The impact of silencing feed-forward parvalbumin-expressing inhibitory interneurons in the cortico-thalamocortical network on seizure generation and behaviour

Panthi, Sandesh; Leitch, Beulah

doi:10.1016/j.nbd.2019.104610

Cited by 32 publications

(40 citation statements)

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“…However, the extent to which this defect weakens FFI within the CTC network and whether this directly contributes toward the generation and maintenance of absence seizures had not been previously established. We recently reported that acute selective silencing of PV+ interneurons in the CTC network (either in the SScortex or the RTN thalamus) impairs FFI and generates absence-like SWDs in normal non-epileptic mice (Panthi and Leitch, 2019). In the current study, the goal was to determine the impact of selectively activating PV+ inhibitory interneurons within the CTC network during absence seizures, to determine if this was sufficient to prevent or reduce seizure activity.…”

Section: Introductionmentioning

confidence: 94%

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Chemogenetic Activation of Feed-Forward Inhibitory Parvalbumin-Expressing Interneurons in the Cortico-Thalamocortical Network During Absence Seizures

Panthi

Leitch

2021

Front. Cell. Neurosci.

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Parvalbumin-expressing (PV+) interneurons are a subset of GABAergic inhibitory interneurons that mediate feed-forward inhibition (FFI) within the cortico-thalamocortical (CTC) network of the brain. The CTC network is a reciprocal loop with connections between cortex and thalamus. FFI PV+ interneurons control the firing of principal excitatory neurons within the CTC network and prevent runaway excitation. Studies have shown that generalized spike-wave discharges (SWDs), the hallmark of absence seizures on electroencephalogram (EEG), originate within the CTC network. In the stargazer mouse model of absence epilepsy, reduced FFI is believed to contribute to absence seizure genesis as there is a specific loss of excitatory α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) at synaptic inputs to PV+ interneurons within the CTC network. However, the degree to which this deficit is directly related to seizure generation has not yet been established. Using chemogenetics and in vivo EEG recording, we recently demonstrated that functional silencing of PV+ interneurons in either the somatosensory cortex (SScortex) or the reticular thalamic nucleus (RTN) is sufficient to generate absence-SWDs. Here, we used the same approach to assess whether activating PV+ FFI interneurons within the CTC network during absence seizures would prevent or reduce seizures. To target these interneurons, mice expressing Cre recombinase in PV+ interneurons (PV-Cre) were bred with mice expressing excitatory Gq-DREADD (hM3Dq-flox) receptors. An intraperitoneal dose of pro-epileptic chemical pentylenetetrazol (PTZ) was used to induce absence seizure. The impact of activation of FFI PV+ interneurons during seizures was tested by focal injection of the “designer drug” clozapine N-oxide (CNO) into either the SScortex or the RTN thalamus. Seizures were assessed in PVCre/Gq-DREADD animals using EEG/video recordings. Overall, DREADD-mediated activation of PV+ interneurons provided anti-epileptic effects against PTZ-induced seizures. CNO activation of FFI either prevented PTZ-induced absence seizures or suppressed their severity. Furthermore, PTZ-induced tonic-clonic seizures were also reduced in severity by activation of FFI PV+ interneurons. In contrast, administration of CNO to non-DREADD wild-type control animals did not afford any protection against PTZ-induced seizures. These data demonstrate that FFI PV+ interneurons within CTC microcircuits could be a potential therapeutic target for anti-absence seizure treatment in some patients.

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Section: Introductionmentioning

confidence: 94%

“…Cre-dependent excitatory Gq-DREADD mice (i.e., hM3Dq-flox mice) were crossed with PV-Cre mice to express Gq-DREADDs in PV+ interneurons (Zhu et al, 2016). Selective activation of FFI within the CTC network was achieved by focal injection of CNO into cortical or thalamic regions of interest (Panthi and Leitch, 2019).…”

Section: Introductionmentioning

confidence: 99%

Chemogenetic Activation of Feed-Forward Inhibitory Parvalbumin-Expressing Interneurons in the Cortico-Thalamocortical Network During Absence Seizures

Panthi

Leitch

2021

Front. Cell. Neurosci.

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“…Indeed, some of the key differences that exist in normal animals between parvalbumin- and somatostatin-positive cortical interneurons ( Ascoli et al , 2008 ) may be altered in the CIN of absence seizure models. Notably, selective inhibition by DREADDS of cortical parvalbumin-positive interneurons has been shown to elicit absence-like seizures in normal mice ( Panthi and Leitch, 2019 ) and genetic ablation of Ca v 2.1 channels in both parvalbumin- and somatostatin-positive cortical interneurons elicit severe generalized seizures and absence seizures ( Rossignol et al , 2013 ). However, whether and how somatostatin-positive interneurons, the main mediators of the dendritic inhibition-dependent regulation of input-output transformations in pyramidal neurons ( Lovett-Barron et al , 2012 ; Wilson et al , 2012 ; Lee et al , 2013 ), may contribute to absence seizure generation remains to be established.…”

Section: Introductionmentioning

confidence: 99%

Clinical and experimental insight into pathophysiology, comorbidity and therapy of absence seizures

