Pharmaco-genetic therapeutics targeting parvalbumin neurons attenuate temporal lobe epilepsy

Wang, Ying; Liang, Jing; Chen, Liying; Shen, Yating; Zhao, Junli; Xu, Cenglin; Wu, Xiaohua; Cheng, Heming; Ying, Xiaoying; Guo, Yi; Wang, Shuang; Zhou, Yifeng; Wang, Yi; Chen, Zhong

doi:10.1016/j.nbd.2018.06.006

Cited by 53 publications

(73 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…9 In this study chemogenetic inhibition of CamKIIα principal neurons as well as activation of parvalbumin interneurons reduced the number of generalized seizures during an 8-hour monitoring period after 1 mg/ kg CNO administration. Administration of a DREADD-agonist (10 mg/kg CNO) has a robust influence on hippocampal EEG of DREADD mice.…”

Section: Discussionmentioning

confidence: 67%

“…5 A selective promotor system carried by a locally injected recombinant adeno-associated viral (rAAV) vector achieves region-and cell-type-specific expression of DREADDs. 9,13 In this study we applied chemogenetics in the intrahippocampal kainic acid mouse (IHKA) model for drug-refractory TLE. Depending on the type of DREADD, neurons can be selectively activated or inhibited.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Long‐term chemogenetic suppression of spontaneous seizures in a mouse model for temporal lobe epilepsy

et al. 2019

View full text Add to dashboard Cite

Objective: More than one-third of patients with temporal lobe epilepsy (TLE) continue to have seizures despite treatment with antiepileptic drugs, and many experience severe drug-related side effects, illustrating the need for novel therapies. Selective expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) allows cell-type-specific reduction of neuronal excitability. In this study, we evaluated the effect of chemogenetic suppression of excitatory pyramidal and granule cell neurons of the sclerotic hippocampus in the intrahippocampal mouse model (IHKA) for temporal lobe epilepsy. Methods: Intrahippocampal IHKA mice were injected with an adeno-associated viral vector carrying the genes for an inhibitory DREADD hM4Di in the sclerotic hippocampus or control vector. Next, animals were treated systemically with different single doses of clozapine-N-oxide (CNO) (1, 3, and 10 mg/kg) and clozapine (0.03 and 0.1 mg/kg) and the effect on spontaneous hippocampal seizures, hippocampal electroencephalography (EEG) power, fast ripples (FRs) and behavior in the open field test was evaluated. Finally, animals received prolonged treatment with clozapine for 3 days and the effect on seizures was monitored. Results: Treatment with both CNO and clozapine resulted in a robust suppression of hippocampal seizures for at least 15 hours only in DREADD-expressing animals. Moreover, total EEG power and the number of FRs were significantly reduced. CNO and/or clozapine had no effects on interictal hippocampal EEG, seizures, or locomotion/anxiety in the open field test in non-DREADD epileptic IHKA mice. Repeated clozapine treatment every 8 hours for 3 days resulted in almost complete seizure suppression in DREADD animals. Significance: This study shows the potency of chemogenetics to robustly and sustainably suppress spontaneous epileptic seizures and pave the way for an epilepsy therapy in which a systemically administered exogenous drug selectively modulates specific cell types in a seizure network, leading to a potent seizure suppression devoid of the typical drug-related side effects. | 2315 DESLOOVERE Et aL.

show abstract

Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Long‐term chemogenetic suppression of spontaneous seizures in a mouse model for temporal lobe epilepsy

et al. 2019

View full text Add to dashboard Cite

show abstract

“…6,7 In line with this evidence, inhibiting interneuron activity during the preictal and ictal period decreases seizure threshold and prolongs the duration of seizures in vivo. [10][11][12] Given the strategic location of perisomatic synapses made by parvalbumin (PV)-positive interneurons onto principal cells, 13 as well as their prominent role in blocking seizures in the kainic acid model 6,14 and in suppressing convulsive seizures induced with 4AP, 15 we investigated whether unilateral long-term optogenetic stimulation of PVpositive interneurons in the CA3 region of the hippocampus can influence the frequency of spontaneous seizures in the pilocarpine model of MTLE. [10][11][12] Given the strategic location of perisomatic synapses made by parvalbumin (PV)-positive interneurons onto principal cells, 13 as well as their prominent role in blocking seizures in the kainic acid model 6,14 and in suppressing convulsive seizures induced with 4AP, 15 we investigated whether unilateral long-term optogenetic stimulation of PVpositive interneurons in the CA3 region of the hippocampus can influence the frequency of spontaneous seizures in the pilocarpine model of MTLE.…”

