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

Panthi, Sandesh; Leitch, Beulah

doi:10.3389/fncel.2021.688905

Cited by 17 publications

(15 citation statements)

References 74 publications

(114 reference statements)

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“…Recently, the group showed DREADD-mediated activation of PV+ interneurons from the reticular thalamic nucleus and e somatosensory cortex provided anti-epileptic effects against PTZ-induced seizures. CNO activation of feedforward inhibition either prevented PTZ-induced or suppressed their severity ( Panthi and Leitch, 2021 ).…”

Section: Interventionmentioning

confidence: 99%

Parvalbumin Role in Epilepsy and Psychiatric Comorbidities: From Mechanism to Intervention

Godoy

Prizon

Rossignoli

et al. 2022

Front. Integr. Neurosci.

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Parvalbumin is a calcium-binding protein present in inhibitory interneurons that play an essential role in regulating many physiological processes, such as intracellular signaling and synaptic transmission. Changes in parvalbumin expression are deeply related to epilepsy, which is considered one of the most disabling neuropathologies. Epilepsy is a complex multi-factor group of disorders characterized by periods of hypersynchronous activity and hyperexcitability within brain networks. In this scenario, inhibitory neurotransmission dysfunction in modulating excitatory transmission related to the loss of subsets of parvalbumin-expressing inhibitory interneuron may have a prominent role in disrupted excitability. Some studies also reported that parvalbumin-positive interneurons altered function might contribute to psychiatric comorbidities associated with epilepsy, such as depression, anxiety, and psychosis. Understanding the epileptogenic process and comorbidities associated with epilepsy have significantly advanced through preclinical and clinical investigation. In this review, evidence from parvalbumin altered function in epilepsy and associated psychiatric comorbidities were explored with a translational perspective. Some advances in potential therapeutic interventions are highlighted, from current antiepileptic and neuroprotective drugs to cutting edge modulation of parvalbumin subpopulations using optogenetics, designer receptors exclusively activated by designer drugs (DREADD) techniques, transcranial magnetic stimulation, genome engineering, and cell grafting. Creating new perspectives on mechanisms and therapeutic strategies is valuable for understanding the pathophysiology of epilepsy and its psychiatric comorbidities and improving efficiency in clinical intervention.

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Section: Interventionmentioning

confidence: 99%

Parvalbumin Role in Epilepsy and Psychiatric Comorbidities: From Mechanism to Intervention

Godoy

Prizon

Rossignoli

et al. 2022

Front. Integr. Neurosci.

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“…They found that inactivating FFI (either in the somatosensory cortex or the RTN thalamus by focal injections of CNO) generates absence-like SWDs in normal non-epileptic mice. Furthermore, selectively activating PV + inhibitory interneurons within the CTC network during chemically-induced absence seizures, was sufficient to prevent or reduce seizure activity ( Panthi and Leitch, 2021 ). In contrast, focal injection of CNO into either the somatosensory cortex or RTN thalamus of non-DREADD wildtype control animals, had no effect on chemical-induced absence seizures.…”

Section: Introductionmentioning

confidence: 99%

The Impact of Glutamatergic Synapse Dysfunction in the Corticothalamocortical Network on Absence Seizure Generation

Leitch

2022

Front. Mol. Neurosci.

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Childhood absence epilepsy (CAE) is the most common pediatric epilepsy affecting 10–18% of all children with epilepsy. It is genetic in origin and the result of dysfunction within the corticothalamocortical (CTC) circuitry. Network dysfunction may arise from multifactorial mechanisms in patients from different genetic backgrounds and thus account for the variability in patient response to currently available anti-epileptic drugs; 30% of children with absence seizures are pharmaco-resistant. This review considers the impact of deficits in AMPA receptor-mediated excitation of feed-forward inhibition (FFI) in the CTC, on absence seizure generation. AMPA receptors are glutamate activated ion channels and are responsible for most of the fast excitatory synaptic transmission throughout the CNS. In the stargazer mouse model of absence epilepsy, the genetic mutation is in stargazin, a transmembrane AMPA receptor trafficking protein (TARP). This leads to a defect in AMPA receptor insertion into synapses in parvalbumin-containing (PV+) inhibitory interneurons in the somatosensory cortex and thalamus. Mutation in the Gria4 gene, which encodes for the AMPA receptor subunit GluA4, the predominant AMPA receptor subunit in cortical and thalamic PV + interneurons, also leads to absence seizures. This review explores the impact of glutamatergic synapse dysfunction in the CTC network on absence seizure generation. It also discusses the cellular and molecular mechanisms involved in the pathogenesis of childhood absence epilepsy.

