Journal
CELL REPORTS
Volume 20, Issue 9, Pages 2156-2168Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2017.08.017
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Funding
- NICHD
- NIGMS
- Northbridge Chair in Pediatric Research
- Tier 1 Canada Research Chair in Neurogenetics
- KI-NIH Doctoral Partnership Program
- Swedish Research Council [K2015-61X-22051-04-4]
- Swedish Brain Foundation [FO2015-0132]
- Ahlens Foundation [mC2/h14]
- Strategic Program in Neurosciences at the Karolinska Institute
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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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