Primary cilia TRP channel regulates hippocampal excitability

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 Ca 2+ 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.

Shared and unique consequences of Joubert Syndrome gene dysfunction on the zebrafish central nervous system

“…Primary cilia are also specialised Ca 2+ signalling organelles. The ciliary Ca 2+ channel PKD2L1 plays a role in regulating hippocampal excitability in mice, and mice lacking PKD2L1 were found to be more susceptible to epileptic seizures (Vien et al 2023). Primary cilia on differentiated neurons within the zebrafish CNS could therefore concentrate receptors or channels that influence neuronal function.…”

A synthetic method to assay polycystin channel biophysics

“…50 . Previous work has genetically identified PKD2L1 and PKD2 as essential ion channel subunit in the primary cilia of the renal collecting duct cells and hippocampal neurons 34,42 . Bottom, average single-channel current amplitudes recorded from primary cilia using K + in the recording electrode solution.…”

“…The medical and biological importance of polycystins is underscored by PKD2 variants associated with autosomal dominant polycystic kidney disease (ADPKD), and this channel's role in fertility and conferring right-left symmetry in embryonic development [31][32][33] . While PKD2L1 variants have yet to be linked to human disease, its loss of expression results in epilepsy susceptibility and autism -like features in mice 34,35 . In this report, we stepwise express and confirm protein expression of polycystin channels using the CFE method; reconstitute channel protein in GUVs containing distinct lipid components; assess correct membrane orientation using self-labeling saturated N-heterocyclic building blocks (SNAP) protein chemistry and evaluate channel properties using electrophysiology 36 .…”

Cilia loss on distinct neuron populations differentially alters cocaine-induced locomotion and reward

“…Interference with ciliary signaling disrupts axon targeting, dendritic arborization, and the formation and maintenance of synapses (Guadiana et al, 2013;Guo et al, 2017Guo et al, , 2019Lee and Gleeson, 2010). Recent data also show that the PK2DL1 ion channel localizes to primary cilia and contributes to regulation of action potentials in interneurons, directly linking this organelle to neuronal excitability and function (Vien et al, 2023).…”

“…In the adult brain, cilia remain relatively stable while exhibiting some dynamic structural responses to extracellular signals (Chakravarthy et al, 2012;Guadiana et al, 2016;Schou et al, 2015;Wheway et al, 2018). Although much remains to be discovered about the capacities of primary cilia in the nervous system, they are implicated in metabolism, cognition/memory, and motivated behaviors (Kirschen and Xiong, 2017;Ramos et al, 2021;Sherafat-Kazemzadeh et al, 2013;Vien et al, 2023). Disruption of ciliary function leads to phenotypes including obesity, cognitive impairments, disrupted food seeking, and impaired social motivation (Brinckman et al, 2013;Green and Mykytyn, 2010;Poretti and Gerner, 2016).…”