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

Cell Rep. 2017 Aug 29;20(9):2156-2168. doi: 10.1016/j.celrep.2017.08.017.


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.

Keywords: cholecystokinin; hippocampus; interneuron; kainite; neto1; neto2; parvalbumin; somatostatin.

MeSH terms

  • Animals
  • Dendrites / metabolism*
  • Gamma Rhythm
  • Interneurons / metabolism*
  • Ion Channel Gating
  • Kainic Acid
  • LDL-Receptor Related Proteins / metabolism*
  • Membrane Proteins / metabolism*
  • Mice, Knockout
  • Mice, Mutant Strains
  • Mutation / genetics
  • Nerve Net / metabolism*
  • Neural Inhibition*
  • Promoter Regions, Genetic / genetics
  • Protein Subunits / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Kainic Acid / metabolism*
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Presynaptic / metabolism*


  • LDL-Receptor Related Proteins
  • Membrane Proteins
  • NETO2 protein, mouse
  • Neto1 protein, mouse
  • Protein Subunits
  • RNA, Messenger
  • Receptors, Kainic Acid
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Presynaptic
  • Kainic Acid