Locally Reducing KCC2 Activity in the Hippocampus is Sufficient to Induce Temporal Lobe Epilepsy

Kelley, Matthew R.; Cardarelli, Ross A.; Smalley, Joshua L.; Ollerhead, Thomas A.; Andrew, Peter M.; Brandon, Nicholas J.; Deeb, Tarek Z.; Moss, Stephen J.

doi:10.1016/j.ebiom.2018.05.029

Cited by 46 publications

(59 citation statements)

References 41 publications

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“…In addition, since KCC2 is involved in a variety of molecular interactions with synaptic proteins (Ivakine et al , 2013; Mahadevan et al , 2014), ion channels (Goutierre et al , 2019) and cytoskeleton-related proteins (Li et al , 2007; Gauvain et al , 2011; Chevy et al , 2015; Llano et al , 2015), the loss of its expression also affects several physiological properties beyond the mere control of chloride transport and GABA signaling (Chamma et al , 2012). Thus, KCC2 knockdown in cortical PCs was shown to also profoundly perturb neuronal excitability as well as network activity (Kelley et al , 2018; Goutierre et al , 2019). Since PV INs exert a critical control over the activity of cortical PCs (Pouille & Scanziani, 2001) and shape their rhythmic activities (Klausberger & Somogyi, 2008; Amilhon et al , 2015; Gan et al , 2017), altered CCC expression in these cells would be expected to profoundly perturb cortical rhythmogenesis.…”

Section: Discussionmentioning

confidence: 99%

Cation-chloride cotransporters and the polarity of GABA signaling in mouse hippocampal parvalbumin interneurons

Otsu

Donneger

Schwartz

et al. 2019

Preprint

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Transmembrane chloride gradients govern the efficacy and polarity of GABA signaling in neurons and are usually maintained by the activity of cation chloride cotransporters, such as KCC2 and NKCC1. Whereas their role is well established in cortical principal neurons, it remains poorly documented in GABAergic interneurons. We used complementary electrophysiological approaches to compare the effects of GABAAR activation in adult mouse hippocampal parvalbumin interneurons (PV INs) and pyramidal cells (PCs). Loose cell attached, tight-seal and gramicidin-perforated patch recordings all show GABAAR-mediated transmission is slightly depolarizing and yet inhibitory in both PV INs and PCs. Focal GABA uncaging in whole-cell recordings reveal that KCC2 and NKCC1 are functional in both PV INs and PCs but differentially contribute to transmembrane chloride gradients in their soma and dendrites. Blocking KCC2 function depolarizes the reversal potential of GABAAR-mediated currents in PV INs and PCs, often beyond firing threshold, showing KCC2 is essential to maintain the inhibitory effect of GABAARs. Finally, we show that repetitive 10 Hz activation of GABAARs in both PV INs and PCs leads to a progressive decline of the postsynaptic response independently of the ion flux direction or KCC2 function. This suggests intraneuronal chloride buildup may not predominantly contribute to activity-dependent plasticity of GABAergic synapses in this frequency range. Altogether our data demonstrate similar mechanisms of chloride regulation in mouse hippocampal PV INs and PCs and suggest KCC2 downregulation in the pathology may affect the valence of GABA signaling in both cell types.Key point summaryCation-chloride cotransporters (CCCs) play a critical role in controlling the efficacy and polarity of GABAA receptor (GABAAR)-mediated transmission in the brain, yet their expression and function in GABAergic interneurons has been overlooked.We compared the polarity of GABA signaling and the function of CCCs in mouse hippocampal pyramidal neurons and parvalbumin-expressing interneurons.Under resting conditions, GABAAR activation was mostly depolarizing and yet inhibitory in both cell types. KCC2 blockade further depolarized the reversal potential of GABAAR-mediated currents often above action potential threshold.However, during repetitive GABAAR activation, the postsynaptic response declined independently of the ion flux direction or KCC2 function, suggesting intracellular chloride buildup is not responsible for this form of plasticity.Our data demonstrate similar mechanisms of chloride regulation in mouse hippocampal pyramidal neurons and parvalbumin interneurons.

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Section: Discussionmentioning

confidence: 99%

Cation-chloride cotransporters and the polarity of GABA signaling in mouse hippocampal parvalbumin interneurons

Otsu

Donneger

Schwartz

et al. 2019

Preprint

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“…In an adult model of limbic epilepsy, prevention of PLCγ1-pathway activation prevented epileptogenesis ( 54, 55 ). Further, AAV- Cre mediated reduction of KCC2 in the CA1 and dentate gyrus of the adult mouse hippocampus resulted in some of the core phenotypes of medial temporal lobe epilepsy, such as spontaneous seizures, gliosis, and neuronal loss ( 56 ). These results from adult mouse models of epilepsy, and the prevalence of pathogenic KCC2 mutations in human epilepsy ( 57 ) support the critical role of KCC2 and pathways that promote its hypofunction in epilepsy.…”

Section: Discussionmentioning

confidence: 99%

TrkB agonists prevent post-ischemic BDNF-TrkB mediated emergence of refractory neonatal seizures in CD-1 pups

