Chronic Stress Causes Projection-Specific Adaptation of Amygdala Neurons via Small-Conductance Calcium-Activated Potassium Channel Downregulation

Zhang, Wenhua; Liu, Wei-Zhu; He, Ye; You, Wen-Jie; Zhang, Junyu; Xu, Hong; Tian, Xiao-Li; Li, Baoming; Mei, Lin; Holmes, Andrew; Pan, Bing‐Xing

doi:10.1016/j.biopsych.2018.12.010

Cited by 51 publications

(54 citation statements)

References 57 publications

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“…To measure neuronal intrinsic excitability, recording pipettes were filled with internal solutions containing 125 mM K-gluconate, 5 mM KCl, 10 mM HEPES, 0.2 mM EGTA, 1 mM MgCl 2 , 4 mM Mg-ATP, 0.3 mM Na-GTP and 10 mM phosphocreatine (pH 7.35, 290 mOsm), the current clamp mode was performed and pulsed depolarization currents with increasing amplitude at steps of 50 pA were injected [ 28 ]. Furthermore, 20 µM CNQX, 50 µM DL-AP5 and 20 µM bicuculline were added to the perfusion buffer to block excitability and inhibitory neurotransmission.…”

Section: Methodsmentioning

confidence: 99%

Metformin Enhances Excitatory Synaptic Transmission onto Hippocampal CA1 Pyramidal Neurons

Chen

Liu

et al. 2020

Brain Sciences

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Metformin (Met) is a first-line drug for type 2 diabetes mellitus (T2DM). Numerous studies have shown that Met exerts beneficial effects on a variety of neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). However, it is still largely unclear how Met acts on neurons. Here, by treating acute hippocampal slices with Met (1 μM and 10 μM) and recording synaptic transmission as well as neuronal excitability of CA1 pyramidal neurons, we found that Met treatments significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs), but not amplitude. Neither frequency nor amplitude of miniature inhibitory postsynaptic currents (mIPSCs) were changed with Met treatments. Analysis of paired-pulse ratios (PPR) demonstrates that enhanced presynaptic glutamate release from terminals innervating CA1 hippocampal pyramidal neurons, while excitability of CA1 pyramidal neurons was not altered. Our results suggest that Met preferentially increases glutamatergic rather than GABAergic transmission in hippocampal CA1, providing a new insight on how Met acts on neurons.

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Section: Methodsmentioning

confidence: 99%

Metformin Enhances Excitatory Synaptic Transmission onto Hippocampal CA1 Pyramidal Neurons

Chen

Liu

et al. 2020

Brain Sciences

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“…In contrast, socially-isolated adolescent rats showed reduced BLA expression of KCa2.2 and KCa2.3 channels, and 1-EBIO reduced anxiety-like behaviors when microinfused into the BLA and bath application normalized hyperexcitability in these BLA pyramidal neurons (62). In adult mice, chronic restraint stress increased anxiety-like behaviors and reduced KCa2.2 channel currents in BLA projection neurons, and KCa2.2 channel overexpression in ventral hippocampal-projecting BLA neurons prevented anxiety-like behaviors in stressed mice (23). Although the relationship between ethanol, stress, and KCa2 channels is complex and depends on brain region and age of stress or ethanol exposure, our findings add to a growing literature that KCa2 channels are a crucial ion channel family that may be a possible pharmacogenetic target for treating comorbid mood and alcohol use disorders.…”

Section: Discussionmentioning

confidence: 95%

“…In rats, Kang and colleagues confirmed that retigabine microinfusion into the lateral habenula reduced anxiety-like behaviors during alcohol withdrawal (20). Additional K + channels, such as KCa2, GIRK1, and KV1.3, influence anxietyrelated behaviors (21)(22)(23). These promising findings have motivated our genetic studies on the role of K + channels as a factor linking negative affective behaviors and excessive drinking.…”

Section: Introductionmentioning

confidence: 91%

Kcnn3 as a target for treating aberrant behaviors in stressed, ethanol-dependent mice

