Glycine receptors control the generation of projection neurons in the developing cerebral cortex

Abstract

The development of the cerebral cortex requires coordinated regulation of proliferation, specification, migration and differentiation of cortical progenitors into functionally integrated neurons. The completion of the neurogenic program requires a dynamic interplay between cell intrinsic regulators and extrinsic cues, such as growth factor and neurotransmitters. We previously demonstrated a role for extrasynaptic glycine receptors (GlyRs) containing the a2 subunit in cerebral cortical neurogenesis, revealing that endogenous GlyR activation promotes interneuron migration in the developing cortical wall. The proliferative compartment of the cortex comprises apical progenitors that give birth to neurons directly or indirectly through the generation of basal progenitors, which serve as amplification step to generate the bulk of cortical neurons. The present work shows that genetic inactivation of Glra2, the gene coding the a2 subunit of GlyRs, disrupts dorsal cortical progenitor homeostasis with an impaired capability of apical progenitors to generate basal progenitors. This defect results in an overall reduction of projection neurons that settle in upper or deep layers of the cerebral cortex. Overall, the depletion of cortical neurons observed in Glra2-knockout embryos leads to moderate microcephaly in newborn Glra2-knockout mice. Taken together, our findings support a contribution of GlyR a2 to early processes in cerebral cortical neurogenesis that are required later for the proper development of cortical circuits. The cerebral cortex develops from the forebrain and contains different classes of neurons distributed within layers that are regionally organized into sensory, motor and association areas. Cerebral cortex layering arises inside-out as progenitors give birth to successive waves of pyramidal projection neurons in the dorsal telencephalon 1 and GABAergic interneurons in the ventral forebrain.2 Projection neurons migrate radially to settle in appropriate layers of the cortical plate (CP) from where they grow axonal projections towards cortical or subcortical targets. Interneurons migrate from the ganglionic eminences along multiple tangential paths to integrate local cortical networks. More generally, the development of the cortex progresses through successive steps including proliferation, specification, migration and neuronal differentiation. Disrupting the completion of one or several of these cellular events may lead to severe cortical malformations underlying neurological disorders characterized by learning and intellectual disability or epilepsy.

Evolutionary origin of Tbr2‐expressing precursor cells and the subventricular zone in the developing cortex

“…The database link for eomesodermin homolog isoform 1 in Mus musculus . The pattern of immunostaining we obtained matched that from previous publications describing immunostaining in mouse telencephalon (Avila et al, 2014; Toyo-oka et al, 2014), the immunostaining we obtained with the rabbit polyclonal in this study, and the immunostaining we had obtained from other Tbr2 antibodies in previous publications (Noctor et al, 2008; Cunningham et al, 2013b). …”

Ethanol effects on glycinergic transmission: From molecular pharmacology to behavior responses

“…During early development, membrane depolarization induced by the activation of α2 containing GlyRs leads to cortical tangential migration and promotes interneuron migration in the cortical wall [42–44,48]. In the case of cultured spinal neurons, it was determined that the expression of α1 and α2 subunits change significantly during development, which is directly related to changes in the pharmacological properties of GlyRs [49].…”

α2‐glycine receptors modulate adult hippocampal neurogenesis and spatial memory

“…Targeted knockout of the a2 subunit at the onset of development reduces the number, as well as the differentiation, of spinal interneurons, thus affecting the formation of rhythm-generating networks (McDearmid et al, 2006). Moreover, a2-GlyRs were found to control the proliferation of progenitor cells during corticogenesis (Avila et al, 2014) and to promote the migration of cortical interneurons (Avila et al, 2013). Although GlyR a2 is expressed at low levels in the adult brain, it is detectable in the cerebellum (Garcia-Alcocer et al, 2008), retina (Jusuf et al, 2005), and some regions of the forebrain (Jonsson et al, 2012), including the hippocampus (Aroeira et al, 2011).…”