Immature Dentate Granule Cells Require Ntrk2/Trkb for the Formation of Functional Hippocampal Circuitry
Sylvia Badurek,
Marilena Griguoli,
Aman Asif-Malik,
Barbara Zonta,
Fei Guo,
Silvia Middei,
Laura Lagostena,
Maria Teresa Jurado-Parras,
Thomas H. Gillingwater,
Agnès Gruart,
José María Delgado-García,
Enrico Cherubini,
Liliana Minichiello
Affiliations
Sylvia Badurek
Centre for Neuroregeneration, University of Edinburgh, Edinburgh, United Kingdom; European Molecular Biology Laboratory, Mouse Biology Unit, Monterotondo, Rome, Italy
Marilena Griguoli
European Brain Research Institute, Rome, Italy
Aman Asif-Malik
Department of Pharmacology, University of Oxford, Oxford, United Kingdom
Barbara Zonta
Department of Pharmacology, University of Oxford, Oxford, United Kingdom
Fei Guo
Department of Pharmacology, University of Oxford, Oxford, United Kingdom
Silvia Middei
Institute of Cell Biology and Neurobiology, National Research Council, Monterotondo, Rome, Italy
Laura Lagostena
International School for Advanced Studies (SISSA), Department of Neuroscience, Trieste, Italy
Maria Teresa Jurado-Parras
Division of Neurosciences, University Pablo de Olavide, Seville, Spain
Thomas H. Gillingwater
Biomedical Sciences, Edinburgh Medical School, University of Edinburgh, Edinburgh, United Kingdom
Agnès Gruart
Division of Neurosciences, University Pablo de Olavide, Seville, Spain
José María Delgado-García
Division of Neurosciences, University Pablo de Olavide, Seville, Spain
Enrico Cherubini
European Brain Research Institute, Rome, Italy; International School for Advanced Studies (SISSA), Department of Neuroscience, Trieste, Italy
Liliana Minichiello
Department of Pharmacology, University of Oxford, Oxford, United Kingdom; Centre for Neuroregeneration, University of Edinburgh, Edinburgh, United Kingdom; European Molecular Biology Laboratory, Mouse Biology Unit, Monterotondo, Rome, Italy; Corresponding author
Summary: Early in brain development, impaired neuronal signaling during time-sensitive windows triggers the onset of neurodevelopmental disorders. GABA, through its depolarizing and excitatory actions, drives early developmental events including neuronal circuit formation and refinement. BDNF/TrkB signaling cooperates with GABA actions. How these developmental processes influence the formation of neural circuits and affect adult brain function is unknown. Here, we show that early deletion of Ntrk2/Trkb from immature mouse hippocampal dentate granule cells (DGCs) affects the integration and maturation of newly formed DGCs in the hippocampal circuitry and drives a premature shift from depolarizing to hyperpolarizing GABAergic actions in the target of DGCs, the CA3 principal cells of the hippocampus, by reducing the expression of the cation-chloride importer Nkcc1. These changes lead to the disruption of early synchronized neuronal activity at the network level and impaired morphological maturation of CA3 pyramidal neurons, ultimately contributing to altered adult hippocampal synaptic plasticity and cognitive processes.
