Induced neural progenitor cells and iPS-neurons from major depressive disorder patients show altered bioenergetics and electrophysiological properties

Abstract

BACKGROUND: The molecular pathomechanisms of major depressive disorder (MDD) are still not completely understood. Here, we follow the hypothesis, that mitochondrial dysfunction which is inevitably associated with bioenergetic misbalance is a risk factor that contributes to the susceptibility of an individual to develop MDD. MDD can be regarded as disease of the mind as well as of the body. Thus, we focused on mitochondrial and cellular function in reprogrammed neural cells from MDD patients and healthy controls. METHODS: We investigated molecular mechanisms related to mitochondrial and cellular functions in induced neuronal progenitor cells (NPCs) as well as in neurons, which were reprogrammed from fibroblasts of depressed patients and non-depressed controls, respectively. RESULTS: We found significantly lower basal respiration rates and a less hyperpolarized mitochondrial membrane potential in NPCs derived from MDD patients. These findings are in line with our earlier observations in patient-derived fibroblasts (1). Furthermore, we differentiated MDD and control NPCs into iPS-neurons and analyzed their passive biophysical and active electrophysiological properties. Interestingly, MDD patient-derived iPS-neurons showed significantly lower membrane capacitance, a more depolarized membrane potential, and increased spontaneous electrical activity. This is the first report showing functional differences in MDD patient-derived and control NPCs and iPS-neurons. CONCLUSION: Our findings indicate that functional differences evident in fibroblasts from depressed patients are also present after reprogramming and differentiation to induced-NPCs and iPS-neurons and might be associated with the aetiology of major depressive disorder.

Cell adhesion molecules play subclass-specific roles in electrophysiological response and Schizophrenia risk

“…Psychiatric disorders have also been associated with changes in diverse cellular phenotypes such as cell adherence 23–25 , cellular energetics 26,27 , and neuron electrophysiological response patterns 26,28 . In a limited number of cases, causal links between psychiatric genetic variants and changes in cellular phenotypic variation have been established.…”