mentioning

confidence: 99%

Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy

Lévesque

Chen

Etter

et al. 2019

Annals of Neurology

View full text Add to dashboard Cite

Objective: To establish the effects induced by long-term, unilateral stimulation of parvalbumin (PV)-positive interneurons on seizures, interictal spikes, and high-frequency oscillations (80-500Hz) occurring after pilocarpine-induced status epilepticus (SE)-a proven model of mesial temporal lobe epilepsy (MTLE)-in transgenic mice expressing or not expressing ChR2. Methods: PV-ChR2 (n = 6) and PV-Cre (n = 6) mice were treated with pilocarpine to induce SE. Three hours after SE onset, unilateral optogenetic stimulation (450nm, 25mW, 20-millisecond pulses delivered at 8Hz for 30 seconds every 2 minutes) of CA3 PV-positive interneurons was implemented for 14 continuous days in both groups. Results: Rates of seizures (p < 0.01), interictal spikes (p < 0.001), and interictal spikes with fast ripples (250-500Hz) (p < 0.001) were lower in PV-ChR2 than in PV-Cre mice. Ripples (80-200Hz) occurring outside of interictal spikes had higher rates in the PV-ChR2 group (p < 0.01), whereas isolated fast ripples had lower rates (p < 0.01). However, seizure probability was higher during optogenetic stimulation in PV-ChR2 compared to PV-Cre animals (p < 0.05). Interpretation: Our findings show that the unilateral activation of CA3 PV-positive interneurons exerts anti-ictogenic effects associated with decreased rates of interictal spikes and fast ripples in this MTLE model. However, PV-positive interneuron stimulation can paradoxically trigger seizures in epileptic animals, supporting the notion that γ-aminobutyric acid type A signaling can also initiate ictogenesis. ANN NEUROL 2019;86:714-728 View this article online at wileyonlinelibrary.com.

show abstract

“…Glia are also important in TLE, thus providing another possible means by which our intervention may have affected learning outcomes in this study. Other results also have shown that PV activation using chemogenetic methods can decrease seizure burden but does not improve learning performance . However, one caveat in the latter study is that the chemogenetic intervention occurred during the learning phase of the OLM task, unlike this current study where optogenetic intervention was instead provided outside of the behavioral task.…”

Section: Discussionmentioning

confidence: 57%

“…For example, seizure suppression was achieved not only by PV interneuron activation, but also by inhibition of principal neurons in the dorsal hippocampus . Fourth, it is unknown if targeting seizures is required for the beneficial effects in learning and memory or if random or periodic PV activation could also work, especially considering experimental results indicating that PV interneuron activation itself can improve different pathologies . Fifth, the long‐term effects of closed‐loop intervention and optogenetic stimulation will need to be determined, that is, whether the beneficial effects of the closed‐loop seizure suppression end immediately after the end of the treatment, or if there are any lasting effects on seizures or cognitive ability.…”

Section: Discussionmentioning

confidence: 99%

Optogenetic intervention of seizures improves spatial memory in a mouse model of chronic temporal lobe epilepsy

et al. 2020

View full text Add to dashboard Cite

Objective To determine if closed‐loop optogenetic seizure intervention, previously shown to reduce seizure duration in a well‐established mouse model chronic temporal lobe epilepsy (TLE), also improves the associated comorbidity of impaired spatial memory. Methods Mice with chronic, spontaneous seizures in the unilateral intrahippocampal kainic acid model of TLE, expressing channelrhodopsin in parvalbumin‐expressing interneurons, were implanted with optical fibers and electrodes, and tested for response to closed‐loop light intervention of seizures. Animals that responded to closed‐loop optogenetic curtailment of seizures were tested in the object location memory test and then given closed‐loop optogenetic intervention on all detected seizures for 2 weeks. Following this, they were tested with a second object location memory test, with different objects and contexts than used previously, to assess if seizure suppression can improve deficits in spatial memory. Results Animals that received closed‐loop optogenetic intervention performed significantly better in the second object location memory test compared to the first test. Epileptic controls with no intervention showed stable frequency and duration of seizures, as well as stable spatial memory deficits, for several months after the precipitating insult. Significance Many currently available treatments for epilepsy target seizures but not the associated comorbidities, therefore there is a need to investigate new potential therapies that may be able to improve both seizure burden and associated comorbidities of epilepsy. In this study, we showed that optogenetic intervention may be able to both shorten seizure duration and improve cognitive outcomes of spatial memory.

show abstract

Pharmaco-genetic therapeutics targeting parvalbumin neurons attenuate temporal lobe epilepsy

Cited by 53 publications

References 63 publications

Long‐term chemogenetic suppression of spontaneous seizures in a mouse model for temporal lobe epilepsy

Long‐term chemogenetic suppression of spontaneous seizures in a mouse model for temporal lobe epilepsy

Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy

Optogenetic intervention of seizures improves spatial memory in a mouse model of chronic temporal lobe epilepsy

Contact Info

Product

Resources

About