1.Transient targeting of hypothalamic orexin neurons alleviates seizures in a mouse model of epilepsy

https://www.nature.com/articles/s41467-024-45515-5

Lateral hypothalamic (LH) hypocretin/orexin neurons (HONs) regulate widespread brain excitation. High excitation leads to seizures, necessitating improved treatments. HON activity fluctuates minutely, yet its role in seizures remains unclear. Investigating in a male mouse model, we found pre-seizure HON activity predicts and modulates subsequent seizure activity and behavior. However, no such correlation was found during seizures. Temporally-targeted LH deep brain stimulation (DBS) inhibited HON activity and provided seizure protection. These findings reveal a critical link between HON activity and seizures, offering a potential treatment avenue for epilepsy.

2.Expression of GCaMP6s in the dentate gyrus induces tonic-clonic seizures

DOI: 10.1038/s41598-024-58819-9

https://www.nature.com/articles/s41598-024-58819-9

GCaMP, a widely-used calcium indicator in neuroscience, can influence intracellular calcium signaling and cell physiology, potentially leading to aberrant activity like seizures. This study investigated the impact of GCaMP6 expression in the dentate gyrus (DG) on epilepsy development. The viral expression of GCaMP6s, but not GCaMP6f, induced tonic-clonic seizures weeks after injection. Further analysis revealed that granule cells (GCs) were crucial in GCaMP6s-induced epilepsy. Slice electrophysiology confirmed that GCaMP6s expression heightened neuronal excitability in GCs. These findings underscore GCaMP6s' role in epileptogenesis associated with the DG, emphasizing the need for caution when using this indicator in neuroscience research.

3.Targeted suppression of mTORC2 reduces seizures across models of epilepsy

https://www.nature.com/articles/s41467-023-42922-y

Epilepsy presents a significant public health concern, with mTORC1 hyperactivation contributing to abnormal brain network activity. While mTORC1 inhibition is considered a therapeutic approach, the role of mTORC2 in seizures remains unclear. Genetic removal of mTORC2 in forebrain neurons protects against seizures induced by kainic acid. Additionally, targeting mTORC2 with a specific antisense oligonucleotide effectively suppresses seizures in various epilepsy models. The study identifies Nav1.2 as an mTORC2 target, linking it to epilepsy and neuronal excitability. These findings suggest that mTORC2 inhibition could offer a broader therapeutic strategy against epilepsy, applicable across multiple seizure models, with potential implications for human treatment.

4.Ictogenesis proceeds through discrete phases in hippocampal CA1 seizures in mice

DOI: 10.1038/s41467-023-41711-x

https://www.nature.com/articles/s41467-023-41711-x

Epilepsy's mechanisms are poorly understood, especially regarding seizure initiation and progression. Using optogenetic stimulation, we induced hypersynchronous activity in the hippocampus of mice to simulate seizure onset. Focused optogenetic activation of potential excitatory neurons reliably triggered convulsive seizures in awake mice. Analyzing EEG data revealed three distinct phases of seizure development: induction, reverberation, and paroxysmal phases, with transitions marking each phase shift. Non-seizure responses occurred during induction or reverberation but not during seizures. Similar phase patterns were observed in spontaneous seizures in a murine temporal lobe epilepsy model. Understanding these ictogenesis phases could provide opportunities to intervene and prevent seizure progression.

5.Chemogenetic attenuation of cortical seizures in nonhuman primates

DOI: 10.1038/s41467-023-36642-6

https://www.nature.com/articles/s41467-023-36642-6

Epilepsy treatment often disrupts normal brain function, necessitating more precise interventions. We investigated the effectiveness of chemogenetic tools, specifically designer receptors exclusively activated by designer drugs (DREADDs), in a nonhuman primate model of focal seizures. By inducing seizures in macaque monkeys with bicuculline infusion, we observed widespread cortical discharges and clonic seizures. Expressing an inhibitory DREADD (hM4Di) in the seizure focus and administering a DREADD-selective agonist promptly suppressed seizures. This study highlights DREADDs' potential for targeted seizure control in nonhuman primates, suggesting a promising avenue for more precise and on-demand epilepsy management.