Pentraxins coordinate excitatory synapse maturation and circuit integration of parvalbumin interneurons

Kenneth A. Pelkey, Elizabeth Barksdale, Michael T. Craig, Xiaoqing Yuan, Madhav Sukumaran, Geoffrey A. Vargish, Robert M. Mitchell, Megan S. Wyeth, Ronald S. Petralia, Ramesh Chittajallu, Rose Marie Karlsson, Heather A. Cameron, Yasunobu Murata, Matthew T. Colonnese, Paul F. Worley, Chris J. McBain

Research output: Contribution to journalArticlepeer-review

Abstract

Circuit computation requires precision in the timing, extent, and synchrony of principal cell (PC) firing thatis 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.

Original languageEnglish (US)
Pages (from-to)1257-1272
Number of pages16
JournalNeuron
Volume85
Issue number6
DOIs
StatePublished - Mar 18 2015

ASJC Scopus subject areas

  • Neuroscience(all)

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