The transcription factor NeuroD2 coordinates synaptic innervation and cell intrinsic properties to control excitability of cortical pyramidal neurons

Abstract

Key pointsr Synaptic excitation and inhibition must be properly balanced in individual neurons and neuronal networks to allow proper brain function.r Disrupting this balance may lead to autism spectral disorders and epilepsy. r We show the basic helix-loop-helix transcription factor NeuroD2 promotes inhibitory synaptic drive but also decreases cell-intrinsic neuronal excitability of cortical pyramidal neurons both in vitro and in vivo.r We identify two genes potentially downstream of NeuroD2-mediated transcription that regulate these parameters: gastrin-releasing peptide and the small conductance, calcium-activated potassium channel, SK2.r Our results reveal an important function for NeuroD2 in balancing synaptic neurotransmission and intrinsic excitability.r Our results offer insight into how synaptic innervation and intrinsic excitability are coordinated during cortical development.Abstract Synaptic excitation and inhibition must be properly balanced in individual neurons and neuronal networks for proper brain function. Disruption of this balance during development may lead to autism spectral disorders and epilepsy. Synaptic excitation is counterbalanced by synaptic inhibition but also by attenuation of cell-intrinsic neuronal excitability. To maintain proper excitation levels during development, neurons must sense activity over time and regulate the expression of genes that control these parameters. While this is a critical process, little is known about the transcription factors involved in coordinating gene expression to control excitatory/inhibitory synaptic balance. We show here that the basic helix-loop-helix transcription factor NeuroD2 promotes inhibitory synaptic drive but also decreases cell-intrinsic neuronal excitability of cortical pyramidal neurons both in vitro and in vivo as shown by ex vivo analysis of a NeuroD2 knockout mouse. Using microarray analysis and comparing wild-type and NeuroD2 knockout cortical networks, we identified two potential gene targets of NeuroD2 that contribute to these processes: gastrin-releasing peptide (GRP) and the small conductance, calcium-activated potassium channel, SK2. We found that the GRP receptor antagonist RC-3059 and the SK2 specific blocker apamin partially reversed the effects of increased NeuroD2 expression on inhibitory synaptic drive and action potential repolarization, respectively. Our results reveal an important

NEUROD2 RegulatesStim1Expression and Store-Operated Calcium Entry in Cortical Neurons

“…In agreement with previous reports focused on Neurod2 mutant phenotypes (Ince-Dunn et al, 2006; Wilke et al, 2012; Chen et al, 2016), our analysis revealed dendrite development and synapse organization as the most enriched functional categories (Fig. 1 F ).…”

“…Since Neurod2 is highly expressed in the cerebral cortex during embryonic and postnatal development (Lin et al, 2004; Ince-Dunn et al, 2006) and Neurod2 knockout mice display defects in neocortical and hippocampal dendritogenesis and synaptogenesis (Ince-Dunn et al, 2006; Wilke et al, 2012; Chen et al, 2016), we decided to identify its genome-wide targets within the cortex during this developmental time period. We dissected cerebral cortex tissue from P0 wild-type mice and conducted ChIP-Seq analysis using three separate NEUROD2 antibodies (Fig.…”

Knowledge-Guided Bioinformatics Model for Identifying Autism Spectrum Disorder Diagnostic MicroRNA Biomarkers

“…RORs have also been demonstrated to play key roles in several neural disorders, including autism37. At the MF level, if we consider TF activity as an example, evidence indicates that several TFs, such as th1 and th2, are dysregulated in autism groups3839. All the results supported the functional importance of the identified autism miRNA biomarkers.…”

Disruption of the transcription factorNEUROD2causes an autism syndrome via cell-autonomous defects in cortical projection neurons

“…CPNs receive reduced mEPSC and mIPSC frequencies but normal amplitudes 20 , we conclude that defects in inputs received by L5 PNs differ from defects in inputs received by L2/3 CPNs in NeuroD2 KO mice.…”

“…NeuroD2 deficient mice have a disorganized barrel cortex although production of layer 4 (L4) CPNs is normal 12 . Electrophysiologically, L2/3 CPNs show increased intrinsic excitability in somatosensory cortex 20 . In spite of this information, the impact of NeuroD2 deletion on cortical development has not been investigated.…”