Oxytocin alters the morphology of hypothalamic neurons via the transcription factor myocyte enhancer factor 2A (MEF-2A)

Myocyte Enhancer Factor 2A (MEF2A) Defines Oxytocin-Induced Morphological Effects and Regulates Mitochondrial Function in Neurons

“…2A), revealing the S408 residue as the main phosphorylation site that orchestrates the OT effect on cellular morphology. We have shown in a previous publication (Meyer et al, 2018) that incubation of H32 cells with 100 nM OT overnight led to a dephosphorylation, and therefore activation, of MEF2A at S408, compared to VEH treated cells. This effect is indirectly mediated via the MAPK pathway, as it is reversed to basal by the MEK1/2 inhibitor U0126.…”

“…Intriguingly, MEF2 regulates transcription of the mitochondrial NADH dehydrogenase 6 gene, which is essential for the function of the oxidative phosphorylation system (Naya et al, 2002;She et al, 2011), which ultimately regulates the production of ATP. In line with that, a significant proportion of ASD patients suffer from abnormal ATP production (Rossignol and Frye, 2014;Siddiqui et al, 2016), suggesting a central role for the OT-regulated transcription factor MEF2 in energy balance, structural plasticity, and ASD (also see (Brusco and Haas, 2015;Fiore et al, 2009;Meyer et al, 2018;Pfeiffer et al, 2010;Shalizi et al, 2006)). To test this hypothesis, we manipulated MEF2A activity in hypothalamic neurons and monitored morphological alterations and mitochondrial functionality.…”

“…OT treatment (as shown in Fig. 2B and (Meyer et al, 2018)) reduced neurite length from about 100 µm to about 75 µm, an effect that was blocked by the CaN inhibitor ( Fig. 3C).…”

“…Furthermore, neurons generated from iPSCs of ASD patients have more complex and longer neurites, causing increased synapse number and a state of hyperconnectivity (Tang et al, 2014;Zaslavsky et al, 2019). MEF2 is one factor being responsible for the regulation of excitatory synapse number (Flavell et al, 2006;Morrow et al, 2008;Shalizi et al, 2006), and we have recently provided evidence for its activation by OT receptor-coupled signaling pathways (Meyer et al, 2018). The activation of Gq protein-coupled OT receptors lead to an increase in intracellular calcium from either intracellular stores (Sanborn, 2007), through cation channels such as TrpV2/4 (van den Burg et al, 2015;Ying et al, 2015) or L-type voltage-gated calcium channels (Zatkova et al, 2018).…”

“…Since OT is produced in the hypothalamus and we have found profound anxiolytic and anti-stress effects of OT infused into the hypothalamic paraventricular nucleus (Blume et al, 2008;Jurek et al, 2015;Jurek et al, 2012;Martinetz et al, 2019), we aimed to determine the intracellular effects of OT in a hypothalamic cell line, as opposed to neuroblastoma or glioblastoma cell types. As a cellular model of OTergic effects, we have characterized the rat hypothalamic neuronal cell line H32, which expresses MEF2A endogenously, and retract their neurites upon OT stimulation, caused by MEF2A activation (Meyer et al, 2018). Neurite retraction was blocked by siRNA-mediated knockdown of MEF2A, or pharmacological blockade of the OT receptor-induced MAPK pathway by U0126.…”