Padula

Rinker

Khan

et al. 2019

Preprint

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Anxiety and mood disorders are often comorbid with alcohol use disorder (AUD) and are considered critical in the development, maintenance, and reinstatement of alcohol dependence and harmful alcoholseeking behaviors. Because of this high comorbidity, it is necessary to determine shared and unique genetic factors driving heavy ethanol drinking and anxiety-related behaviors. We used a model of stressinduced escalation of drinking in ethanol dependent C57BL/6J mice to measure anxiety-like behaviors on the marble burying and novelty-suppressed feeding task (NSFT) during abstinence. In order to identify novel pharmacogenetic targets that may lead to more effective treatment, a targeted bioinformatics analysis was used to quantify the expression of K + channel genes in the amygdala that covary with anxiety-related phenotypes in the well phenotyped and fully sequenced family of BXD strains. A pharmacological approach was used to validate the key bioinformatics finding in ethanol-dependent, stressed C57BL/6J mice during the NSFT. Amygdalar expression of Kcnn3 correlated significantly with just over 40 anxiety-associated phenotypes. Further examination of Kcnn3 expression revealed a strong eigentrait for anxiety-like behaviors in this family. Kcnn3 expression in the amygdala correlated negatively with binge-like and voluntary ethanol drinking. C57BL/6J mice treated with chronic intermittent ethanol exposure and repeated swim stress consumed more ethanol in their home cages and showed hypophagia on the NSFT during prolonged abstinence. Pharmacologically targeting KCNN3 protein with the KCa2 channel positive modulator 1-EBIO decreased ethanol drinking and reduced latency to approach food during the NSFT in ethanol-dependent, stressed mice. Collectively these validation studies provide central nervous system mechanistic links into to the covariance of stress, anxiety, and AUD in the BXD strains. Further this analytical approach is effective in defining targets for treating alcohol dependence and comorbid mood and anxiety disorders.

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“…Paradoxically, our findings indicated that the SK2 channel in the spinal DH was not involved in the modulation of anxiety- and depression-like behaviors. However, it has been reported that SK2 channel overexpression in basolateral amygdala-projecting neurons prevents stress-induced anxiety-like behavior [ 55 ]. In addition, ELS can induce anxiety- and depression-like behaviors via dysregulation of the neuroendocrine system which includes the HPA axis and the serotonergic system, along with changes of brain-derived neurotrophic factor expression [ 56 – 59 ].…”

Section: Discussionmentioning

confidence: 99%

Predisposition of Neonatal Maternal Separation to Visceral Hypersensitivity via Downregulation of Small-Conductance Calcium-Activated Potassium Channel Subtype 2 (SK2) in Mice

Gao

Hua

et al. 2020

Neural Plasticity

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Background. Visceral hypersensitivity is a common occurrence of gastrointestinal diseases such as irritable bowel syndrome (IBS), wherein early-life stress (ELS) may have a high predisposition to the development of visceral hypersensitivity in adulthood, with the specific underlying mechanism still elusive. Herein, we assessed the potential effect of small-conductance calcium-activated potassium channel subtype 2 (SK2) in the spinal dorsal horn (DH) on the pathogenesis of visceral hypersensitivity induced by maternal separation (MS) in mice. Methods. Neonatal mice were subjected to the MS paradigm, an established ELS model. In adulthood, the visceral pain threshold and the abdominal withdrawal reflex (AWR) were measured with an inflatable balloon. The elevated plus maze, open field test, sucrose preference test, and forced swim test were employed to evaluate the anxiety- and depression-like behaviors. The expression levels of SK2 in the spinal DH were determined by immunofluorescence and western blotting. The mRNA of SK2 and membrane palmitoylated protein 2 (MPP2) were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Electrophysiology was applied to evaluate the neuronal firing rates and SK2 channel-mediated afterhyperpolarization current (IAHP). The interaction between MPP2 and SK2 was validated by coimmunoprecipitation. Results. In contrast to the naïve mice, ethological findings in MS mice revealed lowered visceral pain threshold, more evident anxiety- and depression-like behaviors, and downregulated expression of membrane SK2 protein and MPP2 protein. Moreover, electrophysiological results indicated increased neuronal firing rates and decreased IAHP in the spinal DH neurons. Nonetheless, intrathecal injection of the SK2 channel activator 1-ethyl-2-benzimidazolinone (1-EBIO) in MS mice could reverse the electrophysiological alterations and elevate the visceral pain threshold. In the naïve mice, administration of the SK2 channel blocker apamin abated IAHP and elevated spontaneous neuronal firing rates in the spinal DH neurons, reducing the visceral pain threshold. Finally, disruption of the MPP2 expression by small interfering RNA (siRNA) could amplify visceral hypersensitivity in naïve mice. Conclusions. ELS-induced visceral pain and visceral hypersensitivity are associated with the underfunction of SK2 channels in the spinal DH.

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Chronic Stress Causes Projection-Specific Adaptation of Amygdala Neurons via Small-Conductance Calcium-Activated Potassium Channel Downregulation

Cited by 51 publications

References 57 publications

Metformin Enhances Excitatory Synaptic Transmission onto Hippocampal CA1 Pyramidal Neurons

Metformin Enhances Excitatory Synaptic Transmission onto Hippocampal CA1 Pyramidal Neurons

Kcnn3 as a target for treating aberrant behaviors in stressed, ethanol-dependent mice

Predisposition of Neonatal Maternal Separation to Visceral Hypersensitivity via Downregulation of Small-Conductance Calcium-Activated Potassium Channel Subtype 2 (SK2) in Mice

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