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CRISPRa-mediated Kcna1 upregulation decreases neuronal excitability and suppresses seizures in a rodent model of temporal lobe epilepsy

ABSTRACT: CRISPRa-mediated Kcna1 upregulation decreases neuronal excitability and suppresses seizures in a rodent model of temporal lobe epilepsy

PROVIDER: PRJNA553147 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR9621870_1.fastq.gz	Fastqsanger.gz
	SRR9621870_2.fastq.gz	Fastqsanger.gz
	SRR9621871_1.fastq.gz	Fastqsanger.gz
	SRR9621871_2.fastq.gz	Fastqsanger.gz
	SRR9621862_1.fastq.gz	Fastqsanger.gz

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CRISPRa-mediated Kcna1 upregulation decreases neuronal excitability and suppresses seizures in a rodent model of temporal lobe epilepsy [II]

Project description:Epilepsy is a major health burden, calling for new mechanistic and therapeutic insights. CRISPR–mediated gene editing shows promise to cure genetic pathologies, although hitherto it has mostly been applied ex-vivo. Its translational potential for treating non-genetic pathologies is still unexplored. Furthermore, neurological diseases represent an important challenge for the application of CRISPR, because of the need in many cases to manipulate gene function of neurons in situ. A variant of CRISPR, CRISPRa, offers the possibility to modulate the expression of endogenous genes by directly targeting their promoters. We asked if this strategy can be effective to treat acquired focal epilepsy. We applied a doxycycline-inducible CRISPRa technology to increase the expression of the potassium channel gene Kcna1 (encoding Kv1.1) in mouse hippocampal excitatory neurons. CRISPRa-mediated Kv1.1 upregulation led to a substantial decrease in neuronal excitability. Continuous video-EEG telemetry showed that AAV9-mediated delivery of CRISPRa, upon doxycycline administration, decreased spontaneous generalized tonic-clonic seizures in a model of temporal lobe epilepsy. The focal treatment minimizes concerns about off-targets effects in other organs and brain areas. This study provides the proof of principle for a translational CRISPR-based approach to treat neurological diseases characterized by abnormal circuit excitability.

2019-11-15 | GSE133929 | GEO

CRISPRa-mediated Kcna1 upregulation decreases neuronal excitability and suppresses seizures in a rodent model of temporal lobe epilepsy [I]

2019-11-15 | GSE133554 | GEO

CRISPRa-mediated Kcna1 upregulation decreases neuronal excitability and suppresses seizures in a rodent model of temporal lobe epilepsy [I]

Project description:CRISPRa-mediated Kcna1 upregulation decreases neuronal excitability and suppresses seizures in a rodent model of temporal lobe epilepsy [I]

| PRJNA551881 | ENA

CRISPRa-mediated Kcna1 upregulation decreases neuronal excitability and suppresses seizures in a rodent model of temporal lobe epilepsy [II]

Project description:CRISPRa-mediated Kcna1 upregulation decreases neuronal excitability and suppresses seizures in a rodent model of temporal lobe epilepsy [II]

| PRJNA553149 | ENA

CRISPRa-mediated Kcna1 upregulation decreases neuronal excitability and suppresses seizures in a rodent model of temporal lobe epilepsy

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-11-15 | GSE133930 | GEO

In vivo CRISPRa decreases seizures and rescues cognitive deficits in a rodent model of epilepsy.

Project description:Epilepsy is a major health burden, calling for new mechanistic insights and therapies. CRISPR-mediated gene editing shows promise to cure genetic pathologies, although hitherto it has mostly been applied ex vivo. Its translational potential for treating non-genetic pathologies is still unexplored. Furthermore, neurological diseases represent an important challenge for the application of CRISPR, because of the need in many cases to manipulate gene function of neurons in situ. A variant of CRISPR, CRISPRa, offers the possibility to modulate the expression of endogenous genes by directly targeting their promoters. We asked if this strategy can effectively treat acquired focal epilepsy, focusing on ion channels because their manipulation is known be effective in changing network hyperactivity and hypersynchronziation. We applied a doxycycline-inducible CRISPRa technology to increase the expression of the potassium channel gene Kcna1 (encoding Kv1.1) in mouse hippocampal excitatory neurons. CRISPRa-mediated Kv1.1 upregulation led to a substantial decrease in neuronal excitability. Continuous video-EEG telemetry showed that AAV9-mediated delivery of CRISPRa, upon doxycycline administration, decreased spontaneous generalized tonic-clonic seizures in a model of temporal lobe epilepsy, and rescued cognitive impairment and transcriptomic alterations associated with chronic epilepsy. The focal treatment minimizes concerns about off-target effects in other organs and brain areas. This study provides the proof-of-principle for a translational CRISPR-based approach to treat neurological diseases characterized by abnormal circuit excitability.