Kipnis

Sullivan

Carter

et al. 2019

Preprint

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34Refractory neonatal seizures do not respond to first-line anti-seizure medications (ASMs) 35 like phenobarbital (PB), a positive allosteric modulator for GABAA receptors, the most widely 36 used ASM to treat neonatal seizures. GABAA receptor-mediated inhibition is dependent upon 37 neuronal chloride regulation. The electroneutral cation-chloride transporter KCC2 mediates 38 neuronal chloride extrusion; an age-dependent increase of KCC2 expression enables the shift of 39 GABAergic signaling from depolarizing to hyperpolarizing. BDNF-TrkB activation following 40 excitotoxic injury recruits downstream targets like PLCγ1, leading to KCC2 hypofunction. This 41 study investigated the efficacy of partial and full TrkB agonists; LM22A-4 (LM), HIOC and 42 Deoxygedunin (DG) respectively, on PB-refractory seizures, post-ischemic TrkB-pathway 43 activation, and KCC2 membrane stability in a P7 CD-1 mouse model of refractory neonatal 44 seizures. Anti-seizure efficacy was determined by quantifying seizure burdens with continuous 45 video-EEG. LM rescued PB-refractory seizures in a sexually dimorphic manner. LM anti-seizure 46 efficacy was associated with a significant reduction in the post-ischemic phosphorylation of 47 TrkB at Y816, a site known to mediate post-ischemic KCC2 hypofunction via PLCγ1 activation. 48 LM additionally rescued ischemia-induced pKCC2-S940 dephosphorylation preserving its 49 membrane stability. HIOC and DG, two novel full TrkB agonists, also rescued PB-refractoriness 50 and post-ischemic TrkB-PLCγ1 pathway activation. Additionally, chemogenetic inactivation of 51 TrkB significantly reduced post-ischemic neonatal seizure burdens at P7. Developmental 52 expression profiles of TrkB and KCC2 in naïve pups identified developmental differences that 53 may underlie the sex-dependent variance in anti-seizure efficacy. These results support a novel 54 role for the TrkB receptor in the emergence of age-dependent refractory neonatal seizures. 55 56 65 (KCC2) in a mouse model of acute neonatal ischemia associated with phenobarbital (PB)-66 refractory seizures (5). 67The electroneutral cation-chloride transporter KCC2 is the primary neuronal Clextruder 68 and enables hyperpolarizing GABAergic inhibition in the brain. The residue Ser940 (S940) on 69 the C-terminus of KCC2 is associated with its membrane stability and chloride extrusion 70 capacity (6, 7). The developmental switch in GABAergic signaling from depolarizing to 71 hyperpolarizing (8) is enabled by an age-dependent increase of KCC2 expression (9). In the 72 neonatal period, KCC2 expression is low and GABA is depolarizing (8-10). In addition, KCC2 73 is susceptible to degradation following excitotoxic injury (2, 11, 12). In our characterized CD-1 74 mouse model of ischemic neonatal seizures, KCC2 underwent degradation and 75 dephosphorylation of residue S940 (5). This rendered the ASM PB inefficacious (5), as PB is a 76 positive allosteric modulator of GABAA receptors (13). Prevention of BDNF-TrkB mediated 77 KCC2 hypofunction rescued PB-refractori...

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“…The most striking feature of the KCC2 proteome is that it is highly enriched for protein products of genes associated with ASD/Epi. Perturbation of KCC2 itself is associated with autism (59) and epilepsy (14,15,17,59). Of the KCC2-associated proteins, ANK2, SHANK3, and SCN2A are all ranked in the highest group of ASDs by SFARI, mutations in the latter are also a cause of Dravet syndrome (38).…”

Section: Kcc2 Is Associated With a Subset Of Highly Interconnected Asmentioning

confidence: 99%

“…Primary neuron culture Mouse cortical and hippocampal mixed cultures were created from P0 mouse pups as previously described (77). Briefly, P0 mice were anesthetized on ice and the brains removed.…”

Section: Bn-pagementioning

confidence: 99%

“…In keeping with its essential role in determining the efficacy of synaptic inhibition, KCC2 and autism/epilepsy risk gene products humans with mutations in KCC2 develop severe epilepsy soon after birth (14)(15)(16). Deficits in KCC2 activity are also believed to contribute to the development of temporal lobe epilepsy (17,18), in addition to other traumas including ischemia and neuropathic pain (19,20). Given the critical role that KCC2 plays in determining the maturation of inhibitory neurotransmission, subtle changes in its function are also strongly implicated in autism spectrum disorders (ASD) (21).…”

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confidence: 99%

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The K-Cl co-transporter 2 is a point of convergence for multiple autism spectrum disorder and epilepsy risk gene products

Smalley

Kontou

Choi

et al. 2020

Preprint

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KCC2 plays a critical role in determining the efficacy of synaptic inhibition and deficits in its activity lead to epilepsy and neurodevelopmental delay. Here we use unbiased proteomic analyses to demonstrate that KCC2 forms stable protein complexes in the neuronal plasma membrane with 96 autism and/or epilepsy risk gene (ASD/Epi) products including ANKB, ANKG, CNTN1, ITPR1, NCKAP1, SCN2A, SHANK3, SPTAN1, and SPTBN1. Many of these proteins are also targets of Fragile-X mental retardation protein (FMRP), the inactivation of which is the leading monogenic cause of autism. Accordingly, the expression of a subset of these KCC2-binding partners was decreased in Fmr1 knockout mice. Fmr1 knockout compromised KCC2 phosphorylation, a key regulatory mechanism for transporter activity and the postnatal development of GABAergic inhibition. Thus, KCC2 is a point of convergence for multiple ASD/Epi risk genes and therapies targeting this transporter may have broad utility in alleviating these heterogeneous disorders and their associated epilepsies.

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Locally Reducing KCC2 Activity in the Hippocampus is Sufficient to Induce Temporal Lobe Epilepsy

Cited by 46 publications

References 41 publications

Cation-chloride cotransporters and the polarity of GABA signaling in mouse hippocampal parvalbumin interneurons

Cation-chloride cotransporters and the polarity of GABA signaling in mouse hippocampal parvalbumin interneurons

TrkB agonists prevent post-ischemic BDNF-TrkB mediated emergence of refractory neonatal seizures in CD-1 pups

The K-Cl co-transporter 2 is a point of convergence for multiple autism spectrum disorder and epilepsy risk gene products

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