Chronic DREADD Isn’t As Bad As It Sounds

Hyder, Safwan K; Forcelli, Patrick A.

doi:10.1177/1535759720920583

Cited by 3 publications

(3 citation statements)

References 16 publications

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“…Nevertheless, chronic DREADD studies are becoming increasingly common due to the recent developments in selective, potent, and long-acting DREADD ligands such as DCZ, as well as noninvasive ligand administration routes (64)(65)(66). However, it should be pointed out that there are several potential technical concerns associated with chronic DREADD studies, including tolerance and desensitization to the ligand (60).…”

Section: Discussionmentioning

confidence: 99%

GABAergic interneurons contribute to the fatal seizure phenotype of CLN2 disease mice

Takahashi,

Rensing,

Eultgen

et al. 2024

Preprint

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GABAergic interneuron deficits have been implicated in the epileptogenesis of multiple neurological diseases. While epileptic seizures are a key clinical hallmark of CLN2 disease, a childhood-onset neurodegenerative lysosomal storage disorder caused by a deficiency of tripeptidyl peptidase 1 (TPP1), the etiology of these seizures remains elusive. Given thatCln2R207X/R207Xmice display fatal spontaneous seizures and an early loss of several cortical interneuron populations, we hypothesized that those two events might be causally related. To address this hypothesis, we first generated an inducible transgenic mouse expressing lysosomal membrane-tethered TPP1 (TPP1LAMP1) on theCln2R207X/R207Xgenetic background to study the cell-autonomous effects of cell-type-specific TPP1 deficiency. We crossed the TPP1LAMP1 mice withVgat-Cremice to introduce interneuron-specific TPP1 deficiency.Vgat-Cre; TPP1LAMP1 mice displayed storage material accumulation in several interneuron populations both in cortex and striatum, and increased susceptibility to die after PTZ-induced seizures. Secondly, to test the role of GABAergic interneuron activity in seizure progression, we selectively activated these cells inCln2R207X/R207Xmice using Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) inVgat-Cre: Cln2R207X/R207Xmice. EEG monitoring revealed that DREADD-mediated activation of interneurons via chronic deschloroclozapine administration accelerated the onset of spontaneous seizures and seizure-associated death inVgat-Cre: Cln2R207X/R207Xmice, suggesting that modulating interneuron activity can exert influence over epileptiform abnormalities in CLN2 disease. Taken together, these results provide new mechanistic insights into the underlying etiology of seizures and premature death that characterize CLN2 disease.

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Section: Discussionmentioning

confidence: 99%

GABAergic interneurons contribute to the fatal seizure phenotype of CLN2 disease mice

Takahashi,

Rensing,

Eultgen

et al. 2024

Preprint

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“…Even considering some potential drawbacks to the clinic, DREADD may be considered a promising intervention in epilepsy treatment ( Hyder and Forcelli, 2020 ). This technique is not associated with potentially damaging instrumentation as intracerebral drug delivery, deep brain stimulation, or optogenetics, where devices must be physically present.…”

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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“…In fact, electrical and magnetic stimulation have already been tested in human subjects (Jo and Perez, 2020;Shen et al, 2020;Thomaz et al, 2019). Arguments have been made for the application of chemogenetic modulation as a treatment for neurological diseases, such as epilepsy (Desloovere et al, 2019;Hyder and Forcelli, 2020;Magnus et al, 2019), but there are several concerns that must be considered before this method can be applied in a clinical setting. For example, viral gene transfer would be the most likely method for delivery of the DREADD gene, necessitating a safety evaluation for gene therapy.…”

Section: Limitations Of the Studymentioning

confidence: 99%

Long-term selective stimulation of transplanted neural stem/progenitor cells for spinal cord injury improves locomotor function

et al. 2021

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Chronic DREADD Isn’t As Bad As It Sounds

Abstract: [Box: see text]

Cited by 3 publications

References 16 publications

GABAergic interneurons contribute to the fatal seizure phenotype of CLN2 disease mice

GABAergic interneurons contribute to the fatal seizure phenotype of CLN2 disease mice

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

Long-term selective stimulation of transplanted neural stem/progenitor cells for spinal cord injury improves locomotor function

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