Structural and functional plasticity in the dorsolateral geniculate nucleus of mice following bilateral enucleation

Abstract

Within the nervous system, homeostatic mechanisms stabilize network activity following disruption by injury, disease, or degeneration. Vision loss and optic nerve injury in age-related diseases such as glaucoma might trigger homeostatic responses in direct retinal projection targets in the brain in adulthood. We tested this possibility using patch-clamp electrophysiology, optogenetics, and single-cell dendritic analysis to probe the effects of optic nerve injury and vision loss on dLGN thalamocortical (TC) relay neurons and their synaptic inputs following bilateral enucleation. Using vGlut2 immunostaining, we found that retinal axon terminals in the dLGN degenerated over several days post-enucleation, which corresponded with the loss of retinogeniculate (RG) synaptic function as assessed with optogenetic stimulation of ganglion cell axons in acute brain slices. Analysis of TC neuron dendritic structure from single-cell dye fills revealed a gradual loss of dendrites proximal to the soma, where TC neurons receive the bulk of RG inputs. Surprisingly, there was little change to the frequency of miniature post-synaptic currents (mEPSCs), even two weeks post-enucleation, although we did find an increase in the relative proportion of mEPSCs with slower kinetics, hinting at a possible enhancement of corticogeniculate input. Whole-cell current clamp recordings showed that enucleation enhanced TC neuron action potential firing and input resistance, consistent with homeostatic scaling of intrinsic neuronal excitability following perturbation of synaptic inputs. Our findings show that degeneration of the retinal axons/optic nerve and loss of RG synaptic inputs induces structural and functional changes in TC neurons consistent with compensatory homeostatic plasticity in the dLGN.

Bottom-up inputs are required for the establishment of top-down connectivity onto cortical layer 1 neurogliaform cells

“…Previous work from our laboratory and others have demonstrated that superficial NGF cells receive thalamic inputs early (De Marco García, Priya et al 2015, Che, Babij et al 2018). Despite their positioning in superficial cortex, by P15 NGF cells are receive bottom-up activity.…”

“…As enucleation must result in considerable indirect effects through its impact on other areas of the visual system (Williams, Reese et al 2002, Nahmani and Turrigiano 2014, Rose, Jaepel et al 2016, Jaepel, Hübener et al 2017, Bhandari 2020, Hooks and Chen 2020), we wished to see if selective manipulation of the thalamic inputs that specifically project to L1 result in a similar phenotype. To do so, we injected AAV helpers together with RV-FlpO-mCherry virus in NDNF-dgCre pups and followed that with an injection of a Flp -dependent diphtheria toxin subunit A (DTA) in the dLGN (Fig.…”

Mechanisms of functional plasticity in subcortical visual areas

“…The effect of visual deprivation on dLGN relay cell dendritic trees has also been characterized. Both in a mouse model of glaucoma or in mice lacking retinal ganglion cells axons, dendritic trees of surviving relay cells end up showing a strong reduction in size and complexity after an eventual intermediary phase of exuberant branching [69][70][71]. Altogether, developmental and deprivation studies show that retinogeniculate projections have a trophic and necessary role to establish and maintain the morpho-functional complexity of dLGN neurons.…”

Mechanisms of Plasticity in Subcortical Visual Areas

“…The effect of visual deprivation on dLGN relay cell dendritic trees has also been characterized. Both in a mouse model of glaucoma and in mice lacking retinal ganglion cells axons, dendritic trees of surviving relay cells ended up showing a strong reduction in size and complexity after an eventual intermediary phase of exuberant branching [70][71][72]. Similarly, albinism or dyslexia reduces the size of the dLGN [73,74].…”