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

Magdalena Meyer,Julia Winter,Kerstin Kuffner,Benjamin Jurek,Christian H Wetzel,Inga D Neumann

doi:10.3390/ijms21062200

Magdalena Meyer, Julia Winter + Show 4 more

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https://doi.org/10.3390/ijms21062200

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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.

Highlights

Oxytocin (OT) is a neuropeptide profoundly implicated in the regulation of various socio-emotional behaviors and physiological responses [1,2]
In order to study the impact of myocyte enhancer factor 2A (MEF2A) in OT-induced effects on cellular morphology, we used cell lines that lacked, endogenously expressed, or were transfected with MEF2A
The hypothalamic rat cell line H32 was subjected to CRISPR-Cas-mediated knockout of MEF2A (H32∆MEF2A), and retransfected with either wild-type rat MEF2A (H32∆MEF2AMEF2A) or the mutant version H32∆MEF2AMEF2A[S408D], in which site-directed mutagenesis at S408D mimicked a permanently phosphorylated, and transcriptionally inactive transcription factor

Summary

Introduction

Oxytocin (OT) is a neuropeptide profoundly implicated in the regulation of various socio-emotional behaviors and physiological responses [1,2]. Dysregulated plasma or salivary levels of OT have been associated with symptoms of autism spectrum disorder (ASD) [3,4], depression [5], and anxiety [6], and its intranasal application has been described to relieve some of those symptoms [7]. The pro-social effects of OT, as described by multiple groups [8,9,10,11,12], promise to relieve core deficits in social behavior in ASD patients. ASD has been associated with neuronal, morphological and mitochondrial dysfunctions [13,14,15,16,17]. One common factor between ASD, its underlying disturbed cellular functions and the oxytocinergic system, is the transcription factor myocyte enhancer factor (MEF) 2. We provide evidence for the role of MEF2 as the central node in the regulation of those conditions

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