ABSTRACT
Twenty types of GABAergic interneurons form intricate networks to fine-tune neural circuits in the brain. Parvalbumin-positive (PV+) and somatostatin-positive (SST+) interneurons, which are the two largest populations of neocortical interneurons, innervate the soma and/or proximal dendrites, and distal dendrites of pyramidal neurons, respectively. Using PV- and SST-specific knockout mouse models, we show that PV+ interneurons require FGFR2, which responds to FGF7, to drive PV+ inhibitory presynaptic maturation on perisomatic regions of Layer V pyramidal neurons. In contrast, SST+ interneurons rely on both FGFR1 and FGFR2, which respond to FGF10 or FGF22, to promote SST+ inhibitory presynaptic maturation on distal dendrites of pyramidal neurons in cortical Layer I. Mechanistically, FGF-FGFR signaling sustains VGAT protein levels in interneurons through PP2A and Akt pathways. Together, these findings demonstrate that distinct FGF ligand-receptor combinations regulate inhibitory presynaptic differentiation by PV+ and SST+ interneurons, contributing to the formation of compartment-specific synaptic patterns.
Footnotes
Author contributions
Conceptualization: Y.T.; Data curation: Z.W., S.Z., K.B., Y. Liu, Y. Luan, Z.H., Y. Li, Z.Q., X.H., X.D., W.L., H. L.; Formal analysis: Z.W., S.Z., K.B., Y. Liu, Y. Luan, Z.H., Y. Li, Z.Q., X.D., W.L., Y.T.; Funding acquisition: H.H., Y.T.; Investigation: Z.W., S.Z., K.B., Y. Liu, Y. Luan, Z.H., Y. Li, Z.Q., X.H., X.D., W.L., H.L., H.H., Y.T.; Methodology: Z.W., S.Z., K.B., Y. Liu, Y. Luan, Z.H., X.H., X.D., W.L., H.H., Y.T.; Project administration: Y.T.; Resources: Y.T.; Supervision: X.H., H.H., Y.T.; Validation: S.Z., K.B., Y. Liu, Y. Luan, Z.H., Y. Li, X.D., W.L.; Writing – original draft: Y.T.; Writing – review & editing: Z.W., S.Z., K.B., Y. Liu, Y. Luan, Z.H., Y. Li, Z.Q., X.H., X.D., W.L., H. L., H.H., Y.T.
Funding
This work was supported by the Ministry of Science and Technology of the People's Republic of China (2021ZD0201700 to Y.T.) and by the National Natural Science Foundation of China (32170956, 31371075 and 31871030 to Y.T.).
Data and resource availability
All data generated or analyzed during this study are included in this article and its supplementary information.
The people behind the papers
This article has an associated ‘The people behind the papers’ interview with some of the authors.
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