Seizure-Induced Plasticity of h Channels in Entorhinal Cortical Layer III Pyramidal Neurons

Shah, Maulik; Anderson, Anne E.; Leung, Victor C. M.; Lin, Xiaodi; Johnston, Daniel

doi:10.1016/j.neuron.2004.10.011

Cited by 272 publications

(291 citation statements)

References 53 publications

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“…Disruption of REST binding to the hcn1 promoter by means of decoy oligodeoxynucleotides prevented hcn1 repression and restored its ability to maintain normal levels of dendritic excitability. Collectively, these studies indicate that REST is causally related to HCN1 repression, decreased dendritic excitability, and enhanced epileptiform activity in entorhinal cortical layer III pyramidal neurons (Shah et al, 2004;Jung et al, 2007Jung et al, , 2011 (Figure 1b).…”

Section: Transcriptional Regulation By Rest In Epilepsymentioning

confidence: 81%

Epigenetic Mechanisms in Stroke and Epilepsy

Hwang

Aromolaran

Zukin

2012

Neuropsychopharmacol

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Epigenetic remodeling and modifications of chromatin structure by DNA methylation and histone modifications represent central mechanisms for the regulation of neuronal gene expression during brain development, higher-order processing, and memory formation. Emerging evidence implicates epigenetic modifications not only in normal brain function, but also in neuropsychiatric disorders. This review focuses on recent findings that disruption of chromatin modifications have a major role in the neurodegeneration associated with ischemic stroke and epilepsy. Although these disorders differ in their underlying causes and pathophysiology, they share a common feature, in that each disorder activates the gene silencing transcription factor REST (repressor element 1 silencing transcription factor), which orchestrates epigenetic remodeling of a subset of 'transcriptionally responsive targets' implicated in neuronal death. Although ischemic insults activate REST in selectively vulnerable neurons in the hippocampal CA1, seizures activate REST in CA3 neurons destined to die. Profiling the array of genes that are epigenetically dysregulated in response to neuronal insults is likely to advance our understanding of the mechanisms underlying the pathophysiology of these disorders and may lead to the identification of novel therapeutic strategies for the amelioration of these serious human conditions.

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Section: Transcriptional Regulation By Rest In Epilepsymentioning

confidence: 81%

Epigenetic Mechanisms in Stroke and Epilepsy

Hwang

Aromolaran

Zukin

2012

Neuropsychopharmacol

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“…Feedforward inhibition may also be compromised by loss of interneurons (Houser and Esclapez, 1996;Dinocourt et al, 2005). It is also possible that intrinsic, regenerative boosting effects on temporoammonic EPSPs mediated by upregulation of T-type Ca 2ϩ conductance and downregulation of A-type potassium and hyperpolarization-activated H-type cationic conductances in CA1 pyramidal cell dendrites may contribute to enhanced efficacy in this pathway (Su et al, 2002;Shah et al, 2004;Bernard et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Massive and Specific Dysregulation of Direct Cortical Input to the Hippocampus in Temporal Lobe Epilepsy

Ang

Carlson²,

Coulter³

2006

J. Neurosci.

135

115

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Epilepsy affects 1-2% of the population, with temporal lobe epilepsy (TLE) the most common variant in adults. Clinical and experimental studies have demonstrated hippocampal involvement in the seizures underlying TLE. However, identification of specific functional deficits in hippocampal circuits associated with possible roles in seizure generation remains controversial. Significant attention has focused on anatomic and cellular alterations in the dentate gyrus. The dentate gyrus is a primary gateway regulating cortical input to the hippocampus and, thus, a possible contributor to the aberrant cortical-hippocampal interactions underlying the seizures of TLE. Alternate cortical pathways innervating the hippocampus might also contribute to seizure initiation. Despite this potential importance in TLE, these pathways have received little study. Using simultaneous voltage-sensitive dye imaging and patch-clamp recordings in slices from animals with epilepsy, we assessed the relative degree of synaptic excitation activated by multiple cortical inputs to the hippocampus. Surprisingly, dentate gyrus-mediated regulation of the relay of cortical input to the hippocampus is unchanged in epileptic animals, and input via the Schaffer collaterals is actually decreased despite reduction in Schaffer-evoked inhibition. In contrast, a normally weak direct cortical input to area CA1 of hippocampus, the temporoammonic pathway, exhibits a TLE-associated transformation from a spatially restricted, highly regulated pathway to an excitatory projection with Ͼ10-fold increased effectiveness. This dysregulated temporoammonic pathway is critically positioned to mediate generation and/or propagation of seizure activity in the hippocampus.

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“…Based on genetic deletion and pharmacological blockade studies of HCN channels, we predict reduced GPCR signalling will in turn increase dendritic temporal summation (Shah et al . 2004; Huang et al . 2009; Pavlov et al .…”

Section: Gpcr Modulation: a Brief Overviewmentioning

confidence: 99%

Regulation of neuronal chloride homeostasis by neuromodulators

Mahadevan

Woodin

2016

The Journal of Physiology

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KCC2 is the central regulator of neuronal Cl− homeostasis, and is critical for enabling strong hyperpolarizing synaptic inhibition in the mature brain. KCC2 hypofunction results in decreased inhibition and increased network hyperexcitability that underlies numerous disease states including epilepsy, neuropathic pain and neuropsychiatric disorders. The current holy grail of KCC2 biology is to identify how we can rescue KCC2 hypofunction in order to restore physiological levels of synaptic inhibition and neuronal network activity. It is becoming increasingly clear that diverse cellular signals regulate KCC2 surface expression and function including neurotransmitters and neuromodulators. In the present review we explore the existing evidence that G‐protein‐coupled receptor (GPCR) signalling can regulate KCC2 activity in numerous regions of the nervous system including the hypothalamus, hippocampus and spinal cord. We present key evidence from the literature suggesting that GPCR signalling is a conserved mechanism for regulating chloride homeostasis. This evidence includes: (1) the activation of group 1 metabotropic glutamate receptors and metabotropic Zn2+ receptors strengthens GABAergic inhibition in CA3 pyramidal neurons through a regulation of KCC2; (2) activation of the 5‐hydroxytryptamine type 2A serotonin receptors upregulates KCC2 cell surface expression and function, restores endogenous inhibition in motoneurons, and reduces spasticity in rats; and (3) activation of A3A‐type adenosine receptors rescues KCC2 dysfunction and reverses allodynia in a model of neuropathic pain. We propose that GPCR‐signals are novel endogenous Cl− extrusion enhancers that may regulate KCC2 function.

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Seizure-Induced Plasticity of h Channels in Entorhinal Cortical Layer III Pyramidal Neurons

Cited by 272 publications

References 53 publications

Epigenetic Mechanisms in Stroke and Epilepsy

Epigenetic Mechanisms in Stroke and Epilepsy

Massive and Specific Dysregulation of Direct Cortical Input to the Hippocampus in Temporal Lobe Epilepsy

Regulation of neuronal chloride homeostasis by neuromodulators

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