Amblyopia is a loss of vision in one eye caused by inadequate binocular experience. The standard treatments, like patching, are effective only during a critical developmental period. However, it’s difficult to recover from this vision loss in adulthood. Hence, researchers conducted animal studies showing that temporary retinal inactivation with tetrodotoxin (TTX) can reverse long-term monocular deprivation (MD), even when reverse occlusion fails. Animals like monkeys, mice, and cats subjected to this treatment exhibited restored visual responses without adverse effects. This suggests a potential new therapeutic approach. The mechanism underlying this recovery remains unclear, although evidence reports that retinal silencing induces high-frequency burst firing in dorsal lateral geniculate nucleus (dLGN) neurons. A study published in Cell Reports aimed to demonstrate whether this bursting is essential for recovery from vision loss and whether temporary inactivation of the amblyopic eye alone can reverse the effects of chronic MD.
In this study, one eye of mice was injected with TTX to increase the burst firing in dLGN neurons. Multi-channel recordings were performed in awake mice. Researchers found that neurons responsive to the contralateral eye exhibited altered interspike intervals following ipsilateral TTX injection, producing a higher proportion of burst spikes during both spontaneous activity and visual stimulation. Similar effects were reported in amblyopic mice. A significantly reduced interspike interval was observed compared to the control during the inactivation of the ipsilateral eye. Thus, TTX causes a consistent shift in dLGN firing properties.
To assess the role of T-type calcium channels in thalamic bursting, the authors reduced the dLGN neurons’ burst firing using a genetic approach. Transgenic mice with Cav3.1(Cacna1g), which is the major isoform of the T-type calcium channel in the dLGN neurons. These mice received herpes simplex virus (HSV)-Cre-GFP to create a thalamic T-channel knockout (TTKO). Wild-type (WT) littermates served as controls. Two hours after TTX injection, TTKO mice showed reduced bursting and lower correlated firing as well as fewer short interspike intervals compared to controls. Visual stimulation responses and visual evoked potentials (VEPs) remained normal in both mice groups. There was no HSV-related toxicity that had occurred.
The authors then tested whether increased thalamic burst firing is necessary for the therapeutic effect of fellow-eye (ipsilateral) inactivation in mice made amblyopic through long-term MD. All mice in this test received HSV-Cre in the dLGN at P40. Ocular dominance was assessed with single-unit recordings. Three groups were monocularly deprived between P26 and P47 as TTKO+TTX, WT+TTX, and WT+saline. In MD WT mice, a single fellow-eye TTX injection significantly reversed the ocular dominance shift and restored the contralateral eye responses. This recovery was not observed in TTKO mice, which indicated loss of the treatment effect. Fellow-eye TTX increased firing to the amblyopic eye in WT compared to TTKO mice, while the orientation selectivity index (OSI) of neurons remained unchanged.
TTX-induced thalamic bursting without impairing normal visual responses was eliminated by Cav3.1 deletion, which also eliminated the recovery from the amblyopia condition. Stimulus-selective response plasticity and VEPs were similar in TTKO and WT mice, indicating Cav3.1 loss specifically disrupts recovery-specific plasticity but not general cortical plasticity.
This study cannot definitively confirm that burst firing in amblyopic eye pathways directly drives recovery, nor the role of other T-type channels. Spike-sorting limitations may underestimate the bursting, highlighting the need for further mechanistic experiments.
Reference: Echavarri-Leet M, Chauhan T, Cramer TLM, Fong M, Bear MF. Temporary retinal inactivation reverses effects of long-term monocular deprivation in visual cortex by induction of burst mode firing in the thalamus. Cell Reports. 2024;44(11):116566.
