Chronic interleukin‐6 alters the level of synaptic proteins in hippocampus in culture and in vivo

Abstract

There is now considerable evidence that the level of expression of the proinflammatory cytokine, interleukin-6 (IL-6), is increased in the central nervous system (CNS) during neuroinflammatory conditions such as occurs in neurological disorders and in disease and injury. However, our understanding of the consequences of increased expression of IL-6 on the CNS is still limited, especially with respect to the developing nervous system, which is known to be particularly vulnerable to environmental factors. To address this issue, we investigated the properties of cultured hippocampal neurons exposed chronically to IL-6 during the main period of morphological and physiological development, which occurs during the first 2 weeks of culture. IL-6 was tested at 500 U/mL, considered to reflect a pathophysiologic concentration. The morphological features of neuronal development in the control and IL-6-treated cultures appeared similar. However, Western blot analysis showed a significant reduction in the level of Group-II metabotropic receptors (mGluR2/3) and L-type Ca(2+) channels in the IL-6-treated cultures. A similar reduction in mGluR2/3 and L-type Ca(2+) channel protein was observed in transgenic mice that over-express IL-6 in the CNS through astrocyte production starting early in development. Analysis of Ca(2+) signals produced by spontaneous synaptic network activity in the hippocampal cultures and effects of a mGluR2/3 agonist and antagonist showed that the reduced levels of mGluR2/3 impact on the functional properties of hippocampal synaptic network activity. These results have important implications relative to the mechanisms responsible for altered CNS function during conditions associated with increased levels of IL-6 in the CNS.

The chemokine CCL2 activates p38 mitogen-activated protein kinase pathway in cultured rat hippocampal cells

“…Consistent with this result, immunostaining for CCR2 in spinal cord cultures was reported to be intense in neurons with no significant immunostaining of astrocytes (Gosselin et al, 2005). Neurons and glial cells in the hippocampal cultures were identified by morphological criteria developed in previous studies using cell specific antibodies carried out in parallel with electrophysiological or Ca 2+ imaging recordings from the neurons (Nelson and Gruol, 2004;Vereyken et al, 2007). Blocking the antibody with the antigenic peptide used to produce the CCR2 antibody completely eliminated immunostaining for CCR2, indicating that the immunoreactivity was specific for the antigenic sequence (Fig.…”

Modulation of RhoGTPases Improves the Behavioral Phenotype and Reverses Astrocytic Deficits in a Mouse Model of Rett Syndrome

“…As high levels of IL-6 have also been reported to inhibit pro-inflammatory TNF-a (Petersen and Pedersen, 2005), overexpression of IL-6 is not necessarily in contrast with the observed downregulation of TNF-a and could have a role in RTT etiopathology. Indeed, exposure to high levels of IL-6, as observed during normal aging, in certain neurodegenerative diseases and in mice overexpressing IL-6 in glial cells, results in neuropathological and functional alterations, including decreased synaptic plasticity and impaired neurogenesis (Bellinger et al, 1995;Campbell, 1998;Campbell et al, 1997Campbell et al, , 1998Godbout and Johnson, 2004;Heyser et al, 1997;Vallieres et al, 2002;Vereyken et al, 2007).…”

Calcium Signaling in Neuronal Development

“…The selective in vivo deletion of the neuropoietic cytokine receptor subunit gp130 in noradrenergic neurons results in a decrease in the number of cholinergic neurons innervating the sweat glands, although the total number of innervating neurons is unchanged (Stanke et al 2006). Additional studies of hippocampal neurons show that elevated levels of IL-6 both in vivo and in vitro modulate the expression of L-type calcium channels and alter the dynamics of calcium signaling and network activity (Nelson et al 2004;Vereyken et al 2007). These results indicate that signaling through the IL-6 receptor gp130 may regulate neurotransmitter phenotype by modulating calcium signaling.…”