Connexin36 knockout mice display increased sensitivity to pentylenetetrazol-induced seizure-like behaviors

Jacobson, Gregory M.; Voss, Logan J.; Melin, Sofia M.; Mason, John; Cursons, Raymond T.; Steyn-Ross, D. Alistair; Steyn-Ross, Moira L.; Sleigh, James W.

doi:10.1016/j.brainres.2010.09.006

Cited by 36 publications

(40 citation statements)

References 42 publications

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“…Figure 3C compares paired-pulse responses in WT vs KO mice for the 1 st and 10 th 10 Hz stimulation epochs. There was a significant and persistent loss of GABA inhibition (20 and 40 msec ISIs) in WT mice compared to KO mice (P=0.004, F (1,15) =11.4; n=4 each; Figure 3C). …”

Section: Evoked Field Potentials and Paired-pulse Responses In The Dementioning

confidence: 98%

“…Gap junctions are pores constructed between cells from approximately 20 members of the connexin (Cx) protein family by aggregation of six Cx proteins, forming a connexon which associates with a connexon on a neighboring cell [15]. These pores allow for the coupling of membrane voltages between neighboring neurons [16], thereby providing a means for intercellular communication in both the developing and mature nervous system [17].…”

Section: Introductionmentioning

confidence: 99%

“…These pores allow for the coupling of membrane voltages between neighboring neurons [16], thereby providing a means for intercellular communication in both the developing and mature nervous system [17]. Many different connexin proteins are expressed in the various brain cell-types, including glial cells [15]. Glia are now increasingly linked to seizure generation as they are extensively connected via GJs [Cx30, 43, and 26; [18]].…”

Section: Introductionmentioning

confidence: 99%

“…They often govern oscillations in GABA neuron networks [22][23][24], potentially leading to increased excitatory activity or decreased inhibitory activity and thus promoting epileptogenesis [16]. Pro-convulsant drug studies have suggested a role for GJ-mediated intercellular communication in ictogenesis [15]. Despite the fact that GJs are involved in neuronal oscillations and synchrony, evidence for their role in behavioral models has lagged behind the molecular and physiological evidence.…”

Section: Introductionmentioning

confidence: 99%

“…For example, mice lacking neuron-specific Cx36 GJs evince reduced kainate-induced [41] and 4-aminopyridine-induced seizures [42]. One study showed that Cx36 knock-out (KO) mice appear to be more susceptible to druginduced seizures using the excitotoxin kainic acid [15].…”

Section: Introductionmentioning

confidence: 99%

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Connexin-36 Knock-Out Mice have Increased Threshold for Kindled Seizures: Role of GABA Inhibition

Shin¹

2013

Biochem & Pharmacol

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Blockade of gap junctions (GJs) has been shown to reduce seizures in different epilepsy models. Gap junctionmediated, electrically-coupled neuronal networks have been implicated in neuronal synchronization, which is the hallmark of seizure activity. To further understand the role of GJs in seizures, in particular hippocampal seizures, we evaluated electrophysiological responses in the dentate gyrus subfield of the hippocampus, including GABA-mediated recurrent inhibition, seizuregenic stimulation, and seizure activity in response to perforant path kindling in Cx36 knockout (KO) mice compared to wild-type (WT) controls. In anesthetized mice, Cx36 KO mice were characterized by enhanced GABA-mediated recurrent inhibition. Stimulation of the perforant path at 10 Hz for 10 sec (i.e., 100 pulses) markedly enhanced population spike (PS) amplitudes and reduced paired-pulse GABA-mediated inhibition during the stimulation, induced an after discharge for approximately 10 sec at 7-10 sec into the stimulation, and suppressed PS amplitudes postictally for 5-10 min in both KO and WT mice. Repeated epochs of 10 Hz for 10 sec stimulation of the perforant path at 20 min intervals resulted in progressive and persistent disinhibition of paired-pulse responses in WT, but not KO mice. In freely-behaving seizure studies, stimulation of the perforant path (10 Hz for 10 sec) once/day resulted in progressive Stage I-IV seizures in both WT and KO mice. Once Stage IV was achieved, another Stage IV seizure could be elicited each day with the same behavioral response (i.e., Stage V). The threshold for kindled seizures was significantly greater in KO mice compared to WT controls for most stages of seizures. The Cx36 antagonist mefloquine (MFQ) and the typical anticonvulsant pentobarbital reduced Stage IV seizures in both WT and KO mice. Knock-out mice were more sensitive to the anti-epileptic effects of the typical anti-convulsant pentobarbital (20 mg/ kg). Taken together, these findings support the emerging view that reduction in GJ-mediated GABA electrical coupling reduces seizures, perhaps through enhancement of GABAergic feedback inhibition, which results from the uncoupling of the GABA recurrent interneurons from the resistive load that is inherent in their electrical connectivity.

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Section: Evoked Field Potentials and Paired-pulse Responses In The Dementioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Connexin-36 Knock-Out Mice have Increased Threshold for Kindled Seizures: Role of GABA Inhibition

Shin¹

2013

Biochem & Pharmacol

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Connexins and pannexins: At the junction of neuro‐glial homeostasis & disease

Lapato

Tiwari‐Woodruff

2017

J of Neuroscience Research

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In the central nervous system (CNS), connexin and pannexin gap junctions and hemichannels are an integral component of homeostatic neuronal excitability and synaptic plasticity. Neuronal connexin (Cx) gap junctions form electrical synapses across biochemically similar GABAergic networks, allowing rapid and extensive inhibition in response to principle neuron excitation. Glial Cx gap junctions link astrocytes and oligodendrocytes in the pan-glial network that is responsible for removing excitotoxic ions and metabolites. In addition, Cx gap junctions between glia help constrain excessive excitatory activity in neurons and facilitate astrocyte Ca2+ slow wave propagation. Pannexins (Panxs) do not form gap junctions in vivo, but Panx hemichannels participate in autocrine and paracrine gliotransmission alongside connexin hemichannels. ATP and other gliotransmitters released by Cx and Panx hemichannels maintain physiologic glutamatergic tone by strengthening synapses and mitigating aberrant high frequency bursting. Under pathological depolarizing and inflammatory conditions, gap junctions and hemichannels become dysregulated, resulting in aberrant neuronal firing and seizure. In this review, we present known contributions of Cxs and Panxs to physiologic neuronal excitation and explore how disruption of gap junctions and hemichannels lead to aberrant glutamatergic transmission, purinergic signaling, and seizures.

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Gap Junctions, Neural Population Models and

Steyn-Ross

Sleigh

2022

Encyclopedia of Computational Neuroscience

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Connexin36 knockout mice display increased sensitivity to pentylenetetrazol-induced seizure-like behaviors

Abstract: Sleigh, Connexin36 knockout mice display increased sensitivity to pentylenetetrazolinduced seizure-like behaviors, Brain Research (2010),

Cited by 36 publications

References 42 publications

Connexin-36 Knock-Out Mice have Increased Threshold for Kindled Seizures: Role of GABA Inhibition

Connexin-36 Knock-Out Mice have Increased Threshold for Kindled Seizures: Role of GABA Inhibition

Connexins and pannexins: At the junction of neuro‐glial homeostasis & disease

Gap Junctions, Neural Population Models and

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