TNF-α increases the intrinsic excitability of cerebellar Purkinje cells through elevating glutamate release in Bergmann Glia

Abstract

For decades, the glial function has been highlighted not only as the ‘structural glue’, but also as an ‘active participant’ in neural circuits. Here, we suggest that tumor necrosis factor α (TNF-α), a key inflammatory cytokine, alters the neural activity of the cerebellar Purkinje cells (PCs) by facilitating gliotransmission in the juvenile male rat cerebellum. A bath application of TNF-α (100 ng/ml) in acute cerebellar slices elevates spiking activity of PCs with no alterations in the regularity of PC firings. Interestingly, the effect of TNF-α on the intrinsic excitability of PCs was abolished under a condition in which the type1 TNF receptor (TNFR1) in Bergmann glia (BG) was genetically suppressed by viral delivery of an adeno-associated virus (AAV) containing TNFR1-shRNA. In addition, we measured the concentration of glutamate derived from dissociated cerebellar cortical astrocyte cultures treated with TNF-α and observed a progressive increase of glutamate in a time-dependent manner. We hypothesised that TNF-α-induced elevation of glutamate from BGs enveloping the synaptic cleft may directly activate metabotropic glutamate receptor1 (mGluR1). Pharmacological inhibition of mGluR1, indeed, prevented the TNF-α-mediated elevation of the intrinsic excitability in PCs. Taken together, our study reveals that TNF-α triggers glutamate release in BG, thereby increasing the intrinsic excitability of cerebellar PCs in a mGluR1-dependent manner.

Tumor Necrosis Factor-Alpha Alters Electrophysiological Properties of Rabbit Hippocampal Neurons

“…In this study, we used a low dose of TNF-α, which is slightly higher than physiological concentrations [72] but far below those concentrations that can cause neuronal toxicity [75–78], and found that TNF-α demonstrated a range of effects on the membrane properties of hippocampal CA1 neurons. The increased neuronal excitability induced by TNF-α treatment is in line with previous findings in rat cerebellar Purkinje cells [79], cultured cortical neurons [80], dorsal root ganglion [81, 82], rat suprachiasmatic nuclear neurons [83], neurons from rat subfornical organ [84], and in excised guinea pig spinal cord tissue [78]. This increased excitability may be attributed to the changes in neuronal membrane properties [83], including an increase in calcium current observed in cultured rat hippocampal neurons [85] and cultured sympathetic neurons from neonatal rat superior cervical ganglia [86], in transient outward potassium currents in cultured cortical neurons from embryonic rats [75], in sodium current observed in cultured mouse cortical neurons [80] and isolated rat dorsal root ganglion [81], or the suppression of sustained potassium currents in rat small dorsal root ganglion neurons [87].…”

Synergistic excitability plasticity in cerebellar functioning

“…This plasticity resembles the previously reported Ihdownregulation-dependent IP in PCs [47]. While both Yamamoto et al [126] and Shim et al [173] showed that exposure to TNF-a increased the firing frequency of PCs, Shim et al [173] have investigated PC excitability following 1-h of incubation with TNF-a. The time spam would possibly provoke another downstream cascade after the activation of TNF receptors or boosting cytokine releases.…”

“…Related behavioral phenotypes had been observed in other groups [171,172], suggesting the control of animals' mood or sociability by cerebellar anterior lobes (paleocerebellum, i.e., old or ancient cerebellum, Berntson & Torello [36]) and related regions receiving their neural projection. On the other hand, Shim et al [173] have reported an increase in PC excitability via Bergman glial activity, which was accompanied by a decrease in Ih current. This plasticity resembles the previously reported Ihdownregulation-dependent IP in PCs [47].…”

“…On the other hand, Shim et al . [173] have reported an increase in PC excitability via Bergman glial activity, which was accompanied by a decrease in Ih current. This plasticity resembles the previously reported Ih‐downregulation‐dependent IP in PCs [47].…”

Defining novel functions for cerebrospinal fluid in ALS pathophysiology

“…IgG further possesses pro-inflammatory properties, promoting microglia recruitment and upregulation of inflammatory cytokines [124,141,142]. Some of the other chemokines found to be elevated in ALS-CSF include IL-6, TNF-α and TGF-β [81,130,172], with the finding of raised TNF-α levels being particularly interesting, given its associations with glutamate excitotoxicity [43,178,218]. Whilst their direct involvement in ALS pathophysiology is still unknown, the presence of these different immune factors in ALS-CSF, some of which have been shown to be neurotoxic, could suggest an important role for CSF in neuroinflammation, with the neurotoxic environment possibly favoured by altered CSF dynamics and reduced clearance.…”