HCN2 Channels in Cholinergic Interneurons of Nucleus Accumbens Shell Regulate Depressive Behaviors

Cheng, Jia; Umschweif, Gali; Leung, Jason C. S.; Sagi, Yotam; Greengard, Paul

doi:10.1016/j.neuron.2018.12.018

Cited by 100 publications

(98 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies identified a role for p11 in regulating the function of a variety of ion channels (24,25). Very recently we reported that p11 regulates the function of the HCN2 ion channels in cholinergic neurons from the nucleus accumbens (26). The effect by p11 on HCN2 function was mediated via transcriptional regulation of its gene expression.…”

Section: Discussion P11 Regulates Diverse Ion Channels In Different Cmentioning

confidence: 82%

Reduced Kv3.1 Activity in Dentate Gyrus Parvalbumin Cells Induces Vulnerability to Depression

Medrihan¹,

Umschweif

Sinha

et al. 2020

Biological Psychiatry

Self Cite

View full text Add to dashboard Cite

BACKGROUND: Parvalbumin (PV)-expressing interneurons are important for cognitive and emotional behaviors. These neurons express high levels of p11, a protein associated with depression and action of antidepressants. METHODS: We characterized the behavioral response to subthreshold stress in mice with conditional deletion of p11 in PV cells. Using chemogenetics, viral-mediated gene delivery, and a specific ion channel agonist, we studied the role of dentate gyrus PV cells in regulating anxiety-like behavior and resilience to stress. We used electrophysiology, imaging, and biochemical studies in mice and cells to elucidate the function and mechanism of p11 in dentate gyrus PV cells. RESULTS: p11 regulates the subcellular localization and cellular level of the potassium channel Kv3.1 in cells. Deletion of p11 from PV cells resulted in reduced hippocampal level of Kv3.1, attenuated capacity of high-frequency firing in dentate gyrus PV cells, and altered short-term plasticity at synapses on granule cells, as well as anxiety-like behavior and a pattern separation deficit. Chemogenetic inhibition or deletion of p11 in these cells induced vulnerability to depressive behavior, whereas upregulation of Kv3.1 in dentate gyrus PV cells or acute activation of Kv3.1 using a specific agonist induced resilience to depression. CONCLUSIONS: The activity of dentate gyrus PV cells plays a major role in the behavioral response to novelty and stress. Activation of the Kv3.1 channel in dentate gyrus PV cells may represent a target for the development of celltype specific, fast-acting antidepressants.

show abstract

Section: Discussion P11 Regulates Diverse Ion Channels In Different Cmentioning

confidence: 82%

Reduced Kv3.1 Activity in Dentate Gyrus Parvalbumin Cells Induces Vulnerability to Depression

Medrihan¹,

Umschweif

Sinha

et al. 2020

Biological Psychiatry

Self Cite

View full text Add to dashboard Cite

show abstract

“…To inhibit astrocyte, CNO (Clozapine Noxide, 1 mg/kg/day, i.p., (MCE, Shanghai, China)) or saline (equal volume to CNO, i.p.) were injected into mice according to a former study [25].…”

Section: Adeno-associated Virus (Aav) Stereotaxic Injection and Cno Tmentioning

confidence: 99%

Hippocampal microglial activation triggers a neurotoxic-specific astrocyte response and mediates etomidate-induced long-term synaptic inhibition

Chen

Meng

et al. 2020

J Neuroinflammation

View full text Add to dashboard Cite

Background: Accumulating evidence has highlighted the importance of microglial and astrocyte responses in the pathological development of postoperative cognitive dysfunction (POCD). However, the mechanisms involved are not well understood. Methods: A perioperative neurocognitive disorders (PND) mouse model was generated by administering etomidate, and cognitive function was assessed using the Morris water maze and novel object recognition tests. Excitatory and inhibitory postsynaptic currents were recorded to analyze neuronal activity. In addition, microglia and astrocytes were isolated by magnetic-activated cell sorting, and genes that were activated in these cells were identified using quantitative polymerase chain reaction. Results: We observed dramatic cognitive impairment at 1 and 3 weeks after etomidate was administered to 18 month-old mice. Microglia and astrocytes isolated from the hippocampus showed significant microglial activation during the early pathological stage (i.e., 1 week after etomidate injection) and an A1-specific astrocyte response during the late pathological stage (i.e., 3 weeks after etomidate injection). Furthermore, when microglia were eliminated before etomidate was injected, the A1-specific astrocyte activation response was significantly reduced, and cognitive function improved. However, when microglia were eliminated after etomidate application, astrocyte activation and cognitive function were not significantly altered. In addition, activating microglia immediately after a sedative dose of etomidate was injected markedly increased A1-specific astrocyte activation and cognitive dysfunction. Conclusions: A1-specific astrocyte activation is triggered by activated microglia during the initial pathological stage of PND and induces long-term synaptic inhibition and cognitive deficiencies. These results improve our understanding of how PND develops and may suggest therapeutic targets.

show abstract

“…We exposed male mice to 3 wk of the CUMS protocol and compared tLTP amplitude with those of control mice to determine whether stress exposure affected the above-reported STDP. A depressive-like phenotype in CUMS mice was validated by using the forced swim test (FST) (28), sucrose preference test (SPT) (29), and elevated plus maze (EPM) (30) (Fig. 2 B-D).…”

Section: Cums Treatment Affects Timing-dependent Ltp In Shell Accumbensmentioning

confidence: 99%

Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels

Aceto

Colussi

Leone

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that glycogen-synthase kinase 3β (GSK3β) plays a key role in memory formation, yet its role in mood regulation remains controversial. Here, we investigated whether GSK3β activity in the nucleus accumbens (NAc) is associated with depression-like behaviors and synaptic plasticity. We performed whole-cell patch-clamp recordings of medium spiny neurons (MSNs) in the NAc and determined the role of GSK3β in spike timing-dependent long-term potentiation (tLTP) in the chronic unpredictable mild stress (CUMS) mouse model of depression. To assess the specific role of GSK3β in tLTP, we used in vivo genetic silencing by an adeno-associated viral vector (AAV2) short hairpin RNA against GSK3β. In addition, we examined the role of the voltage-gated potassium Kv4.2 subunit, a molecular determinant of A-type K+currents, as a potential downstream target of GSK3β. We found increased levels of active GSK3β and augmented tLTP in CUMS mice, a phenotype that was prevented by selective GSK3β knockdown. Furthermore, knockdown of GSK3β in the NAc ameliorated depressive-like behavior in CUMS mice. Electrophysiological, immunohistochemical, biochemical, and pharmacological experiments revealed that inhibition of the Kv4.2 channel through direct phosphorylation at Ser-616 mediated the GSK3β-dependent tLTP changes in CUMS mice. Our results identify GSK3β regulation of Kv4.2 channels as a molecular mechanism of MSN maladaptive plasticity underlying depression-like behaviors and suggest that the GSK3β–Kv4.2 axis may be an attractive therapeutic target for MDD.

show abstract

HCN2 Channels in Cholinergic Interneurons of Nucleus Accumbens Shell Regulate Depressive Behaviors

Cited by 100 publications

References 54 publications

Reduced Kv3.1 Activity in Dentate Gyrus Parvalbumin Cells Induces Vulnerability to Depression

Reduced Kv3.1 Activity in Dentate Gyrus Parvalbumin Cells Induces Vulnerability to Depression

Hippocampal microglial activation triggers a neurotoxic-specific astrocyte response and mediates etomidate-induced long-term synaptic inhibition

Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels

Contact Info

Product

Resources

About