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

Abstract

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. 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. 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. Global brain delivery of NL2 by systemic administration of AAV vector may provide a non-invasive therapeutic approach for generalized epilepsy.