Abstract
Polycystins (PKD2, PKD2L1, and PKD2L2) are members of the transient receptor potential family, which form ciliary ion channels. Most notably, PKD2 dysregulation in the kidney nephron cilia is associated with polycystic kidney disease, but the function of PKD2L1 in neurons is undefined. In this report, we develop animal models to track the expression and subcellular localization of PKD2L1 in the brain. We discover that PKD2L1 localizes and functions as a Ca2+ channel in the primary cilia of hippocampal neurons that apically radiate from the soma. Loss of PKD2L1 expression ablates primary ciliary maturation and attenuates neuronal high-frequency excitability, which precipitates seizure susceptibility and autism spectrum disorder–like behavior in mice. The disproportionate impairment of interneuron excitability suggests that circuit disinhibition underlies the neurophenotypic features of these mice. Our results identify PKD2L1 channels as regulators of hippocampal excitability and the neuronal primary cilia as organelle mediators of brain electrical signaling.
| Original language | English (US) |
|---|---|
| Article number | e2219686120 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 120 |
| Issue number | 22 |
| DOIs | |
| State | Published - May 30 2023 |
Funding
We acknowledge Jennifer Kearney PhD and Nicole Hawkins PhD of Northwestern University’s Department of Pharmacology for their assistance collecting in vivo EEG monitoring data. We are thankful to Trung Le Tran, Toshihiro Nomura PhD, John Armstrong PhD, and Max Anstotz PhD Northwestern University Interdepartmental Neuroscience Program (NUIN) and Northwestern University Department of Neuroscience, who provided training or conducted exploratory experiments related to this study. Genetically engineered mouse strains were generated by Northwestern University’s Transgenic and Targeted Mutagenesis Laboratory with funds from the NUGoKidney (NIH P30 DK114857) and used to generate preliminary data. L.F.K. was supported by a fellowship from the Sao Paulo Research Foundation (FAPESP-2019/26414-2). P.G.D. was supported by the NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01 DK123463-01 and R01 DK131118-01. ACKNOWLEDGMENTS. We acknowledge Jennifer Kearney PhD and Nicole Hawkins PhD of Northwestern University’s Department of Pharmacology for their assistance collecting in vivo EEG monitoring data. We are thankful to Trung Le Tran, Toshihiro Nomura PhD, John Armstrong PhD, and Max Anstotz PhD Northwestern University Interdepartmental Neuroscience Program (NUIN) and Northwestern University Department of Neuroscience, who provided training or conducted exploratory experiments related to this study. Genetically engineered mouse strains were generated by Northwestern University’s Transgenic and Targeted Mutagenesis Laboratory with funds from the NUGoKidney (NIH P30 DK114857) and used to generate preliminary data. L.F.K. was supported by a fellowship from the Sao Paulo Research Foundation (FAPESP-2019/26414-2). P.G.D. was supported by the NIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants R01 DK123463-01 and R01 DK131118-01.
Keywords
- TRP channels
- channelopathy
- ciliopathy
- polycystins
- primary cilia
ASJC Scopus subject areas
- General
