An adaptive role of TNFα in the regulation of striatal synapses

J Neurosci. 2014 Apr 30;34(18):6146-55. doi: 10.1523/JNEUROSCI.3481-13.2014.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biotinylation
  • CA1 Region, Hippocampal / physiology
  • Catalepsy / genetics
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Dopamine Antagonists / pharmacology
  • Dyskinesia, Drug-Induced / drug therapy
  • Dyskinesia, Drug-Induced / etiology
  • Electric Stimulation
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Excitatory Postsynaptic Potentials / physiology*
  • Haloperidol / adverse effects
  • Haloperidol / pharmacology
  • In Vitro Techniques
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mouth / drug effects
  • Mouth / physiology
  • Patch-Clamp Techniques
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Synapses / drug effects
  • Synapses / physiology*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology


  • Dopamine Antagonists
  • Tumor Necrosis Factor-alpha
  • Haloperidol