Abstract
Multiple sclerosis (MS) patients exhibit neuropsychological symptoms in early disease despite the immune attack occurring predominantly in white matter and spinal cord. It is unclear why neurodegeneration may start early in the disease and is prominent in later stages. We assessed cortical microcircuit activity by employing spiking-specific two-photon Ca2+ imaging in proteolipid protein-immunized relapsing-remitting SJL/J mice in vivo. We identified the emergence of hyperactive cortical neurons in remission only, independent of direct immune-mediated damage and paralleled by elevated anxiety. High levels of neuronal activity were accompanied by increased caspase-3 expression. Cortical TNFα expression was mainly increased by excitatory neurons in remission; blockade with intraventricular infliximab restored AMPA spontaneous excitatory postsynaptic current frequencies, completely recovered normal neuronal network activity patterns and alleviated elevated anxiety. This suggests a dysregulation of cortical networks attempting to achieve functional compensation by synaptic plasticity mechanisms, indicating a link between immune attack and early start of neurodegeneration.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
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Carbazoles / therapeutic use
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Cells, Cultured
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Cerebral Cortex / physiopathology*
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Cerebral Cortex / ultrastructure
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Cuprizone / toxicity
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Disease Models, Animal
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Egtazic Acid / analogs & derivatives
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Egtazic Acid / pharmacokinetics
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Encephalomyelitis, Autoimmune, Experimental / chemically induced
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Encephalomyelitis, Autoimmune, Experimental / complications*
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Encephalomyelitis, Autoimmune, Experimental / drug therapy
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Encephalomyelitis, Autoimmune, Experimental / pathology*
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Excitatory Amino Acid Antagonists / pharmacology
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Female
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Freund's Adjuvant / toxicity
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Hyperkinesis / etiology*
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Membrane Potentials / drug effects
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Membrane Potentials / genetics
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Mice
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Mice, Transgenic
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Microglia / pathology
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Myelin Proteolipid Protein / toxicity
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Peptide Fragments / toxicity
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Proto-Oncogene Proteins c-fos / genetics
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Proto-Oncogene Proteins c-fos / metabolism
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Quinoxalines / pharmacology
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Recovery of Function / physiology*
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Sodium Channel Blockers / pharmacology
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Tetrodotoxin / pharmacology
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Carbazoles
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Excitatory Amino Acid Antagonists
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Myelin Proteolipid Protein
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Peptide Fragments
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Proto-Oncogene Proteins c-fos
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Quinoxalines
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Sodium Channel Blockers
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myelin proteolipid protein (139-151)
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1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester
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Tetrodotoxin
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Egtazic Acid
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Cuprizone
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FG 9041
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Freund's Adjuvant
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carprofen