Kidney Week

Abstract: FR-PO634

Pkd1 Mutation Modulates Cognitive Function via N-methyl-D-aspartate Receptor-Mediated Synaptic Transmission and Autophagy

Session Information

• Cystic Kidney Diseases: Mechanisms and Models
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Firdaus, Zeba, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States

Zeba Firdaus

• Li, Lu, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States

Lu Li, MD, PhD

• Mao, Xinyue, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States

Xinyue Mao, MD, PhD

• Zhou, Xia, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States

Xia Zhou, MD, PhD

• Li, Xiaogang, Mayo Clinic Department of Internal Medicine, Rochester, Minnesota, United States

Xiaogang Li, PhD

Background

ADPKD is a prevalent, life-threatening monogenic disorder linked to PKD gene mutations. However, whether this mutation affects brain function is unknown. In this study, we investigate whether PKD1 mutation activates N-methyl D aspartate receptors (NMDAR), dominant calcium channels, and impairs autophagy in brain to disrupt synaptic transmission and contribute to cognitive dysfunction.

Methods

We performed behavioral experiment (Y-maze test) to evaluate the anxiety in wild type (WT) and Pkd1^RC/RC mice. To understand the underlying molecular mechanisms, we isolated cerebral cortex (CC) and hippocampus (HP) from WT and Pkd1^RC/RC brain and did Western blot and qRT-PCR analysis. We also checked the effect of senolytic treatment on brain in Pkd1^RC/RC mice. Lastly, we did the co-IP to check the interaction between GluN2a and carboxy-terminal end of PC1 using N2a cells.

Results

We observed increased anxiety-like behavior in Pkd1^RC/RC mice compared to WT controls. The expression of NMDAR subunit GluN2A, synaptic protein PSD-95, and neurotrophic factor BDNF was increased in the CC and HP of Pkd1^RC/RC mice compared to WT control, suggesting an increase of synaptic signaling, whereas the expression of RE-1 silencing transcription factor (REST), responsible for repression of synaptic proteins, was downregulated in Pkd1^RC/RC brains. In addition, impaired autophagy, as characterized by the increase of p62 and pTFEB and the decrease of Atg7, beclin1, and LC3 in Pkd1^RC/RC mice brains compared to WT controls. Treatment with senolytic combination of Dasatinib and Quercetin (DQ), improved anxiety-like behavior in Pkd1^RC/RC mice and restored the expression of above autophagy markers. Treatment with DQ also normalized the expression of synaptic proteins as seen by a decrease of the upregulated GluN2A, PSD-95, and BDNF, and an increase of the downregulated REST. Moreover, the carboxy-terminal of PC1 interacts with GluN2A, indicating that PC1 may suppress this NMDAR subunit in wild-type brains through this interaction.

Conclusion

This study finds that Pkd1 mutation alters NMDAR and REST expression, along with impaired autophagy, leading to increased synaptic protein availability at synapses, thereby amplifying synaptic transmission and causing excitability. Consequently, Pkd1 mutation induces anxiety in an ADPKD animal model, resulting in mild cognitive dysfunction.