Cell Reports (Aug 2017)

Neto Auxiliary Subunits Regulate Interneuron Somatodendritic and Presynaptic Kainate Receptors to Control Network Inhibition

  • Megan S. Wyeth,
  • Kenneth A. Pelkey,
  • Xiaoqing Yuan,
  • Geoffrey Vargish,
  • April D. Johnston,
  • Steven Hunt,
  • Calvin Fang,
  • Daniel Abebe,
  • Vivek Mahadevan,
  • André Fisahn,
  • Michael W. Salter,
  • Roderick R. McInnes,
  • Ramesh Chittajallu,
  • Chris J. McBain

DOI
https://doi.org/10.1016/j.celrep.2017.08.017
Journal volume & issue
Vol. 20, no. 9
pp. 2156 – 2168

Abstract

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Although Netos are considered auxiliary subunits critical for kainate receptor (KAR) function, direct evidence for their regulation of native KARs is limited. Because Neto KAR regulation is GluK subunit/Neto isoform specific, such regulation must be determined in cell-type-specific contexts. We demonstrate Neto1/2 expression in somatostatin (SOM)-, cholecystokinin/cannabinoid receptor 1 (CCK/CB1)-, and parvalbumin (PV)-containing interneurons. KAR-mediated excitation of these interneurons is contingent upon Neto1 because kainate yields comparable effects in Neto2 knockouts and wild-types but fails to excite interneurons or recruit inhibition in Neto1 knockouts. In contrast, presynaptic KARs in CCK/CB1 interneurons are dually regulated by both Neto1 and Neto2. Neto association promotes tonic presynaptic KAR activation, dampening CCK/CB1 interneuron output, and loss of this brake in Neto mutants profoundly increases CCK/CB1 interneuron-mediated inhibition. Our results confirm that Neto1 regulates endogenous somatodendritic KARs in diverse interneurons and demonstrate Neto regulation of presynaptic KARs in mature inhibitory presynaptic terminals.

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