Zinc Selectively Blocks Neurosteroid-Sensitive Extrasynaptic  GABAA Receptors in the Hippocampus

Carver, Chase M.; Chuang, Shu-Hui; Reddy, Doodipala Samba

doi:10.1523/jneurosci.3393-15.2016

Cited by 34 publications

(26 citation statements)

References 48 publications

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“…That current magnitude was then normalized by the cell’s capacitance, a direct measure of the cell surface, to obtain a value that reflects the current density. This characterization of tonic inhibition has the advantage of being independent of the endogenous levels of extracellular GABA (Carver et al, 2016), which might vary from slice to slice.…”

Section: Resultsmentioning

confidence: 99%

Enhanced postsynaptic inhibitory strength in hippocampal principal cells in high-performing aged rats

Tran

Gallagher

Kirkwood

2018

Neurobiology of Aging

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Hyperactivity within the hippocampal formation, frequently observed in aged individuals, is thought to be a potential contributing mechanism to the memory decline often associated with aging. Consequently, we evaluated the postsynaptic strength of excitatory and inhibitory synapses in the granule cells of the dentate gyrus and CA1 pyramidal cells of a rat model of aging, in which each individual was behaviorally characterized as aged impaired (AI) or aged unimpaired (AU, with performance comparable to young (Y) individuals). In hippocampal slices of these 3 aged groups (Y, AI, AU), we found that compared to the young, the miniature excitatory and inhibitory currents (mEPSCs and mIPSCs) were larger in amplitude in the granule cells of the AU group and smaller in the AI group. In contrast, in CA1 cells, neither the mEPSCs nor the mIPSCs were affected by age, whereas the extrasynaptic conductance responsible for tonic inhibition was selectively enhanced in CA1 cells of AU individuals. Tonic inhibition conductance was not affected by age in the granule cells. These results support the notion that upregulation of synaptic inhibition could be a necessary condition for the maintenance of performance during aging. These findings also underscore the notions that successful aging requires adaptive upregulation, not merely the preservation of youthful functionality, and that age effects are not homogeneous across hippocampal subfields.

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Section: Resultsmentioning

confidence: 99%

Enhanced postsynaptic inhibitory strength in hippocampal principal cells in high-performing aged rats

Tran

Gallagher

Kirkwood

2018

Neurobiology of Aging

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“…It should also be mentioned that in some of electrophysiological recordings, KYNA (i.e., around 300 μM) had been put into the bathing solution for tissues or cells studied, in attempts to preclude any possible interference with excitatory glutaminergic neurotransmission appearing in the preparations [ 60 , 61 , 62 , 63 , 64 , 65 , 66 ]. Under this scenario, the experiments results could have been ambiguous (i.e., either under- or over-emphasized) owing possibly to the direct actions on ionic currents (e.g., the overstimulation of I K(M) ) presented herein.…”

Section: Discussionmentioning

confidence: 99%

Effective Activation by Kynurenic Acid and Its Aminoalkylated Derivatives on M-Type K+ Current

