An Adaptive Role of TNFα in the Regulation of Striatal Synapses

Abstract

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, TNF␣ 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, TNF␣ drives the internalization of AMPARs and reduces corticostriatal synaptic strength, dephosphorylates DARPP-32 and GluA1, and results in a preferential removal of Ca 2ϩ -permeable AMPARs. Striatal TNF␣ signaling appears to be adaptive in nature, as TNF␣ 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 TNF␣ 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.

Genetic ablation of soluble tumor necrosis factor with preservation of membrane tumor necrosis factor is associated with neuroprotection after focal cerebral ischemia

“…Though alterations in these functions in TNF À/À mice were often ascribed to abnormal serotonine metabolism 69 or changes in nerve growth factor levels, 59 they are likely also associated with the important role of glial-derived TNF in homeostatic activity-dependent regulation of synaptic connectivity 13 and control of synaptic strength. 14,70,71 Despite this evidence demonstrating a role for TNF in behavioral function, in the present study, we did not observe any changes in cognitive function in mTNF Á/Á mice compared to mTNF wt/wt littermates, suggesting that mTNF alone is necessary and sufficient for maintenance of cognitive function under physiological conditions.…”

A metaplasticity view of the interaction between homeostatic and Hebbian plasticity

“…Additionally, IB cells showed input-specific potentiation (Hebbian LTP) that required CaMKII autophosphorylation. Although the molecular and cellular pathway leading from neuronal activity to TNFa biosynthesis has yet to be discovered, recent studies show that striatal microglial produce TNFa [126,127]. As opposed to its role in hippocampus, where it mediates excitatory synaptic strengthening, in striatum, TNFa was shown to drive synaptic AMPA receptor internalization, thus reducing glutamatergic synaptic strength.…”

Cytokine Correlations in Youth with Tic Disorders

“…Although the exact mechanism is still unknown, oxidative stress and resultant motor neuron cell death, which are the consequences of neuroinflammation, have been proposed. However, several studies have pointed toward excitotoxicity from TNF-a induced modulation of glutamate signaling as well as GABA and glutamate receptors expression (Lewitus et al 2014;Olmos and Llado 2014). The actions of TNF-a in ALS may shed light on its role in tic disorders given the comparable clinical observations, including the association of increased TNF-a levels and symptom severity and the involvement of the GABA systems ( Jijun et al 2010;Lerner et al 2012).…”

“…In SC, a group A streptococcal (GAS) mediated disorder occurring in a subset of individuals with rheumatic fever (RF), patients experience involuntary movements and a manifestation of neuropsychiatric symptoms including obsessions/compulsions and anxiety, which are thought to be the result antistreptococcal antibodies targeting structures in the basal ganglia, dopamine receptors, and neuronal proteins (Kirvan et al 2003;Dale et al 2012;Ben-Pazi et al 2013). There has also been increasing evidence to support an equally important role for cytokines in disease pathology, given observations of increased serum cytokine levels in patients with cytokine-related neuropathology in similar movement disorders (Church et al 2003;Lewitus et al 2014). These pathologies, particularly increases in serum cytokine levels, have also been observed in patients with tic disorders, along with abnormal immunological responses to GAS and basal ganglia pathologies (Giedd et al 2000;Kalanithi et al 2005;Bombaci et al 2009).…”