| S-EPMC7089667 | biostudies-literature

Severe deficiency of voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice

Project description:Scn2a encodes voltage-gated sodium channel NaV1.2, a main mediator of neuronal action potential firing. The current paradigm suggests that NaV1.2 gain-of-function variants enhance neuronal excitability resulting in epilepsy, whereas NaV1.2 deficiency impairs excitability contributing to autism. This paradigm, however, does not explain why 20~30% of patients with NaV1.2 deficiency still develop seizures. Here we report a counterintuitive finding that severe NaV1.2 deficiency results in increased neuronal excitability. Using a unique NaV1.2-deficient mouse model, we found enhanced intrinsic excitabilities of principal neurons in the prefrontal cortex and striatum, brain regions known to be involved in Scn2a-related seizures. This increased excitability is autonomous, and is reversible by the genetic restoration of Scn2a expression in adult mice. RNA-sequencing revealed that the downregulation of multiple potassium channels including KV1.1, and KV channel openers alleviated hyperexcitability of NaV1.2-deficient neurons. This unexpected neuronal hyperexcitability may serve as a cellular basis underlying NaV1.2 deficiency-related seizures.

2021-07-13 | GSE179818 | GEO

Leukocyte gene expression predicts human temporal lobe epilepsy seizure frequency

Project description:This study was performed to test the hypothesis that systemic leukocyte gene expression has prognostic value differentiating low from high seizure frequency refractory temporal lobe epilepsy (TLE). A consecutive series of sixteen patients with refractory temporal lobe epilepsy was studied. Based on a median baseline seizure frequency of 2.0 seizures per month, low versus high seizure frequency was defined as < 2 seizures/month and > 2 seizures/month, respectively.

2022-11-15 | GSE217726 | GEO

Altered expression of signaling pathways regulating neuronal excitability in hippocampal tissue of temporal lobe epilepsy patients with low and high seizure frequency

Project description:Despite recent advances in our understanding of synaptic transmission associated with epileptogenesis, the molecular mechanisms that control seizure frequency in patients with temporal lobe epilepsy (TLE) remain obscure. RNA-Seq was performed on hippocampal tissue resected from 12 medically intractable TLE patients with pre-surgery seizure frequencies ranging from 0.33 to 120 seizures per month. Differential expression (DE) analysis of individuals with low (LSF, mean= 4 seizure/month) versus high (HSF, mean= 60 seizures/month) seizure frequency identified 979 genes with ≥2-fold change in transcript abundance (FDR-adjusted p-value <0.05). Comparisons with post-mortem controls revealed a large number of downregulated genes in the HSF (1,676) versus LSF (399) groups. More than 50 signaling pathways were inferred to be deactivated or activated, with Signal Transduction as the central hub in the pathway network. While neuroinflammation pathways were activated in both groups, key neuronal system pathways were systematically deactivated in the HSF group, including calcium, CREB and Opioid signaling. We also infer that enhanced expression of a signaling cascade promoting synaptic downscaling may have played a key role in maintaining a higher seizure threshold in the LSF cohort. These results suggest that therapeutic approaches targeting synaptic scaling pathways may aid in the treatment of seizures in TLE.

2019-03-06 | GSE127871 | GEO

Food intake precipitates seizures in temporal lobe epilepsy.

Project description:Various factors have been considered as potential seizure precipitants. We here assessed the temporal association of food intake and seizure occurrence, and characteristics of seizures and epilepsy syndromes involved. 596 seizures from 100 consecutive patients undergoing long-term video-EEG monitoring were analyzed. Preictal periods of 60 min were assessed as to the occurrence of food intake, and latencies between food intake and seizure onset were analyzed. Seizures of temporal origin were highly significantly more frequently preceded by food intake compared to those of extratemporal origin; and were associated with shorter food intake-seizure latency. Seizure precipitation by food intake showed male predominance. Shorter food intake-seizure latency was associated with less severe seizures and less frequent contralateral spread of epileptic discharges. We here show for the first time that not only in specific rare reflex epilepsies but in the most frequent form of focal epilepsy, temporal lobe epilepsy, seizures are significantly precipitated by food intake. Seizure occurrence was increased over a period of up to one hour following food intake, and remained more localized in terms of both ictal EEG spread and as reflected by seizure severity. This finding supports the emerging concepts of ictogenesis, implying a continuum between reflex and spontaneous seizures-instead a dichotomy between them.

| S-EPMC8363749 | biostudies-literature

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