Crunelli

Lőrincz

McCafferty

et al. 2020

Brain

150

159

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Absence seizures in children and teenagers are generally considered relatively benign because of their non-convulsive nature and the large incidence of remittance in early adulthood. Recent studies, however, show that 30% of children with absence seizures are pharmaco-resistant and 60% are affected by severe neuropsychiatric comorbid conditions, including impairments in attention, cognition, memory and mood. In particular, attention deficits can be detected before the epilepsy diagnosis, may persist even when seizures are pharmacologically controlled and are aggravated by valproic acid monotherapy. New functional MRI-magnetoencephalography and functional MRI-EEG studies provide conclusive evidence that changes in blood oxygenation level-dependent signal amplitude and frequency in children with absence seizures can be detected in specific cortical networks at least 1 min before the start of a seizure, spike-wave discharges are not generalized at seizure onset and abnormal cortical network states remain during interictal periods. From a neurobiological perspective, recent electrical recordings and imaging of large neuronal ensembles with single-cell resolution in non-anaesthetized models show that, in contrast to the predominant opinion, cortical mechanisms, rather than an exclusively thalamic rhythmogenesis, are key in driving seizure ictogenesis and determining spike-wave frequency. Though synchronous ictal firing characterizes cortical and thalamic activity at the population level, individual cortico-thalamic and thalamocortical neurons are sparsely recruited to successive seizures and consecutive paroxysmal cycles within a seizure. New evidence strengthens previous findings on the essential role for basal ganglia networks in absence seizures, in particular the ictal increase in firing of substantia nigra GABAergic neurons. Thus, a key feature of thalamic ictogenesis is the powerful increase in the inhibition of thalamocortical neurons that originates at least from two sources, substantia nigra and thalamic reticular nucleus. This undoubtedly provides a major contribution to the ictal decrease in total firing and the ictal increase of T-type calcium channel-mediated burst firing of thalamocortical neurons, though the latter is not essential for seizure expression. Moreover, in some children and animal models with absence seizures, the ictal increase in thalamic inhibition is enhanced by the loss-of-function of the astrocytic GABA transporter GAT-1 that does not necessarily derive from a mutation in its gene. Together, these novel clinical and experimental findings bring about paradigm-shifting views of our understanding of absence seizures and demand careful choice of initial monotherapy and continuous neuropsychiatric evaluation of affected children. These issues are discussed here to focus future clinical and experimental research and help to identify novel therapeutic targets for treating both absence seizures and their comorbidities.

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“…Fast-spiking interneurons are essential for proper network oscillations and disrupting the function of PV+INTs can generate spontaneous recurrent seizures (Drexel et al, 2017;Panthi and Leitch, 2019). Recent transcriptomics suggests that there are several genomically distinct subpopulations of PV+INTs (Hodge et al, 2019;Gouwens et al, 2020), some of which may correspond to unique PV+INT subtypes that have remained largely understudied relative to the canonical FS subtypes listed above.…”

Section: Introductionmentioning

confidence: 99%

“…PV-containing inhibitory interneurons (PV+INTs) are often classified as ‘fast-spiking’ cells due to their ability to sustain high-frequency discharges of action potentials with minimal spike-frequency adaptation/accommodation ( Pelkey et al, 2017 ). Fast-spiking interneurons are essential for proper network oscillations and disrupting the function of PV+INTs can generate spontaneous recurrent seizures ( Drexel et al, 2017 ; Panthi and Leitch, 2019 ). Recent transcriptomics suggests that there are several genomically distinct subpopulations of PV+INTs ( Hodge et al, 2019 ; Gouwens et al, 2020 ), some of which may correspond to unique PV+INT subtypes that have remained largely understudied relative to the canonical FS subtypes listed above.…”

Section: Introductionmentioning

confidence: 99%

Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type I lissencephaly

Ekins

Mahadevan

Zhang

et al. 2020

eLife

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Type I lissencephaly is a neuronal migration disorder caused by haploinsuffiency of the PAFAH1B1 (mouse: Pafah1b1) gene and is characterized by brain malformation, developmental delays, and epilepsy. Here, we investigate the impact of Pafah1b1 mutation on the cellular migration, morphophysiology, microcircuitry and transcriptomics of mouse hippocampal CA1 parvalbumin-containing inhibitory interneurons (PV+INTs). We find that WT PV+INTs consist of two physiological subtypes (80% fast-spiking (FS), 20% non-fast-spiking (NFS)) and four morphological subtypes. We find that cell-autonomous mutations within interneurons disrupts morphophysiological development of PV+INTs and results in the emergence of a non-canonical 'intermediate spiking (IS)' subset of PV+INTs. We also find that now dominant IS/NFS cells are prone to entering depolarization block, causing them to temporarily lose the ability to initiate action potentials and control network excitation, potentially promoting seizures. Finally, single-cell nuclear RNAsequencing of PV+INTs revealed several misregulated genes related to morphogenesis, cellular excitability, and synapse formation.

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The impact of silencing feed-forward parvalbumin-expressing inhibitory interneurons in the cortico-thalamocortical network on seizure generation and behaviour

Cited by 32 publications

References 100 publications

Chemogenetic Activation of Feed-Forward Inhibitory Parvalbumin-Expressing Interneurons in the Cortico-Thalamocortical Network During Absence Seizures

Chemogenetic Activation of Feed-Forward Inhibitory Parvalbumin-Expressing Interneurons in the Cortico-Thalamocortical Network During Absence Seizures

Clinical and experimental insight into pathophysiology, comorbidity and therapy of absence seizures

Emergence of non-canonical parvalbumin-containing interneurons in hippocampus of a murine model of type I lissencephaly

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