Altered excitatory-inhibitory balance within somatosensory cortex is associated with enhanced plasticity and pain sensitivity in a mouse model of multiple sclerosis.
Chronic neuropathic pain is a common symptom of multiple sclerosis (MS). MOG35-55-induced experimental autoimmune encephalomyelitis (EAE) has been used as an animal model to investigate the mechanisms of pain in MS. Previous studies have implicated sensitization of spinal nociceptive networks in the pathogenesis of pain in EAE. However, the involvement of supraspinal sites of nociceptive integration, such as the primary somatosensory cortex (S1), has not been defined. We therefore examined functional, structural, and immunological alterations in S1 during the early stages of EAE, when pain behaviors first appear. We also assessed the effects of the antidepressant phenelzine (PLZ) on S1 alterations and nociceptive (mechanical) sensitivity in early EAE. PLZ has been shown to restore central nervous system (CNS) tissue concentrations of GABA and the monoamines (5-HT, NA) in EAE. We hypothesized that PLZ treatment would also normalize nociceptive sensitivity in EAE by restoring the balance of excitation and inhibition (E-I) in the CNS.



We used in vivo flavoprotein autofluorescence imaging (FAI) to assess neural ensemble responses in S1 to vibrotactile stimulation of the limbs in early EAE. We also used immunohistochemistry (IHC), and Golgi-Cox staining, to examine synaptic changes and neuroinflammation in S1. Mechanical sensitivity was assessed at the clinical onset of EAE with Von Frey hairs.



Mice with early EAE exhibited significantly intensified and expanded FAI responses in S1 compared to controls. IHC revealed increased vesicular glutamate transporter (VGLUT1) expression and disrupted parvalbumin+ (PV+) interneuron connectivity in S1 of EAE mice. Furthermore, peri-neuronal nets (PNNs) were significantly reduced in S1. Morphological analysis of excitatory neurons in S1 revealed increased dendritic spine densities. Iba-1+ cortical microglia were significantly elevated early in the disease. Chronic PLZ treatment was found to normalize mechanical thresholds in EAE. PLZ also normalized S1 FAI responses, neuronal morphologies, and cortical microglia numbers and attenuated VGLUT1 reactivity-but did not significantly attenuate the loss of PNNs.



These findings implicate a pro-excitatory shift in the E-I balance of the somatosensory CNS, arising early in the pathogenesis EAE and leading to large-scale functional and structural plasticity in S1. They also suggest a novel antinociceptive effect of PLZ treatment.
Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2E1, Canada.|Department of Anesthesiology and Pain Medicine, University of Alberta, Clinical Sciences Building, 8-120, Edmonton, AB, T6G 2G3, Canada.
Liam E
LE
Potter
Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2E1, Canada.|Department of Psychiatry (NRU), University of Alberta, Edmonton, AB, T6G 2B7, Canada.
John W
JW
Paylor
Department of Anesthesiology and Pain Medicine, University of Alberta, Clinical Sciences Building, 8-120, Edmonton, AB, T6G 2G3, Canada.
Jee Su
JS
Suh
Department of Anesthesiology and Pain Medicine, University of Alberta, Clinical Sciences Building, 8-120, Edmonton, AB, T6G 2G3, Canada.
Gustavo
G
Tenorio
Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2E1, Canada.|Department of Psychology, University of Alberta, Edmonton, AB, T6G 2E9, Canada.
Jayalakshmi
J
Caliaperumal
Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2E1, Canada.|Department of Psychology, University of Alberta, Edmonton, AB, T6G 2E9, Canada.
Fred
F
Colbourne
Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2E1, Canada.|Department of Psychiatry (NRU), University of Alberta, Edmonton, AB, T6G 2B7, Canada.
Glen
G
Baker
Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2E1, Canada.|Department of Psychiatry (NRU), University of Alberta, Edmonton, AB, T6G 2B7, Canada.
Ian
I
Winship
Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2E1, Canada. bradley.kerr@ualberta.ca.|Department of Pharmacology, University of Alberta, Edmonton, AB, T6E 2H7, Canada. bradley.kerr@ualberta.ca.|Department of Anesthesiology and Pain Medicine, University of Alberta, Clinical Sciences Building, 8-120, Edmonton, AB, T6G 2G3, Canada. bradley.kerr@ualberta.ca.
Bradley J
BJ
Kerr
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000150:complications* / Q000276:immunology; D005260:Female; D005620:Freund's Adjuvant / Q000633:toxicity; D006930:Hyperalgesia / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology / Q000633:toxicity; D009437:Neuralgia / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology*; D010320:Parvalbumins / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology / Q000633:toxicity; D010624:Phenelzine / Q000494:pharmacology / Q000627:therapeutic use; D037121:Plant Lectins / Q000378:metabolism; D034781:Receptors, N-Acetylglucosamine / Q000378:metabolism; D013003:Somatosensory Cortex / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D013569:Synapses / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure
C491049:Aif1 protein, mouse; D000928:Antidepressive Agents; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010320:Parvalbumins; D010446:Peptide Fragments; D037121:Plant Lectins; D034781:Receptors, N-Acetylglucosamine; C445081:myelin oligodendrocyte glycoprotein (35-55); C040129:wisteria lectin; D005620:Freund's Adjuvant; D010624:Phenelzine