Complexin Facilitates Exocytosis and Synchronizes Vesicle Release in Two Secretory Model Systems.

Complexin Facilitates Exocytosis and Synchronizes Vesicle Release in Two Secretory Model Systems.

Filed under: Depression Treatment

J Physiol. 2013 Feb 11;
Lin MY, Rohan JG, Cai H, Reim K, Ko CP, Chow RH

Complexins (Cplxs) are small, SNARE-associated proteins believed to regulate fast, calcium-triggered exocytosis. However, studies have pointed to either an inhibitory and/or facilitatory role in exocytosis, and the role of Cplxs in synchronizing exocytosis is relatively unexplored. Here, we compare the function of Cplx 1 and 2 in two model systems of calcium-dependent exocytosis. In mouse neuromuscular junctions (NMJs), we find that lack of Cplx 1 significantly reduces and desynchronizes calcium-triggered synaptic transmission; furthermore, high-frequency stimulation elicits synaptic facilitation, instead of normal synaptic depression, and the degree of facilitation is highly sensitive to the amount of cytoplasmic calcium buffering. In Cplx 2-null adrenal chromaffin cells, we also find decreased and desynchronized evoked release, and identify a significant loss in the vesicle pool close to the calcium channels (immediately releasable pool, IRP). Viral transduction with either Cplx 1 or 2 rescues both the size of the evoked response and the synchronicity of release, and it restores the IRP size. Our findings in two model systems are mutually compatible and indicate a role of Cplx 1 and 2 in facilitating vesicle priming, but also lead to the new hypothesis that Cplxs may synchronize vesicle release by promoting coupling between secretory vesicles and calcium channels.
HubMed – depression

Cholinergic signaling in the hippocampus regulates social stress resilience and anxiety- and depression-like behavior.

Filed under: Depression Treatment

Proc Natl Acad Sci U S A. 2013 Feb 11;
Mineur YS, Obayemi A, Wigestrand MB, Fote GM, Calarco CA, Li AM, Picciotto MR

Symptoms of depression can be induced in humans through blockade of acetylcholinesterase (AChE) whereas antidepressant-like effects can be produced in animal models and some clinical trials by limiting activity of acetylcholine (ACh) receptors. Thus, ACh signaling could contribute to the etiology of mood regulation. To test this hypothesis, we administered the AChE inhibitor physostigmine to mice and demonstrated an increase in anxiety- and depression-like behaviors that was reversed by administration of nicotinic or muscarinic antagonists. The behavioral effects of physostigmine were also reversed by administration of the selective serotonin reuptake inhibitor fluoxetine. Administration of fluoxetine also increased AChE activity throughout the brain, with the greatest change in the hippocampus. To determine whether cholinergic signaling in the hippocampus could contribute to the systemic effects of cholinergic drugs, we infused physostigmine or virally delivered shRNAs targeting AChE into the hippocampus. Both pharmacological and molecular genetic decreases in hippocampal AChE activity increased anxiety- and depression-like behaviors and decreased resilience to repeated stress in a social defeat paradigm. The behavioral changes due to shRNA-mediated knockdown of AChE were rescued by coinfusion of an shRNA-resistant AChE transgene into the hippocampus and reversed by systemic administration of fluoxetine. These data demonstrate that ACh signaling in the hippocampus promotes behaviors related to anxiety and depression. The sensitivity of these effects to fluoxetine suggests that shRNA-mediated knockdown of hippocampal AChE represents a model for anxiety- and depression-like phenotypes. Furthermore, abnormalities in the cholinergic system may be critical for the etiology of mood disorders and could represent an endophenotype of depression.
HubMed – depression

Moderate-vigorous physical activity improves long-term clinical outcomes without worsening pain in fibromyalgia.

Filed under: Depression Treatment

Arthritis Care Res (Hoboken). 2013 Feb 11;
Kaleth AS, Saha CK, Jensen MP, Slaven JE, Ang DC

OBJECTIVE: To evaluate the relationship between long-term maintenance of moderate-vigorous physical activity (MVPA) and clinical outcomes in fibromyalgia (FM). METHODS: Patients with FM (n=170) received individualized exercise prescriptions and completed baseline and follow-up physical activity assessments using the Community Health Activities Model Program for Seniors (CHAMPS) questionnaire at weeks 12, 24, and 36. The primary outcome was the change in the Fibromyalgia Impact Questionnaire-Physical Impairment (FIQ-PI) score. Secondary outcomes included improvements in overall well-being (FIQ-Total), pain severity ratings, and depression. RESULTS: Using a threshold increase in MVPA of ?10 metabolic equivalent hours per week (MET h/wk) above usual activities, 27 subjects (15.9%) increased and sustained (SUS-PA), 68 (40%) increased, but then declined (UNSUS-PA), and 75 (44.1%) did not achieve this benchmark (LO-PA). Compared to LO-PA subjects, both SUS-PA and UNSUS-PA subjects reported greater improvement in FIQ-PI (p<0.01) and FIQ-Total (p<0.05). Additionally, the SUS-PA group reported greater improvement in pain severity compared to the LO-PA group (p<0.05). However, there were no significant group differences between SUS-PA and UNSUS-PA for any primary or secondary outcome measure. CONCLUSION: Increased participation in MVPA for at least 12 weeks improves physical function and overall well-being in patients with FM. Although sustained physical activity was not associated with greater clinical benefit compared to unsustained physical activity, these findings also suggest that performing greater volumes of physical activity is not associated with worsening pain in FM. Future research is needed to determine the relationship between sustained MVPA participation and subsequent improvement in patient outcomes. HubMed – depression

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