title: Excitability governs neural development in a hippocampal region-specific manner.
abstract: Neuronal activity, including intrinsic neuronal excitability and synaptic transmission, is an essential regulator of brain development. However, how the intrinsic neuronal excitability of distinct neurons affects their integration into developing circuits remains poorly understood. To investigate this problem, we created several transgenic mouse lines in which intrinsic excitability is suppressed, and the neurons are effectively silenced, in different excitatory neuronal populations of the hippocampus. Here we show that CA1, CA3 and dentate gyrus neurons each have unique responses to suppressed intrinsic excitability during circuit development. Silenced CA1 pyramidal neurons show altered spine development and synaptic transmission after postnatal day 15. By contrast, silenced CA3 pyramidal neurons seem to develop normally. Silenced dentate granule cells develop with input-specific decreases in spine density starting at postnatal day 11; however, a compensatory enhancement of neurotransmitter release onto these neurons maintains normal levels of synaptic activity. The synaptic changes in CA1 and dentate granule neurons are not observed when synaptic transmission, rather than intrinsic excitability, is blocked in these neurons. Thus, our results demonstrate a crucial role for intrinsic neuronal excitability in establishing hippocampal connectivity and reveal that neuronal development in each hippocampal region is distinctly regulated by excitability.
authors.affiliation: Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA Molecular & Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Johnson-Venkatesh
authors.affiliation: Molecular & Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Mudassar N
authors.initials: MN
authors.lastname: Khan
authors.affiliation: Molecular & Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Geoffrey G
authors.initials: GG
authors.lastname: Murphy
authors.affiliation: Molecular & Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109, USA masutton@umich.edu hisashi.umemori@childrens.harvard.edu.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Sutton
authors.affiliation: Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA Molecular & Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USA masutton@umich.edu hisashi.umemori@childrens.harvard.edu.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Umemori
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000166:cytology; D056654:CA3 Region, Hippocampal / Q000166:cytology; D002452:Cell Count; D003712:Dendrites / Q000648:ultrastructure; D018891:Dentate Gyrus / Q000166:cytology; D006624:Hippocampus / Q000196:embryology*; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D055495:Neurogenesis / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D017966:Pyramidal Cells / Q000166:cytology / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*
keywords: Dendritic spines; Hippocampus; Neural activity; Synaptogenesis; Transgenic mice