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

Abstract

The neuropeptide oxytocin (OT) is a well-described modulator of socio-emotional traits, such as anxiety, stress, social behavior, and pair bonding. However, when dysregulated, it is associated with adverse psychiatric traits, such as various aspects of autism spectrum disorder (ASD). In this study, we identify the transcription factor myocyte enhancer factor 2A (MEF2A) as the common link between OT and cellular changes symptomatic for ASD, encompassing neuronal morphology, connectivity, and mitochondrial function. We provide evidence for MEF2A as the decisive factor defining the cellular response to OT: while OT induces neurite retraction in MEF2A expressing neurons, OT causes neurite outgrowth in absence of MEF2A. A CRISPR-Cas-mediated knockout of MEF2A and retransfection of an active version or permanently inactive mutant, respectively, validated our findings. We also identified the phosphatase calcineurin as the main upstream regulator of OT-induced MEF2A signaling. Further, MEF2A signaling dampens mitochondrial functioning in neurons, as MEF2A knockout cells show increased maximal cellular respiration, spare respiratory capacity, and total cellular ATP. In summary, we reveal a central role for OT-induced MEF2A activity as major regulator of cellular morphology as well as neuronal connectivity and mitochondrial functioning, with broad implications for a potential treatment of disorders based on morphological alterations or mitochondrial dysfunction.

Co-Stimulation of Oxytocin and Arginine-Vasopressin Receptors Affect Hypothalamic Neurospheroid Size

“…We detected a similar antiapoptotic response of the same cell line, H32 cells, to various concentrations of OXT and the selective agonist TGOT and confirmed the positive effect of AVP on cell viability [5]. Moreover, OXT and AVP exert similar effects on cellular morphology, i.e., neurite outgrowth or retraction, via their respective receptors [4,5,21].…”

“…Morphological alterations in neurons consist of neurite outgrowth or retraction. We [4,5] and others [64,65] previously showed that OXT induces morphological alterations in neurons and glia cells in a conventional 2D cell culture. With this study, we hope to prompt future studies that use 3D spheroid models to validate those 2D-derived findings.…”

“…Cellular proliferation aligns with other measurable cellular functions, such as increased metabolism of provided substrates (referred to as cellular viability), mitochondrial ATP production, and the formation or retraction of cellular processes (e.g., dendritogenesis [60]). We previously showed that those cellular functions are initiated and regulated by the activation of the OXTR in conventional 2D cell cultures [4,5].…”

“…The neuropeptide oxytocin (OXT) is not only involved in the classical neuroendocrine regulation of physiological processes such as milk letdown or labor but also of various social and emotional behaviors such as maternal behavior, anxiety, or social motivation [1][2][3]. We previously showed on a cellular level that OXT regulates neuronal morphology, ATP production, and calcium signaling [4,5], which are processes that regulate neuronal connectivity. Neuronal connectivity can be compromised in autism spectrum disorder (ASD), which might explain why some ASD patients benefit from intranasal OXT treatment [6].…”

MEF2A Is the Trigger of Resveratrol Exerting Protection on Vascular Endothelial Cell

“…MEF2A is a very important transcriptional regulatory factor, which is necessary for cell differentiation, cell proliferation, cell survival, morphogenesis and other life processes (16,17). The important role of MEF2A in neural differentiation, maturation and synapsis has been supported by a great deal of evidence (18)(19)(20), but its role in cardiovascular disease is still controversial. In 2003, Wang et al (21) revealed that the 21bp deletion in exon 11 of MEF2A was co-isolated from the patient with premature coronary heart disease in a general pedigree, and MEF2A has become the first identified autosomal dominant genetic variation in the risk of coronary heart disease (named ADCAD1).…”