Global brain delivery of neuroligin 2 gene ameliorates seizures in a mouse model of epilepsy

Abstract

Background Despite the increasing availability of effective drugs, around one‐third of patients with epilepsy are still resistant to pharmacotherapy. Gene therapy has been suggested as a plausible approach to achieve seizure control, in particular for patients with focal epilepsy. Because seizures develop across wide spans of the brain in many forms of epilepsy, global delivery of the vectors is necessary to tackle such generalized seizures. Neuroligin 2 (NL2) is a postsynaptic cell adhesion molecule that induces or strengthens inhibitory synaptic function by specifically combining with neurexin 1. Methods In the present study, we applied an adeno‐associated virus (AAV) type 9 vector expressing NL2 to modulate neuronal excitability in broad areas of the brain in epileptic (EL) mice, a model of polygene epilepsy. We administered the AAV vector expressing Flag‐tagged NL2 under the synapsin I promoter (AAV‐NL2) via cardiac injection 6 weeks after birth. Results Significant reductions in the duration, strength and frequency of seizure were observed during a 14‐week observation period in NL2‐treated EL mice compared to untreated or AAV‐green fluorescent protein‐treated EL mice. No behavioral abnormality was observed in NL2‐treated EL mice in an open‐field test. Immunohistochemical examination at 14 weeks after AAV‐NL2 injection revealed the expression of exogenous NL2 in broad areas of the brain, including the hippocampus and, in these areas, NL2 co‐localized with postsynaptic inhibitory molecule gephyrin. Conclusions Global brain delivery of NL2 by systemic administration of AAV vector may provide a non‐invasive therapeutic approach for generalized epilepsy.

CNS/PNS proteoglycans functionalize neuronal and astrocyte niche microenvironments optimizing cellular activity by preserving membrane polarization dynamics, ionic microenvironments, ion fluxes, neuronal activation, and network neurotransductive capacity

“…NRXN–neuroligin interactions promote synaptic development and function; however, incorrect interactions can lead to autism and schizophrenia (Zhang et al., 2018). Mutations in genes encoding the NRXNs and their ligands have been observed in schizophrenia, autism, epilepsy, and Tourette syndrome, showing that the central roles NRXNs play in the control of synaptic plasticity and function (Blundell et al., 2009; Cao & Tabuchi, 2017; Cuttler et al., 2021; Gauthier et al., 2011; Lai et al., 2021; Maćkowiak et al., 2014; Oguro et al., 2022; Südhof, 2008; Trobiani et al., 2020; Uchigashima et al., 2021; Wang et al., 2018). Pikachurin and eyes shut interact with α‐DG (dystroglycan) to stabilize photoreceptor ribbon synapse interactions with retinal bipolar neurons.…”

HS, an Ancient Molecular Recognition and Information Storage Glycosaminoglycan, Equips HS-Proteoglycans with Diverse Matrix and Cell-Interactive Properties Operative in Tissue Development and Tissue Function in Health and Disease

“…Neuroligins are major post-synaptic adhesion molecules that interact with the neurexins, these occur in a very diverse range of alternatively spliced forms offering a large range of synaptic regulatory signals [ 304 ]. Mutations in genes encoding the neurexins and their ligands have been observed in neuropsychiatric disorders such as schizophrenia, autism, epilepsy, and Tourette syndrome, showing the neurexins have central roles to play in the control of synaptic plasticity [ 306 , 307 , 308 , 309 , 310 , 311 , 312 , 313 , 314 , 315 , 316 ]. HS-PGs have critical roles to play in the development of Alzheimer’s disease (AD) [ 317 ].…”

The Glycosaminoglycan Side Chains and Modular Core Proteins of Heparan Sulphate Proteoglycans and the Varied Ways They Provide Tissue Protection by Regulating Physiological Processes and Cellular Behaviour

“…Neuroligins are major post-synaptic neurexin interactive adhesion molecules [ 179 ]. Mutations in genes encoding the neurexins and their ligands have been observed in neuropsychiatric disorders such as schizophrenia, autism, epilepsy, and Tourette syndrome, showing the central roles neurexins play in the control of synaptic plasticity and function [ 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 ].…”