Lin

Fang

et al. 2021

IJMS

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Kynurenic acid (KYNA, 4-oxoquinoline-2-carboxylic acid), an intermediate of the tryptophan metabolism, has been recognized to exert different neuroactive actions; however, the need of how it or its aminoalkylated amide derivative N-(2-(dimethylamino)ethyl)-3-(morpholinomethyl)-4-oxo-1,4-dihydroquinoline-2-carboxamide (KYNA-A4) exerts any effects on ion currents in excitable cells remains largely unmet. In this study, the investigations of how KYNA and other structurally similar KYNA derivatives have any adjustments on different ionic currents in pituitary GH3 cells and hippocampal mHippoE-14 neurons were performed by patch-clamp technique. KYNA or KYNA-A4 increased the amplitude of M-type K+ current (IK(M)) and concomitantly enhanced the activation time course of the current. The EC50 value required for KYNA- or KYNA-A4 -stimulated IK(M) was yielded to be 18.1 or 6.4 μM, respectively. The presence of KYNA or KYNA-A4 shifted the relationship of normalized IK(M)-conductance versus membrane potential to more depolarized potential with no change in the gating charge of the current. The voltage-dependent hysteretic area of IK(M) elicited by long-lasting triangular ramp pulse was observed in GH3 cells and that was increased during exposure to KYNA or KYNA-A4. In cell-attached current recordings, addition of KYNA raised the open probability of M-type K+ channels, along with increased mean open time of the channel. Cell exposure to KYNA or KYNA-A4 mildly inhibited delayed-rectifying K+ current; however, neither erg-mediated K+ current, hyperpolarization-activated cation current, nor voltage-gated Na+ current in GH3 cells was changed by KYNA or KYNA-A4. Under whole-cell, current-clamp recordings, exposure to KYNA or KYNA-A4 diminished the frequency of spontaneous action potentials; moreover, their reduction in firing frequency was attenuated by linopirdine, yet not by iberiotoxin or apamin. In hippocampal mHippoE-14 neurons, the addition of KYNA also increased the IK(M) amplitude effectively. Taken together, the actions presented herein would be one of the noticeable mechanisms through which they modulate functional activities of excitable cells occurring in vivo.

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“…The major isoforms of the pentameric receptor consist of 2α, 2β, and 1γ or δ subunits. Neurosteroids will bind to all GABA‐A‐receptor isoforms, but preferentially act on δ‐containing extrasynaptic GABA‐A receptors that mediate tonic inhibition (Belelli et al, ; Wohlfarth et al, ; Stell et al, ; Carver et al, ). These interactions can exert distinct anticonvulsant properties (Reddy, ).…”

Section: Introductionmentioning

confidence: 99%

Catamenial‐like seizure exacerbation in mice with targeted ablation of extrasynaptic δGABA‐a receptors in the brain

Clossen

Reddy

2017

J of Neuroscience Research

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Neurosteroids play a key role in catamenial epilepsy, a menstrual cycle-related seizure clustering in women with epilepsy. While neurosteroids act on all GABA-A receptor isoforms, they cause greater effects on extrasynaptic δGABA-A receptors that mediate tonic inhibition in the brain. Previously, we identified a potential GABA-A receptor mechanism for catamenial epilepsy. However, the precise functional role of extrasynaptic δGABA-A receptors in the pathophysiology of catamenial epilepsy remains unclear. In this study, we utilized mice lacking extrasynaptic δGABA-A receptors (δKO) to investigate whether reduction of tonic inhibition affects catamenial seizure susceptibility or intensity. Intact female wildtype (WT) and δKO mice were subjected to hippocampus kindling until they exhibited stage 5 seizures. Elevated gonadal hormone-based neurosteroid levels were induced by standard gonadotropin regimen and neurosteroid withdrawal (NSW) was triggered by finasteride. NSW increased susceptibility to, as well the intensity of evoked catamenial-like seizures in WT and δKO mice. However, fully-kindled δKO mice exhibited an accelerated and augmented response to NSW, with a more rapid increase in seizure susceptibility and intensity than WT mice undergoing the NSW paradigm. Moreover, δKO mice in NSW showed reduced benzodiazepine sensitivity, but in stark contrast to the increased neurosteroid sensitivity observed in WT animals, δKO mice displayed no change in neurosteroid sensitivity in response to NSW. The increased catamenial seizure exacerbation and alterations in antiseizure drug responses are consistent with NSW-induced changes in the abundance of δGABA-A receptors. Collectively, these findings provide evidence of a potential protective role for extrasynaptic δGABA-A receptors in catamenial-like seizures.

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Zinc Selectively Blocks Neurosteroid-Sensitive Extrasynaptic GABAA Receptors in the Hippocampus

Cited by 34 publications

References 48 publications

Enhanced postsynaptic inhibitory strength in hippocampal principal cells in high-performing aged rats

Enhanced postsynaptic inhibitory strength in hippocampal principal cells in high-performing aged rats

Effective Activation by Kynurenic Acid and Its Aminoalkylated Derivatives on M-Type K+ Current

Catamenial‐like seizure exacerbation in mice with targeted ablation of extrasynaptic δGABA‐a receptors in the brain

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