Interneuron odyssey: molecular mechanisms of tangential migration

Abstract

Cortical GABAergic interneurons are critical components of neural networks. They provide local and long-range inhibition and help coordinate network activities involved in various brain functions, including signal processing, learning, memory and adaptative responses. Disruption of cortical GABAergic interneuron migration thus induces profound deficits in neural network organization and function, and results in a variety of neurodevelopmental and neuropsychiatric disorders including epilepsy, intellectual disability, autism spectrum disorders and schizophrenia. It is thus of paramount importance to elucidate the specific mechanisms that govern the migration of interneurons to clarify some of the underlying disease mechanisms. GABAergic interneurons destined to populate the cortex arise from multipotent ventral progenitor cells located in the ganglionic eminences and pre-optic area. Post-mitotic interneurons exit their place of origin in the ventral forebrain and migrate dorsally using defined migratory streams to reach the cortical plate, which they enter through radial migration before dispersing to settle in their final laminar allocation. While migrating, cortical interneurons constantly change their morphology through the dynamic remodeling of actomyosin and microtubule cytoskeleton as they detect and integrate extracellular guidance cues generated by neuronal and non-neuronal sources distributed along their migratory routes. These processes ensure proper distribution of GABAergic interneurons across cortical areas and lamina, supporting the development of adequate network connectivity and brain function. This short review summarizes current knowledge on the cellular and molecular mechanisms controlling cortical GABAergic interneuron migration, with a focus on tangential migration, and addresses potential avenues for cell-based interneuron progenitor transplants in the treatment of neurodevelopmental disorders and epilepsy.

Morphogenetic theory of mental and cognitive disorders: the role of neurotrophic and guidance molecules

“…The urokinase plasminogen activator (uPA)/urokinase plasminogen activator receptor (uPAR) system plays a significant role in the migration of interneurons (INs). This system is involved in various processes, including extracellular matrix degradation, cell migration, growth cone guidance, and angiogenesis (Semina et al, 2016(Semina et al, , 2017Toudji et al, 2023).…”

“…As INs mature and reach their designated cortical regions, their tangential migration halts, and a switch from tangential to radial migration occurs. Loss of sensitivity to CXCL12 coupled with increased sensitivity to GABA (Bortone and Polleux, 2009), along with activation of the NRG3/ERBB4 signaling axis are considered to be the main mechanisms launching tangential-to-radial switch (Llorca and Deogracias, 2022;Toudji et al, 2023). Additionally, microvessels and radial glia have been described as guiding tracks for the radially migrating INs in some studies (Yokota et al, 2007;Léger et al, 2020).…”