Peripheral elevation of TNF-α leads to early synaptic abnormalities in the mouse somatosensory cortex in experimental autoimmune encephalomyelitis

Abstract

Sensory abnormalities such as numbness and paresthesias are often the earliest symptoms in neuroinflammatory diseases including multiple sclerosis. The increased production of various cytokines occurs in the early stages of neuroinflammation and could have detrimental effects on the central nervous system, thereby contributing to sensory and cognitive deficits. However, it remains unknown whether and when elevation of cytokines causes changes in brain structure and function under inflammatory conditions. To address this question, we used a mouse model for experimental autoimmune encephalomyelitis (EAE) to examine the effect of inflammation and cytokine elevation on synaptic connections in the primary somatosensory cortex. Using in vivo two-photon microscopy, we found that the elimination and formation rates of dendritic spines and axonal boutons increased within 7 d of EAE induction-several days before the onset of paralysis-and continued to rise during the course of the disease. This synaptic instability occurred before T-cell infiltration and microglial activation in the central nervous system and was in conjunction with peripheral, but not central, production of TNF-α. Peripheral administration of a soluble TNF inhibitor prevented abnormal turnover of dendritic spines and axonal boutons in presymptomatic EAE mice. These findings indicate that peripheral production of TNF-α is a key mediator of synaptic instability in the primary somatosensory cortex and may contribute to sensory and cognitive deficits seen in autoimmune diseases.

FGF-1 Triggers Pannexin-1 Hemichannel Opening in Spinal Astrocytes of Rodents and Promotes Inflammatory Responses in Acute Spinal Cord Slices

“…P2X 7 Rs can over seconds allow larger molecules, such as Etd ϩ , to permeate, which was interpreted as a consequence of pore dilation by some workers (Yan et al, 2008;Browne et al, 2013). However, others have failed to see P2X 7 R pore dilation at the single-channel level (Riedel et al, 2007).…”

“…In cultured hippocampal neurons, IL-1␤ enhances NMDAmediated neurotoxicity (Viviani et al, 2003) and in vivo it has been shown to be the primary mediator of vasogenic edema in ischemic injury (Basu et al, 2005). Furthermore, IL-1␤ impairs neuronal signaling in vitro by suppressing BDNF-dependent synaptic plasticity (Tong et al, 2012) and, in vivo, may decrease formation of new dendritic spines induced by microglia-derived BDNF (Parkhurst et al, 2013). In contrast to IL-1␤, IL-6 may have a dual role in CNS, preventing tissue damage and protecting different populations of neurons against excitotoxicity, or being detrimental if chronically upregulated (Spooren et al, 2011).…”

“…9 A, B; see Materials and Methods) (Parkhurst et al, 2013). In spinal cord slices depleted of microglia (Fig.…”

“…In cerebral cortex, FGF signaling maintains astrocytes in an unreactive state and reduces activation after a stab wound (Kang et al, 2014). In contrast, FGF-2, which also acts on FGF receptors, is associated with inflammatory changes in spinal cord and neuropathic pain (Ji et al, 2013). Furthermore, FGF-1 can activate spinal cord astrocytes in culture and increase the production of neurotoxic factors .…”

Altered Expression of Oligodendrocyte and Neuronal Marker Genes Predicts the Clinical Onset of Autoimmune Encephalomyelitis and Indicates the Effectiveness of Multiple Sclerosis–Directed Therapeutics

“…Further, enhanced glutamate transmission and expression of the AMPA receptor GluR1 subunit have been detected in the striatum starting from the presymptomatic phase of EAE (9). Recent evidence shows that synaptic abnormalities occur in the primary somatosensory cortex prior to T cell infiltration and microglial activation and are prevented by the peripheral administration of the soluble TNF inhibitor, XPro1595 (50). It is possible that early changes in the expression of functionally relevant neuronal genes, including those described in this article, underlie such effects.…”