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
Affiliations
Megan S. Wyeth
Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, 35 Lincoln Drive, MSC 3715, Bethesda, MD 20892, USA
Kenneth A. Pelkey
Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, 35 Lincoln Drive, MSC 3715, Bethesda, MD 20892, USA
Xiaoqing Yuan
Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, 35 Lincoln Drive, MSC 3715, Bethesda, MD 20892, USA
Geoffrey Vargish
Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, 35 Lincoln Drive, MSC 3715, Bethesda, MD 20892, USA
April D. Johnston
Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, 35 Lincoln Drive, MSC 3715, Bethesda, MD 20892, USA
Steven Hunt
Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, 35 Lincoln Drive, MSC 3715, Bethesda, MD 20892, USA
Calvin Fang
Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, 35 Lincoln Drive, MSC 3715, Bethesda, MD 20892, USA
Daniel Abebe
Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, 35 Lincoln Drive, MSC 3715, Bethesda, MD 20892, USA
Vivek Mahadevan
Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, 35 Lincoln Drive, MSC 3715, Bethesda, MD 20892, USA
André Fisahn
Neuronal Oscillations Laboratory, Division for Neurogeriatrics, Center for Alzheimer Research, Department NVS, Karolinska Institutet, 17177 Stockholm, Sweden
Michael W. Salter
Program in Neurosciences & Mental Health, Hospital for Sick Children, and Department of Physiology, University of Toronto, 555 University Avenue, Toronto, ON M5G 1X8, Canada
Roderick R. McInnes
Lady Davis Research Institute, Jewish General Hospital and Departments of Human Genetics and Biochemistry, McGill University, Montreal, QC H3T 1E2, Canada
Ramesh Chittajallu
Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, 35 Lincoln Drive, MSC 3715, Bethesda, MD 20892, USA
Chris J. McBain
Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, 35 Lincoln Drive, MSC 3715, Bethesda, MD 20892, USA
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.
