Differential modulation of repetitive firing and synchronous network activity in neocortical interneurons by inhibition of A-type K+ channels and Ih

Williams, Sidney B.; Hablitz, John J.

doi:10.3389/fncel.2015.00089

Cited by 22 publications

(33 citation statements)

References 148 publications

(223 reference statements)

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“…6A; Table 1), confirming a previous report that 4AP can cause a broadening of neuronal action potentials (Mitterdorfer and Bean, 2002). We concluded that 4AP affects PV-interneuron firing more than it does SST and pyramidal firing, leading to a preferential activation of the PV cell class, supporting previous findings which were not performed in the blockade of both glutamatergic and GABAergic currents (Williams and Hablitz, 2015). PV interneurons are, thus, likely to be the main source of the persistent pathological discharges following application of glutamate receptor blockers, in this model.…”

Section: Ap Preferentially Activates Pv Interneuronssupporting

confidence: 91%

Divergent paths to seizure‐like events

et al. 2019

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Much debate exists about how the brain transitions into an epileptic seizure. One source of confusion is that there are likely to be critical differences between experimental seizure models. To address this, we have compared the evolving activity patterns in two widely used in vitro models of epileptic discharges. Brain slices from young adult mice were prepared in the same way and bathed either in 0 Mg2+ or 100 µmol/L 4AP artificial cerebrospinal fluid. We have found that while local field potential recordings of epileptiform discharges in the two models appear broadly similar, patch‐clamp analysis reveals an important difference in the relative degree of glutamatergic involvement. 4AP affects parvalbumin‐expressing interneurons more than other cortical populations, destabilizing their resting state and inducing spontaneous bursting behavior. Consequently, the most prominent pattern of transient discharge (“interictal event”) in this model is almost purely GABAergic, although the transition to seizure‐like events (SLEs) involves pyramidal recruitment. In contrast, interictal discharges in 0 Mg2+ are only maintained by a very large glutamatergic component that also involves transient discharges of the interneurons. Seizure‐like events in 0 Mg2+ have significantly higher power in the high gamma frequency band (60–120Hz) than these events do in 4AP, and are greatly delayed in onset by diazepam, unlike 4AP events. We, therefore, conclude that the 0 Mg2+ and 4AP models display fundamentally different levels of glutamatergic drive, demonstrating how ostensibly similar pathological discharges can arise from different sources. We contend that similar interpretative issues will also be relevant to clinical practice.

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Section: Ap Preferentially Activates Pv Interneuronssupporting

confidence: 91%

Divergent paths to seizure‐like events

et al. 2019

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“…This hypothesis proposes that synchronous activation of inhibitory interneurons 515 (the "initial step" investigated here) gives rise to a strong inhibitory signal that 516 activates the excitatory, pyramidal cell population via PIR [12] (see Fig 1). As 517 experimental support for this theory accumulates [1,[8][9][10][11][12][13], computational insights such 518 as those presented here can provide further support for its viability by proposing synchrony and predominantly GABAergic IIS [29,51], and thus 4-AP is a commonly 526 used epilepsy model [31,32]. This experimental evidence justifies not only the use of has also been shown to underlie IIS in the in vivo pilocarpine model of epilepsy [13], 531 precede seizures in both the low-Mg, high K+ model [26,28] and electrical stimulation 532 models of seizure initiation [52], and more generally precede seizures in rodents [9,29].…”

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confidence: 75%

“…125 The rest of the parameter values (a, b, d, k low , k high ) were chosen through a 126 parameter exploration to match the difference in rheobase caused by treatment of Unpublished in-house experiments were used for the rheobase values of control and 128 4-AP interneurons, as recorded in the same cell, given that such details are not available 129 in the existing literature. An increase in spike-frequency adaptation in the 4-AP setting 130 is also implied by the literature [32] and correspondingly influenced the determination of 131 these parameters. As the model of Ferguson et.…”

Section: Neuron Models 92mentioning

confidence: 89%

Modeling implicates inhibitory network bistability as an underpinning of seizure initiation

