title: Pentraxins coordinate excitatory synapse maturation and circuit integration of parvalbumin interneurons.
abstract: Circuit computation requires precision in the timing, extent, and synchrony of principal cell (PC) firing that is largely enforced by parvalbumin-expressing, fast-spiking interneurons (PVFSIs). To reliably coordinate network activity, PVFSIs exhibit specialized synaptic and membrane properties that promote efficient afferent recruitment such as expression of high-conductance, rapidly gating, GluA4-containing AMPA receptors (AMPARs). We found that PVFSIs upregulate GluA4 during the second postnatal week coincident with increases in the AMPAR clustering proteins NPTX2 and NPTXR. Moreover, GluA4 is dramatically reduced in NPTX2(-/-)/NPTXR(-/-) mice with consequent reductions in PVFSI AMPAR function. Early postnatal NPTX2(-/-)/NPTXR(-/-) mice exhibit delayed circuit maturation with a prolonged critical period permissive for giant depolarizing potentials. Juvenile NPTX2(-/-)/NPTXR(-/-) mice display reduced feedforward inhibition yielding a circuit deficient in rhythmogenesis and prone to epileptiform discharges. Our findings demonstrate an essential role for NPTXs in controlling network dynamics highlighting potential therapeutic targets for disorders with inhibition/excitation imbalances such as schizophrenia.
authors.affiliation: Program in Developmental Neuroscience, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD 20892, USA. Electronic address: pelkeyk2@mail.nih.gov.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Pelkey
authors.affiliation: Program in Developmental Neuroscience, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD 20892, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Barksdale
authors.affiliation: Program in Developmental Neuroscience, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD 20892, USA.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Craig
authors.affiliation: Program in Developmental Neuroscience, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD 20892, USA.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Program in Developmental Neuroscience, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD 20892, USA.
authors.forename: Madhav
authors.initials: M
authors.lastname: Sukumaran
authors.affiliation: Program in Developmental Neuroscience, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD 20892, USA.
authors.forename: Geoffrey A
authors.initials: GA
authors.lastname: Vargish
authors.affiliation: Program in Developmental Neuroscience, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD 20892, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Mitchell
authors.affiliation: Program in Developmental Neuroscience, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD 20892, USA.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Wyeth
authors.affiliation: Advanced Imaging Core National Institute of Deafness and Other Communication Disorders, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD 20892, USA.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Petralia
authors.affiliation: Program in Developmental Neuroscience, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD 20892, USA.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Chittajallu
authors.affiliation: Section on Neuroplasticity, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD 20892, USA.
authors.forename: Rose-Marie
authors.initials: RM
authors.lastname: Karlsson
authors.affiliation: Section on Neuroplasticity, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD 20892, USA.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Cameron
authors.affiliation: Department of Pharmacology and Physiology, and Institute for Neuroscience, George Washington University, 2300 Eye Street, Washington, DC 20037, USA.
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Murata
authors.affiliation: Department of Pharmacology and Physiology, and Institute for Neuroscience, George Washington University, 2300 Eye Street, Washington, DC 20037, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Colonnese
authors.affiliation: The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, 725 N. Wolfe Street, Baltimore, MD 21205, USA.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Worley
authors.affiliation: Program in Developmental Neuroscience, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, National Institutes of Health, 35 Lincoln Drive, Bethesda, MD 20892, USA.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: McBain
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D002097:C-Reactive Protein / Q000172:deficiency / Q000378:metabolism*; D004195:Disease Models, Animal; D007395:Interneurons / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009415:Nerve Net / Q000254:growth & development*; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D010320:Parvalbumins / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D000099153:Pentraxins
chemical_list: D002097:C-Reactive Protein; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; D000099153:Pentraxins