A novel optic nerve demyelination mouse model: Insights into secondary impairment of the visual cortical circuit.

Abstract

Demyelinating optic neuritis (DON) results in significant visual impairment. In the central nervous system (CNS), neurons and neural circuitry spatially separate from the primary lesion site can be compromised in the way of trans-synaptic degeneration. This study aims to investigate the anterograde alterations in the primary visual cortex (V1) induced by DON-related optic nerve (ON) myelin loss and explore potential treatment approaches targeting underlying mechanisms. Here, we developed a novel mouse model of focal optic nerve demyelination (OND) by combined use of a conditional gene knockout system and diphtheria toxin-ablation strategy. OND treatment induced a pan-synaptic deficit in the V1, as evidenced by reduced puncta density for both excitatory and inhibitory presynaptic terminals. The increased neuronal apoptosis and microglial NLRP3 activation in the V1 represent a proximal secondary response following insult to the distal ON. The Clemastine administration but not NLRP3 inhibition, significantly increased synaptic puncta of V1 and ameliorate the visual dysfunction of OND mice. Our findings indicate that primary ON myelin loss triggers anterograde trans-synaptic degeneration through the visual pathway, resulting in visual cortical impairments. Therefore, intact ON myelin is essential to V1 neuronal viability and circuit integrity. Pharmacological oligodendrogenesis strategies represent a promising therapeutic approach to prevent V1 secondary degeneration. The established model provides a novel tool to identify therapeutic targets and evaluate pharmacotherapies for DON.