α-Synuclein induced toxicity in brain stem serotonin neurons mediated by an AAV vector driven by the tryptophan hydroxylase promoter

We studied the impact of α-synuclein overexpression in brainstem serotonin neurons using a novel vector construct where the expression of human wildtype α-synuclein is driven by the tryptophan hydroxylase promoter, allowing expression of α-synuclein at elevated levels, and with high selectivity, in serotonergic neurons. α-Synuclein induced degenerative changes in axons and dendrites, displaying a distorted appearance, suggesting accumulation and aggregation of α-synuclein as a result of impaired axonal transport, accompanied by a 40% loss of terminals, as assessed in the hippocampus. Tissue levels of serotonin and its major metabolite 5-HIAA remained largely unaltered, and the performance of the α-synuclein overexpressing rats in tests of spatial learning (water maze), anxiety related behavior (elevated plus maze) and depressive-like behavior (forced swim test) was not different from control, suggesting that the impact of the developing axonal pathology on serotonin neurotransmission was relatively mild. Overexpression of α-synuclein in the raphe nuclei, combined with overexpression in basal forebrain cholinergic neurons, resulted in more pronounced axonal pathology and significant impairment in the elevated plus maze. We conclude that α-synuclein pathology in serotonergic or cholinergic neurons alone is not sufficient to impair non-motor behaviors, but that it is their simultaneous involvement that determines severity of such symptoms

Acute Stress Induces Contrasting Changes in AMPA Receptor Subunit Phosphorylation within the Prefrontal Cortex, Amygdala and Hippocampus

Exposure to stress causes differential neural modifications in various limbic regions, namely the prefrontal cortex, hippocampus and amygdala. We investigated whether α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) phosphorylation is involved with these stress effects. Using an acute inescapable stress protocol with rats, we found opposite effects on AMPA receptor phosphorylation in the medial prefrontal cortex (mPFC) and dorsal hippocampus (DH) compared to the amygdala and ventral hippocampus (VH). After stress, the phosphorylation of Ser831-GluA1 was markedly decreased in the mPFC and DH, whereas the phosphorylation of Ser845-GluA1 was increased in the amygdala and VH. Stress also modulated the GluA2 subunit with a decrease in the phosphorylation of both Tyr876-GluA2 and Ser880-GluA2 residues in the amygdala, and an increase in the phosphorylation of Ser880-GluA2 in the mPFC. These results demonstrate that exposure to acute stress causes subunit-specific and region-specific changes in glutamatergic transmission, which likely lead to the reduced synaptic efficacy in the mPFC and DH and augmented activity in the amygdala and VH. In addition, these findings suggest that modifications of glutamate receptor phosphorylation could mediate the disruptive effects of stress on cognition. They also provide a means to reconcile the contrasting effects that stress has on synaptic plasticity in these regions. Taken together, the results provide support for a brain region-oriented approach to therapeutics

Skeletal muscle relaxant effect of a standardized extract of Valeriana officinalis L. after acute administration in mice

Valeriana officinalis L. root extracts are traditionally taken for their sedative and anxiolytic properties and are also used for muscle relaxation. Relaxant effects were clearly observed on smooth muscle whereas data on effects on skeletal muscle are scarce and inconsistent. The aim of this study was to assess whether a standardized extract (SE) of V. officinalis had myorelaxant effects by decreasing skeletal muscle strength and/or neuromuscular tone in mice. Mice received an acute dose of V. officinalis SE (2 or 5 g/kg per os) or tetrazepam (10 mg/kg ip), a standard myorelaxant drug. Thirty minutes later, the maximal muscle strength was measured using a grip test, while global skeletal muscle function (endurance and neuromuscular tone) was assessed in a wire hanging test. Compared to tetrazepam, both doses of V. officinalis SE induced a pronounced decrease in skeletal muscle strength without any significant effects on endurance and neuromuscular tone. This study provides clear evidence that the extract of V. officinalis tested has a relaxant effect on skeletal muscle. By decreasing skeletal muscle strength without impacting endurance and neuromuscular tone, V. officinalis SE could induce less undesirable side effects than standard myorelaxant agents, and be particularly useful for avoiding falls in the elderly. Keywords: Valeriana officinalis, Skeletal muscle relaxant, Strength, Hydroethanolic root extract, Acute treatment, Mous

Characterization of brain dystrophins absence and impact in dystrophin-deficient Dmdmdx rat model

International audienceCharacterization of brain dystrophins absence and impact in dystrophin-deficient Dmdmdx rat mode

Phosphorylation states at multiple AMPAR subunits after acute stress.

<p>Immunoblots and histograms of the ratio between the phosphorylated form and total amount of the protein (white bars: no stress group, cross hatched bars: stress group). In the mPFC (A), stress decreased Ser831-GluA1 phosphorylation (p<0.05) and increased Ser880-GluA2 phosphorylation (p<0.05). In the amygdala (B), stress increased Ser845-GluA1 phosphorylation (p<0.05) and decreased Tyr876-GluA2 and Ser880-GluA2 phosphorylation (p<0.05. In the DH (C), stress decreased Ser831-GluA1 phosphorylation (p<0.05). In the VH (D), stress increased Ser845-GluA1 phosphorylation (p<0.05) and decreased Ser880-GluA2 phosphorylation (p<0.05). Immunoblots (100 kDa) illustrate the phosphorylated form of the protein (left: control, right: stress). The number of animals per group is 10 for controls and 11 for stress. Unpaired, two-tailed, Student's T-test. *, p<0.05, compared with the corresponding control group.</p

Summary of changes in AMPAR phosphorylation of GluA1 and GluA2 subunits after stress in the four regions studied.

<p>Summary of changes in AMPAR phosphorylation of GluA1 and GluA2 subunits after stress in the four regions studied.</p