title: Neurodevelopmental role for VGLUT2 in pyramidal neuron plasticity, dendritic refinement, and in spatial learning.
abstract: The level and integrity of glutamate transmission during critical periods of postnatal development plays an important role in the refinement of pyramidal neuron dendritic arbor, synaptic plasticity, and cognition. Presently, it is not clear how excitatory transmission via the two predominant isoforms of the vesicular glutamate transporter (VGLUT1 and VGLUT2) participate in this process. To assess a neurodevelopmental role for VGLUT2 in pyramidal neuron maturation, we generated recombinant VGLUT2 knock-out mice and inactivated VGLUT2 throughout development using Emx1-Cre(+/+) knock-in mice. We show that VGLUT2 deficiency in corticolimbic circuits results in reduced evoked glutamate transmission, release probability, and LTD at hippocampal CA3-CA1 synapses during a formative developmental period (postnatal days 11-14). In adults, we find a marked reduction in the amount of dendritic arbor across the span of the dendritic tree of CA1 pyramidal neurons and reduced long-term potentiation and levels of synaptic markers spinophilin and VGLUT1. Loss of dendritic arbor is accompanied by corresponding reductions in the number of dendritic spines, suggesting widespread alterations in synaptic connectivity. Conditional VGLUT2 knock-out mice exhibit increased open-field exploratory activity yet impaired spatial learning and memory, endophenotypes similar to those of NMDA receptor knock-down mice. Remarkably, the impairment in learning can be partially restored by selectively increasing NMDA receptor-mediated glutamate transmission in adult mice by prolonged treatment with d-serine and a d-amino acid oxidase inhibitor. Our data indicate that VGLUT2 expression is pivotal to the proper development of mature pyramidal neuronal architecture and plasticity, and that such glutamatergic deficiency leads to cognitive malfunction as observed in several neurodevelopmental psychiatric disorders.
authors.affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA.
authors.forename: Hongbo
authors.initials: H
authors.lastname: He
authors.forename: Amanda H
authors.initials: AH
authors.lastname: Mahnke
authors.forename: Sukhjeevan
authors.initials: S
authors.lastname: Doyle
authors.forename: Ni
authors.initials: N
authors.lastname: Fan
authors.forename: Chih-Chieh
authors.initials: CC
authors.lastname: Wang
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Hall
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Tang
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Inglis
authors.forename: Chu
authors.initials: C
authors.lastname: Chen
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Erickson
mesh_terms: D000818:Animals; D003712:Dendrites / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism; D006624:Hippocampus / Q000502:physiology; D007858:Learning / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology*; D017966:Pyramidal Cells / Q000502:physiology*; D013028:Space Perception / Q000502:physiology*; D013037:Spatial Behavior / Q000502:physiology; D013569:Synapses / Q000502:physiology; D050598:Vesicular Glutamate Transport Protein 1 / Q000235:genetics / Q000378:metabolism; D050599:Vesicular Glutamate Transport Protein 2 / Q000235:genetics / Q000378:metabolism*; D000099273:Neurabins
chemical_list: D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D050598:Vesicular Glutamate Transport Protein 1; D050599:Vesicular Glutamate Transport Protein 2; D000099273:Neurabins