Degeneration of serotonergic neurons in amyotrophic lateral sclerosis: a link to spasticity

Abstract

Spasticity is a common and disabling symptom observed in patients with central nervous system diseases, including amyotrophic lateral sclerosis, a disease affecting both upper and lower motor neurons. In amyotrophic lateral sclerosis, spasticity is traditionally thought to be the result of degeneration of the upper motor neurons in the cerebral cortex, although degeneration of other neuronal types, in particular serotonergic neurons, might also represent a cause of spasticity. We performed a pathology study in seven patients with amyotrophic lateral sclerosis and six control subjects and observed that central serotonergic neurons suffer from a degenerative process with prominent neuritic degeneration, and sometimes loss of cell bodies in patients with amyotrophic lateral sclerosis. Moreover, distal serotonergic projections to spinal cord motor neurons and hippocampus systematically degenerated in patients with amyotrophic lateral sclerosis. In SOD1 (G86R) mice, a transgenic model of amyotrophic lateral sclerosis, serotonin levels were decreased in brainstem and spinal cord before onset of motor symptoms. Furthermore, there was noticeable atrophy of serotonin neuronal cell bodies along with neuritic degeneration at disease onset. We hypothesized that degeneration of serotonergic neurons could underlie spasticity in amyotrophic lateral sclerosis and investigated this hypothesis in vivo using tail muscle spastic-like contractions in response to mechanical stimulation as a measure of spasticity. In SOD1 (G86R) mice, tail muscle spastic-like contractions were observed at end-stage. Importantly, they were abolished by 5-hydroxytryptamine-2b/c receptors inverse agonists. In line with this, 5-hydroxytryptamine-2b receptor expression was strongly increased at disease onset. In all, we show that serotonergic neurons degenerate during amyotrophic lateral sclerosis, and that this might underlie spasticity in mice. Further research is needed to determine whether inverse agonists of 5-hydroxytryptamine-2b/c receptors could be of interest in treating spasticity in patients with amyotrophic lateral sclerosis.

Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis

“…Consistent with previous results [15], mRNA expression of Htr2b mRNA was strongly upregulated in spinal cord of SOD1(G86R) mice (Fig. 1a) but also of SOD1(G37R) mice (Fig.…”

“…3e). Thus, consistent with its overexpression at symptom onset in SOD1(G86R) spinal cord [15], the lack of 5-HT 2B R potently accelerates disease progression of SOD1(G86R) mice after onset.…”

“…Htr2b mRNA expression was restricted to CD11b-positive cells purified from spinal cord and brainstem, thus originating from mononuclear phagocytes, either microglia or infiltrating monocytes. Second, the late occurrence of Htr2b upregulation [15] coincides with activation of mononuclear phagocytes in SOD1(G86R) mice. Third, the effects of Htr2b ablation on ALS progression are strikingly similar to interventions performed on mononuclear phagocytes.…”

“…Transgenic mice carrying SOD1 G86R mutation [18] and their non-transgenic littermates on a FVB/N background were genotyped and onset of symptoms was defined according to previous studies [15]. Dynactin mice expressing G59S mutation of P150 Glued have been previously described [43], and were used according to previous studies [67].…”

“…Recently, we observed that serotonin 2B receptor (5-HT 2B R) mRNA levels were strongly upregulated in the spinal cord of a mouse model of ALS -SOD1(G86R) mice, notably at later stages and coincident with development El Oussini and collaborators 4 of spasticity [15]. 5-HT 2B R is expressed in microglia in the CNS [40], with expression in other cell types including brain serotonin neurons [16].…”