Multifunctional requirements for ERK1/2 signaling in the development of ganglionic eminence derived glia and cortical inhibitory neurons

• DOI: 10.7554/elife.88313
• Publication Date: 2023-07-21T09:53:56Z
• Authors: Sara J. Knowles; Michael C. Holter; Guohui Li; George R. Bjorklund; Katherina P. Rees; Johan S. Martinez...; Kenji J. Nishimura; Ariana E. Afshari; Noah Fry; April M Stafford; Daniel Vogt; Marco Mangone; Trent Anderson; Jason M. Newbern
• Keywords: 0303 health sciences; 03 medical and health sciences

Abstract The RAS/RAF/MEK/ERK1/2 intracellular signaling pathway is activated by numerous cues during brain development and dysregulated in neurodevelopmental syndromes, particularly the RASopathies and certain forms of autism. Cortical excitatory/inhibitory imbalance is thought to be critical in the neuropathogenesis of these conditions. However, the developmental functions of ERK1/2 signaling in cortical inhibitory neurons (CINs) and other medial ganglionic eminence (MGE)-derived non-neuronal cells are poorly understood. Here, we genetically modulated ERK1/2 signaling in mouse MGE neural progenitors or GABAergic neurons in vivo. We find that MEK-ERK1/2 signaling is essential for regulating MGE-derived oligodendrocyte number in the anterior commissure. While Erk1/2 inactivation does not alter CIN number, we discovered a significant and persistent reduction in somatostatin, but not parvalbumin, expression in a subset of CINs. ERK1/2 signaling is also necessary for chemogenetic activity-dependent FOSB expression in CINs in vivo. Interestingly, one week of chronic chemogenetic stimulation in juvenile or adult animals partially rescues the decrease in somatostatin expression in Erk1/2 mutant CINs. Our data demonstrate ERK1/2 signaling is required for the establishment of MGE-derived glia, whereas in CINs, ERK1/2 drives activity dependent-responses and the expression of somatostatin in a subset of neurons.