Rich

Rafiee

et al. 2019

Preprint

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A plethora of recent experimental literature implicates the abrupt, synchronous activation of GABAergic interneurons in driving the sudden change in brain activity that heralds seizure initiation. However, the mechanisms predisposing an inhibitory network toward sudden coherence specifically during ictogenesis remain unknown. We address this question by comparing simulated inhibitory networks containing control interneurons and networks containing hyper-excitable interneurons modeled to mimic treatment with 4-Aminopyridine (4-AP), an agent commonly used to model seizures in vivo and in vitro. Our in silico study demonstrates that model inhibitory networks with 4-AP interneurons are more prone than their control counterparts to exist in a bistable state in which asynchronously firing networks can abruptly transition into synchrony due to a brief perturbation. We further show that perturbations driving this transition could reasonably arise in vivo based on models of background excitatory synaptic activity in the cortex. Thus, these results propose a mechanism by which an inhibitory network can transition from incoherent to coherent dynamics in a fashion that may precipitate seizure as a downstream effect. Moreover, this mechanism specifically April 11, 2019 1/36Recently, some studies of seizure initiation have shifted focus to over-activity of 25 inhibitory interneurons. This literature has yielded convincing evidence that 26 interneurons serve a causal role in seizure initiation [1,[8][9][10][11][12][13], laying the groundwork for 27 a novel hypothesis for seizure initiation (a "GABAergic initiation hypothesis") in which 28 synchronous activation of inhibitory interneurons precipitates the onset of a seizure, as 29 diagrammed in Fig 1 [12]. Given the contemporaneous nature of this hypothesis it is an 30ideal target for rigorous computational study; here, such research aims to unearth a 31 mechanism explaining the predisposition of inhibitory interneurons in a hyper-excitable 32April 11, 2019 2/36 environment to suddenly transition into synchrony, the necessary initial step in this 33 hypothesis. We thus focus on the earliest time in the transition to seizure and not 34 aspects of propagation and termination. 35The study of inhibitory network synchrony is decades old, dating back to the work of 36 Wang and Rinzel [14]. Various mechanisms have been proposed to explain the 37 generation of oscillations in purely inhibitory networks, the most prominent of which 38 may be the Interneuron Network Gamma (ING) mechanism [15-20]. Previous work has 39 shown that inhibitory networks built to examine population activity in an in vitro 40 hippocampal preparation manifest "sharp transitions" into coherent population activity 41 caused by a small, permanent increase to the external drive to the network [21]. 42 Additional studies have explored the effect of connection probabilities and cell 43 characteristics manifested by classifications of cell excitability on inhibitory network 44 synchrony [22, 23], and have noted that bist...

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“…In the current study, we show that mouse NGFCs express Kv4 and auxiliary subunit transcripts that translates to a functional IKA conductance. Although the ramifications of Kv4 channel and auxiliary subunits have been mainly investigated in pyramidal cells, their expression and role in modulating subthreshold membrane dynamics, firing properties and dendritic excitability of IN subtypes have been described 1,65,67,72,74,75,76,77,78,79 . We extend these observations to NGFCs and demonstrate IKA can effectively influence delay to spike and action potential threshold resulting in increased intrinsic excitability similar to that seen in STP-SE ultimately resulting in enhanced dendritic integration.…”

Section: Discussionmentioning

confidence: 99%

Activity-dependent tuning of intrinsic excitability in mouse and human neurogliaform cells

Chittajallu

Auville

Mahadevan

et al. 2020

Preprint

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Spatiotemporal interactions between glutamatergic excitatory and GABAergic inhibitory neuronsunderly input-output transformations critical for complex brain functions. However, the extent of malleability in this interplay particularly that occuring via modifications in GABAergic interneuron recruitment and output is relatively unexplored in humans. We demonstrate that a specialized interneuron subtype collectively termed neurogliaform cells embedded in both mouse and human neural circuits are susceptible to remarkably similar activity-dependent modulation in their intrinsic properties including the previously characterized distal axonal phenomenon known as barrage firing. Interestingly, we reveal a parallel yet hitherto undescribed plasticity, occurring in the absence of barrage firing manifesting as an enhanced efficacy of excitatory depolarizing inputs to somatodendritic domains in eliciting action potential output. In principle, these evolutionary conserved plasticity routes tune the extent of inhibition mediated by neurogliaform cells constituting circuit mechanisms relevant for human cognitive processing and behavior.only in rodents but also in non-human primates and humans revealing both similar and divergent properties across these species 17,24,30, 36, 37 . However, only a few reports have described short and longterm plasticity impacting recruitment and activity of mouse NGFCs 38, 39 with a conspicuous lack of published evidence demonstrating any such mechanisms in their human counterparts 15 .In the current study we demonstrate that adult mouse and human NGFCs can undergo analogous forms of activity-dependent modulation of their intrinsic properties. In particular, we reveal a previously undescribed plasticity manifesting as a short-term enhancement in the ability of depolarizing inputs to evoke action potential output which, in mouse, is in part due to functional regulation of subthreshold, transient K + -conductance(s) (including those mediated by Kv4-containing channels).Although the underlying induction and expression mechanisms remain to be fully determined, this evolutionary retention demonstrates that the ability to modulate NGFC excitability represents canonical mechanisms stressing their importance. From a research perspective, this conservation also highlights the relevance of the mouse model as a predictive tool in basic science research aimed at further unravelling the behavioral correlates dependent on the tuning of NGFC mediated inhibition 40 under physiological and pathological contexts in humans. RESULTS Activity-dependent enhancement in intrinsic excitability of NGFCs manifested by barrage firing is evolutionary conserved.EGFP+ interneurons (INs) with soma located in the superficial portion of stratum lacunosummoleculare (SLM) of mid-ventral hippocampi and Layer I (LI) of cortex (lateral to mid-ventral hippocampi) interneurons in P35-P60 GAD65-EGFP or Htr3A-EGFP mice were targeted 41, 42, 43 . Using the approach outlined above our data was restricted to NGFCs derived from progenitors ...

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Differential modulation of repetitive firing and synchronous network activity in neocortical interneurons by inhibition of A-type K+ channels and Ih

Cited by 22 publications

References 148 publications

Divergent paths to seizure‐like events

Divergent paths to seizure‐like events

Modeling implicates inhibitory network bistability as an underpinning of seizure initiation

Activity-dependent tuning of intrinsic excitability in mouse and human neurogliaform cells

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