An adaptive role of TNFα in the regulation of striatal synapses.
Elevation of inflammatory cytokines in the striatum precedes symptoms in a number of motor dysfunctions, but it is unclear whether this is part of the disease process or an adaptive response to the pathology. In pyramidal cells, TNFα drives the insertion of AMPA-type glutamate receptors into synapses, and contributes to the homeostatic regulation of circuit activity in the developing neocortex. Here we demonstrate that in the mouse dorsolateral striatum, TNFα drives the internalization of AMPARs and reduces corticostriatal synaptic strength, dephosphorylates DARPP-32 and GluA1, and results in a preferential removal of Ca(2+)-permeable AMPARs. Striatal TNFα signaling appears to be adaptive in nature, as TNFα is upregulated in response to the prolonged blockade of D2 dopamine receptors and is necessary to reduce the expression of extrapyramidal symptoms induced by chronic haloperidol treatment. These data indicate that TNFα is a regulator of glutamatergic synaptic strength in the adult striatum in a manner distinct from its regulation of synapses on pyramidal cells and mediates an adaptive response during pathological conditions.
Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, The Research Institute of the McGill University Health Center, Montreal, Quebec H3G 1A4, Canada, and McGill Psychiatry Program, Douglas Hospital Research Center, McGill University, Verdun, Quebec H3A 0G4, Canada.
Gil M
GM
Lewitus
Horia
H
Pribiag
Rachna
R
Duseja
Michel
M
St-Hilaire
David
D
Stellwagen
D000818:Animals; D019921:Biotinylation; D056547:CA1 Region, Hippocampal / Q000502:physiology; D002375:Catalepsy / Q000235:genetics; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000209:etiology; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006220:Haloperidol / Q000009:adverse effects / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009055:Mouth / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
D018492:Dopamine Antagonists; D014409:Tumor Necrosis Factor-alpha; D006220:Haloperidol