Autonomous and non-autonomous roles for ephrin-B in interneuron migration

Asghar Talebian,Rachel Britton,Simon Ammanuel,Asim Bepari,Francis Sprouse,Shari G Birnbaum,Gábor Szabó,Nobuaki Tamamaki,Jay Gibson,Mark Henkemeyer

doi:10.1016/j.ydbio.2017.09.024

Abstract

While several studies indicate the importance of ephrin-B/EphB bidirectional signaling in excitatory neurons, potential roles for these molecules in inhibitory neurons are largely unknown. We identify here an autonomous receptor-like role for ephrin-B reverse signaling in the tangential migration of interneurons into the neocortex using ephrin-B (EfnB1/B2/B3) conditional triple mutant (TMlz) mice and a forebrain inhibitory neuron specific Cre driver. Inhibitory neuron deletion of the three EfnB genes leads to reduced interneuron migration, abnormal cortical excitability, and lethal audiogenic seizures. Truncated and intracellular point mutations confirm the importance of ephrin-B reverse signaling in interneuron migration and cortical excitability. A non-autonomous ligand-like role was also identified for ephrin-B2 that is expressed in neocortical radial glial cells and required for proper tangential migration of GAD65-positive interneurons. Our studies thus define both receptor-like and ligand-like roles for the ephrin-B molecules in controlling the migration of interneurons as they populate the neocortex and help establish excitatory/inhibitory (E/I) homeostasis.

Highlights

Normal functioning of the cerebral cortex depends on the precise synaptic balance of excitatory neurons and inhibitory neurons, which together control the flow of information and synchronization of neural networks necessary for higher order brain activity
Growing evidence suggests interneuron dysfunction can affect the delicate balance between excitation and inhibition, leading to hyperexcitability and many psychiatric disorders including those associated with seizure activity such as epilepsy, autism spectrum disorders, fragile X syndrome, other intellectual disabilities, as well as schizophrenia, mood and anxiety disorders, sleep disorders, and drug addiction (Levy and Degnan, 2013; Lewis et al, 2005; Marin, 2012; Rossignol, 2011)
While the expression of ephrin-B and EphB molecules is well documented in excitatory neurons, there is scant information concerning their expression within inhibitory neurons

Summary

Introduction

Normal functioning of the cerebral cortex depends on the precise synaptic balance of excitatory neurons and inhibitory neurons, which together control the flow of information and synchronization of neural networks necessary for higher order brain activity. Growing evidence suggests interneuron dysfunction can affect the delicate balance between excitation and inhibition, leading to hyperexcitability and many psychiatric disorders including those associated with seizure activity such as epilepsy, autism spectrum disorders, fragile X syndrome, other intellectual disabilities, as well as schizophrenia, mood and anxiety disorders, sleep disorders, and drug addiction (Levy and Degnan, 2013; Lewis et al, 2005; Marin, 2012; Rossignol, 2011). While these conditions are distinct from each other, they typically have in common disruptions in the number/distribution/function of forebrain interneurons. This simplified view of psychiatric disorders is complicated by the fact that cortical interneurons constitute one of the most diverse groups of cells in the central nervous system as at least 20 different subtypes can be identified based on their morphological, electrophysiological, and neurochemical characteristics (Markram et al, 2004; Monyer and Markram, 2004)

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