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“…Here, we have addressed the consequences of a chronic postnatal activation of PV-positive inhibitory interneurons on the emergence of adult anxio-depressive behaviors. We used a strategy of chemogenetically activating PV-positive interneurons in bigenic mouse models (PV-Cre::hM3Dq-DREADD) (Panthi and Leitch, 2021) expressing the hM3Dq-DREADD under the control of the PV-promoter, and stimulated the hM3Dq-DREADD with the exogenous ligand clozapine-N-oxide (CNO) in bigenic mouse pups during the postnatal window (postnatal day: P2 -P14). Our results indicate that chemogenetic PV-positive interneuron activation during this postnatal window results in a significant decline in the emergence of adult anxiety and despair-like behavior, in a task-specific and sex-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

Chronic hM3Dq-DREADD mediated chemogenetic activation of parvalbumin-positive inhibitory interneurons in postnatal life alters anxiety and despair-like behavior in adulthood in a task and sex-dependent manner

Banerjee

Pati

Tiwari

et al. 2022

Preprint

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Animal models of early adversity or neurodevelopmental disorders are associated with altered parvalbumin (PV)-positive inhibitory interneuron number and function, correlated with a dysregulated excitation-inhibition (E/I) balance that is implicated in the pathophysiology of neuropsychiatric disorders. We sought to address whether altering neuronal activity of PV-positive interneurons during the postnatal developmental window influences the emergence of anxio-depressive behaviors in adulthood, which are known to be perturbed in models of early adversity and neurodevelopmental disorders. We used a PV-Cre::hM3Dq-DREADD bigenic mouse line that selectively expresses the hM3Dq-DREADD receptor in PV-positive interneurons, and chemogenetically enhanced Gq signaling in PV-positive interneurons during the postnatal window via administration of the DREADD agonist, clozapine-N-oxide. Immunofluorescence studies indicated the selective expression of hM3Dq-DREADD in PV-positive interneurons in limbic circuits, and revealed a reduction in expression of the neuronal activity marker, c-Fos, in these circuits, following chemogenetic hM3Dq-DREADD mediated activation of PV-positive inhibitory interneurons. We noted no change in either growth or sensorimotor reflex milestones following chronic hM3Dq-DREADD mediated chemogenetic activation of PV-positive inhibitory interneurons in postnatal life. Adult male and female PV-Cre::hM3Dq-DREADD bigenic mice with a history of postnatal chemogenetic activation of PV-positive interneurons exhibited a reduction in anxiety and despair-like behavior in adulthood, which was noted in both a behavioral task and sex-dependent manner. These results indicate that altering neuronal activity within PV-positive interneurons during the critical postnatal developmental window can shape the emergence of anxio-depressive behaviors in adulthood, and suggest that interactions with sex as a variable play a key role in determining behavioral outcomes.

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

Cited by 17 publications

References 74 publications

Parvalbumin Role in Epilepsy and Psychiatric Comorbidities: From Mechanism to Intervention

Parvalbumin Role in Epilepsy and Psychiatric Comorbidities: From Mechanism to Intervention

The Impact of Glutamatergic Synapse Dysfunction in the Corticothalamocortical Network on Absence Seizure Generation

Chronic hM3Dq-DREADD mediated chemogenetic activation of parvalbumin-positive inhibitory interneurons in postnatal life alters anxiety and despair-like behavior in adulthood in a task and sex-dependent manner

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