Glycine receptors alpha 2 tune cortical network formation

Abstract

The development of the brain ranges from early embryogenesis to adolescence in humans. Initially, proliferation and migration of neurons allow the increase in number and correct placement of the neurons in the brain. These neurons will be part of the inhibitory and excitatory circuits of the brain arising after cell differentiation and formation of the synapses. Specifically, intrinsic cues (genetic imprinting) and extrinsic cues (extracellular signals present in the environment) modulate the processes that lead to the proper formation of the brain. Neurotransmitters and their receptors belong to the extrinsic cues influencing all developmental stages. GlyRs are complexes of transmembrane receptors composed by five subunits surrounding a central pore. These five subunits are divided in four different alpha subunits and one beta subunit. The arrangement of these subunits forms either an alpha-homomeric or a heteromeric receptor in which beta subunit are present. GlyRs are activated by glycine and other ligands such as taurine, alanine and GABA at high concentrations. These activators bind the extracellular domain of the GlyRs promoting its central pore opening and inducing the efflux/influx of chloride and bicarbonates. In facts, GlyRs flux of ions is dependent on the electrochemical gradient of the ions across the membranes. Recent studies showed that GlyRs are expressed in different areas of the brain displaying a developmental shift of its subunits. Interestingly, the alpha 2 subunit has been shown to be important during early embryonic development for both projection neurons and interneurons in the brain. Alpha 2 containing GlyRs has been shown to affect migration of interneurons reaching the cerebral cortex and that also projection neurons express GlyRs in embryos and adult mice. However, the information about their role in other stage of development and their functions is yet unknown. Therefore, we aim to investigate the role of GlyR during early stages of the embryonic brain development and postnatal ages in the modulation of the formation of a functional mature brain and circuitry. The first chapter of this thesis introduces the main topic of the research including the aims of the work. The following chapters two to five describe the experimental results. In the second chapter of this thesis we elucidate the role of GlyRs in neurogenesis of projection neurons. This study demonstrates that GlyRs containing alpha 2 are important in the modulation of the rate of cell neurogenesis inducing microcephaly when the receptor is disrupted. Chapter three displays a general introduction about GlyRs in the postnatal cerebral cortex identifying their expression throughout different experimental approaches. Here, we show that GlyRs are expressed by interneurons and projection neurons of the cortex and they are present only at extra-synaptic level. The last two parts of the results (Chapters four and five) display early postnatal morphological and cellular defects in both cerebral cortex and hippocampus. These morphological and cellular defects contribute to the disruption in the circuitry and connectivity of these areas. In particular, genetic disruption of alpha 2 containing GlyRs cause and imbalance of the excitatory/inhibitory cortical circuitry leading to a higher susceptibility to induced epileptic seizures. Lastly, chapter six contains the conclusions and perspectives for future research.