Isoform-specific regulation of HCN4 channels by a family of endoplasmic reticulum proteins

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