Euchromatin histone methyltransferase 1 regulates cortical neuronal network development.

Jessica Classen,Lisa Epping,Paul Tiesinga,Monica Frega,Dirk Schubert,Hans van Bokhoven,Marco Benevento,Nael Nadif Kasri,Marijn Bart Martens,Elske Bijvank

doi:10.1038/srep35756

Abstract

Heterozygous mutations or deletions in the human Euchromatin histone methyltransferase 1 (EHMT1) gene cause Kleefstra syndrome, a neurodevelopmental disorder that is characterized by autistic-like features and severe intellectual disability (ID). Neurodevelopmental disorders including ID and autism may be related to deficits in activity-dependent wiring of brain circuits during development. Although Kleefstra syndrome has been associated with dendritic and synaptic defects in mice and Drosophila, little is known about the role of EHMT1 in the development of cortical neuronal networks. Here we used micro-electrode arrays and whole-cell patch-clamp recordings to investigate the impact of EHMT1 deficiency at the network and single cell level. We show that EHMT1 deficiency impaired neural network activity during the transition from uncorrelated background action potential firing to synchronized network bursting. Spontaneous bursting and excitatory synaptic currents were transiently reduced, whereas miniature excitatory postsynaptic currents were not affected. Finally, we show that loss of function of EHMT1 ultimately resulted in less regular network bursting patterns later in development. These data suggest that the developmental impairments observed in EHMT1-deficient networks may result in a temporal misalignment between activity-dependent developmental processes thereby contributing to the pathophysiology of Kleefstra syndrome.

Highlights

9 (H3K9me2), a post-translational modification associated with repression of gene transcription[17]
We recorded a modest reduction of 18% in the mean firing rate (MFR) for the EHMT1-deficient networks compared to the control networks during the early developmental stage of day in vitro (DIV) 13 (p = 0.037, Fig. 1D)
We demonstrated that the emergence of spontaneous network activity was delayed in cortical neurons deficient in EHMT1 compared to control conditions

Summary

Introduction

9 (H3K9me2), a post-translational modification associated with repression of gene transcription[17]. Loss of EHMT1 prevented synaptic scaling up in vitro and in vivo These results point toward a synaptic deficit, it is still unknown what the impact is of EHMT1 deficiency during critical periods of early postnatal development at the level of cortical network activity. Using MEA and patch-clamp recordings, we found that EHMT1 deficiency impaired spontaneous network activity and lowered firing rates during early development, whereas basal, action potential-independent excitatory synaptic transmission was unaffected. We found that later in development EHMT1 deficiency led to network activity with increased irregularity in the timing of network bursts. These data indicate that EHMT1 is required for proper cortical neural circuitry development

Methods

Results

Conclusion