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Adeno-associated virus (AAV) has been studied as a safe delivery tool for gene therapy of retinal blinding diseases such as Leber's congenital amaurosis (LCA). The tropism of recombinant AAV (rAAV) including its specificity and efficiency in targeting retinal cell types has been studied with native or engineered capsids, along with specific promoters. However, one of the rAAV serotypes, rAAV2/6, has not been well-studied based on a report of low infection efficiency in the retina. We investigated the tropism of several rAAVs by subretinal injection in the adult mouse and found that rAAV2/6 predominantly infected cone photoreceptors including the main spectral type. Our data suggest that subretinal injection with rAAV2/6 may provide both an efficacious and specific means of gene delivery to cone photoreceptors in murine retinas. Image 1 • Cone photoreceptors are targets for gene therapy for diseases such as mid-stage retinitis pigmentosa and achromatopsia. • rAAV has been considered as an effective and safe delivery tool for gene therapy in the retina. • The tropism of rAAV2/6 has been studied in the retina but not in detail. • We show that subretinally injected rAAV2/6 predominantly infects cone photoreceptors as opposed to rods. • Our results suggest that AAV2/6 may be an appropriate vector for introducing therapeutic genes into cones. [ABSTRACT FROM AUTHOR]

Unlike an electrical circuit, the hardware of the brain is susceptible to change. Repeated electrical brain stimulation mimics epileptogenesis. After such "kindling" process, a moderate stimulus would become sufficient in triggering a severe seizure. Here, we report that optogenetic neuronal stimulation can also convert the rat brain to a hyperexcitable state. However, continued stimulation once again converted the brain to a state that was strongly resistant to seizure induction. Histochemical examinations showed that moderate astrocyte activation was coincident with resilience acquisition. Administration of an adenosine A1 receptor antagonist instantly reverted the brain back to a hyperexcitable state, suggesting that hyperexcitability was suppressed by adenosine. Furthermore, an increase in basal adenosine was confirmed using in vivo microdialysis. Daily neuron-to-astrocyte signaling likely prompted a homeostatic increase in the endogenous actions of adenosine. Our data suggest that a certain stimulation paradigm could convert the brain circuit resilient to epilepsy without exogenous drug administration. • Functional engineering and plastic conversion of the brain state were attempted. • Optogenetic neuronal stimulation succeeded in creating a seizure-resistant brain. • Daily neuron-to-astrocyte signaling likely prompted endogenous adenosine release. • Homeostasis of the brain has the potential of local containment of hyperexcitation. [ABSTRACT FROM AUTHOR]