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Converging evidence indicates that major depressive disorder (MDD) and metabolic disorders might be mediated by shared (patho)biological pathways. However, the converging cellular and molecular signatures remain unknown. Here, we investigated metabolic dysfunction on a systemic, cellular, and molecular level in unmedicated patients with MDD compared with matched healthy controls (HC). Despite comparable BMI scores and absence of cardiometabolic disease, patients with MDD presented with significant dyslipidemia. On a cellular level, T cells obtained from patients with MDD exhibited reduced respiratory and glycolytic capacity. Gene expression analysis revealed increased carnitine palmitoyltransferase IA ( CPT1a ) levels in T cells, the rate-limiting enzyme for mitochondrial long-chain fatty acid oxidation. Together, our results indicate metabolic dysfunction in unmedicated, non-overweight patients with MDD on a systemic, cellular, and molecular level. This evidence for reduced mitochondrial respiration in T cells of patients with MDD provides translation of previous animal studies regarding a putative role of altered immunometabolism in depression pathobiology., Competing Interests: C.O. reports personal fees from Allergan, Ferring, Janssen, Fortbildungskolleg, Limes Kliniken, Medical Tribune, and Sage Therapeutics. S.M.G. reports personal fees from Almirall S.A., Mylan GmbH, Celgene, and Forum für Medizinische Fortbildung (FomF) and in-kind research contributions from GAIA Group. M.S.H. and S.K. are employees of metaSysX. All other authors report no potential conflict of interest., (© 2021 The Authors.)

We aimed to evaluate SIGLEC1 (CD169) as a biomarker in multiple sclerosis (MS) and Neuromyelitis optica spectrum disorder (NMOSD) and to evaluate the presence of SIGLEC1 + myeloid cells in demyelinating diseases. We performed flow cytometry-based measurements of SIGLEC1 expression on monocytes in 86 MS patients, 41 NMOSD patients and 31 healthy controls. Additionally, we histologically evaluated the presence of SIGLEC1 + myeloid cells in acute and chronic MS brain lesions as well as other neurological diseases. We found elevated SIGLEC1 expression in 16/86 (18.6%) MS patients and 4/41 (9.8%) NMOSD patients. Almost all MS patients with high SIGLEC1 levels received exogenous interferon beta as an immunomodulatory treatment and only a small fraction of MS patients without interferon treatment had increased SIGLEC1 expression. In our cohort, SIGLEC1 expression on monocytes was-apart from those patients receiving interferon treatment-not significantly increased in patients with MS and NMOSD, nor were levels associated with more severe disease. SIGLEC1 + myeloid cells were abundantly present in active MS lesions as well as in a range of acute infectious and malignant diseases of the central nervous system, but not chronic MS lesions. The presence of SIGLEC1 + myeloid cells in brain lesions could be used to investigate the activity in an inflammatory CNS lesion.

Objective: An increase of neuronal Ca v 1.3 L-type calcium channels (LTCCs) has been observed in various animal models of epilepsy. However, LTCC inhibitors failed in clinical trials of epileptic treatment. There is compelling evidence that paroxysmal depolarization shifts (PDSs) involve Ca 2+ influx through LTCCs. PDSs represent a hallmark of epileptiform activity. In recent years, a probable epileptogenic role for PDSs has been proposed. However, the implication of the two neuronal LTCC isoforms, Ca v 1.2 and Ca v 1.3, in PDSs remained unknown. Moreover, Ca 2+ -dependent nonspecific cation (CAN) channels have also been suspected to contribute to PDSs. Nevertheless, direct experimental support of an important role of CAN channel activation in PDS formation is still lacking., Methods: Primary neuronal networks derived from dissociated hippocampal neurons were generated from mice expressing a dihydropyridine-insensitive Ca v 1.2 mutant (Ca v 1.2DHP -/- mice) or from Ca v 1.3 -/- knockout mice. To investigate the role of Ca v 1.2 and Ca v 1.3, perforated patch-clamp recordings were made of epileptiform activity, which was elicited using either bicuculline or caffeine. LTCC activity was modulated using the dihydropyridines Bay K 8644 (agonist) and isradipine (antagonist)., Results: Distinct PDS could be elicited upon LTCC potentiation in Ca v 1.2DHP -/- neurons but not in Ca v 1.3 -/- neurons. In contrast, when bicuculline led to long-lasting, seizure-like discharge events rather than PDS, these were prolonged in Ca v 1.3 -/- neurons but not in Ca v 1.2DHP -/- neurons. Because only the Ca v 1.2 isoform is functionally coupled to CAN channels in primary hippocampal networks, PDS formation does not require CAN channel activity., Significance: Our data suggest that the LTCC requirement of PDS relates primarily to Ca v 1.3 channels rather than to Ca v 1.2 channels and CAN channels in hippocampal neurons. Hence, Ca v 1.3 may represent a new therapeutic target for suppression of PDS development. The proposed epileptogenic role of PDSs may allow for a prophylactic rather than the unsuccessful seizure suppressing application of LTCC inhibitors., (Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.)