Inflammatory demyelination alters subcortical visual circuits

Abstract

BackgroundMultiple sclerosis (MS) is an inflammatory demyelinating disease classically associated with axonal damage and loss; more recently, however, synaptic changes have been recognized as additional contributing factors. An anatomical area commonly affected in MS is the visual pathway; yet, changes other than those associated with inflammatory demyelination of the optic nerve, i.e., optic neuritis, have not been described in detail.MethodsAdult mice were subjected to a diet containing cuprizone to mimic certain aspects of inflammatory demyelination as seen in MS. Demyelination and inflammation were assessed by real-time polymerase chain reaction and immunohistochemistry. Synaptic changes associated with inflammatory demyelination in the dorsal lateral geniculate nucleus (dLGN) were determined by immunohistochemistry, Western blot analysis, and electrophysiological field potential recordings.ResultsIn the cuprizone model, demyelination was observed in retinorecipient regions of the subcortical visual system, in particular the dLGN, where it was found accompanied by microglia activation and astrogliosis. In contrast, anterior parts of the pathway, i.e., the optic nerve and tract, appeared largely unaffected. Under the inflammatory demyelinating conditions, as seen in the dLGN of cuprizone-treated mice, there was an overall decrease in excitatory synaptic inputs from retinal ganglion cells. At the same time, the number of synaptic complexes arising from gamma-aminobutyric acid (GABA)-generating inhibitory neurons was found increased, as were the synapses that contain the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2B and converge onto inhibitory neurons. These synaptic changes were functionally found associated with a shift toward an overall increase in network inhibition.ConclusionsUsing the cuprizone model of inflammatory demyelination, our data reveal a novel form of synaptic (mal)adaption in the CNS that is characterized by a shift of the excitation/inhibition balance toward inhibitory network activity associated with an increase in GABAergic inhibitory synapses and a possible increase in excitatory input onto inhibitory interneurons. In addition, our data recognize the cuprizone model as a suitable tool in which to assess the effects of inflammatory demyelination on subcortical retinorecipient regions of the visual system, such as the dLGN, in the absence of overt optic neuritis.

Retrograde interferon‐gamma signaling induces major histocompatibility class I expression in human‐induced pluripotent stem cell‐derived neurons

“…Evidence also suggests that MHC I is involved with synaptic pruning during cortical development12, 13, 14, 16, 17, 18, 19, 20, 21 and following injury22, 23, 24, 25 and contributes to neuronal plasticity 16, 17, 26, 27. These findings also suggest that retrogradely induced MHC class I may contribute to the diffuse synaptopathy observed in MS and other neurodegenerative diseases 28, 29, 30, 31, 32, 33, 34, 35. However, whether human neurons and axons respond to inflammatory stress in this way is unknown, and the dearth of methods for efficiently culturing human neurons and isolated axons has prevented robust analysis.…”

“…On the other hand, a pathogenic role for retrograde induction of MHC I by IFN γ in MS is likely to be associated with gray matter pathology that occurs remotely from active demyelinating lesions. Diffuse synapse loss with altered cortical connectivity, as well as diffuse neuron and axon loss, are all commonly found in MS tissue 28, 29, 30, 31, 32, 33, 34, 60, 61, 62, 63 and could be driven by somatic or axonal MHC I expression. For example, neuronal MHC I has an established role in neuronal plasticity16 via mechanisms involving postsynaptic interactions with glutamate receptors and presynaptic interactions with the immunoreceptor tyrosine‐based inhibitory motif‐containing leukocyte immunoglobulin‐like receptor PirB 64.…”

Remyelination alters the pattern of myelin in the cerebral cortex

“…Consistent with this hypothesis, demyelination within the cortex in diseases such as MS is closely associated with cognitive impairment and increased morbidity. Moreover, many neurodegenerative diseases and affective disorders are associated with profound alterations in myelin (Gouw et al, 2008; Ihara et al, 2010; Stedehouder & Kushner, 2017), and recent studies indicate that demyelination triggers a dramatic decrease in excitatory synapses (Araújo et al, 2017; Werneburg et al, 2020), suggesting that disruptions in these sheaths may also influence both structural and functional aspects of circuits. Although preserving cortical myelination appears paramount, the highly variable patterns of myelin within cortical circuits and the sparseness of these neuron-glial associations create considerable challenges for regenerating specific myelin sheaths after injury or disease.…”

Targeted complement inhibition at synapses prevents microglial synaptic engulfment and synapse loss in demyelinating disease

“…Similar results have been found in rodent models of demyelinating disease. For example, in a cuprizone model of demyelination, a significant decrease in excitatory synapses was observed in the visual thalamus concomitant with reactive gliosis and subcortical demyelination (Araujo et al, 2017). In another study, experimental autoimmune encephalomyelitis (EAE)-induced demyelination in mice resulted in a ∼28% decrease in PSD-95-positive postsynaptic densities in the hippocampus, which was observed in the absence of hippocampal demyelination, but in the presence of reactive, phagocytic microglia (Bellizzi et al, 2016).…”