The Clustered Protocadherins in the Form and Function of Cerebellar Purkinje Cells
Bibliographic record
Abstract
The cerebellum is a brain region that regulates the control of movement. It also participates in non-motor functions, such as social and repetitive behaviours. At the heart of the cerebellar circuitry are the Purkinje cells (PCs). These neurons provide the sole exit of neural information from the cerebellar cortex. PCs possess distinguishing features: 1) their exuberant dendrites are uniformly distributed with minimal self-overlap through a process called dendrite self-avoidance; 2) they fire intrinsically at regular and high-frequency intervals even without synaptic input. PCs prominently express the clustered Protocadherins (cPCDHS), a group of cell surface recognition molecules. They are encoded by 58 genes, divided into three clusters: α-Pcdh (Pcdha), β-Pcdh (Pcdhb), and γ-Pcdh (Pcdhg). Previously, we showed that PCDHGs regulate PC dendrite self-avoidance (Lefebvre et al., 2012). However, the roles of the other clusters in PC self-avoidance and overall, the cPCDHs’ roles in PC function have not been elucidated. Here, I investigated the functional interactions between the Pcdha and Pcdhg clusters in PC dendrite self-avoidance, as well as their roles in PC firing and behavioural output. My PC self-avoidance analysis demonstrated that the loss of Pcdhas leads to defects of similar severity to loss of Pcdhgs, suggesting that both clusters are equally required. Dendrite self-crossing defects were exacerbated in Pcdha; Pcdhg double mutant PCs compared to single mutants, revealing partial redundancy. Developmental PCs lacking Pcdhgs displayed increased dendrite density and malformed filopodia, suggesting deficits in filopodia retraction lead to self-avoidance defects. The cPcdhs also influenced PC functions. Mouse mutants harboring a PC-specific deletion of Pcdhgs, with or without an additional global Pcdha heterozygous deletion, displayed motor impairments on the rotarod and in their gait. Non-motor functions were spared. Motor deficits were accompanied by dysfunctional PC firing properties. Mutant PCs exhibited lower intrinsic firing rates and excitability with elevated potassium currents, possibly resulting from Kv3.3 channel disinhibition. In CHO cells, a PCDHG isoform physically interacted with Kv3.3 channels, revealing a potential mechanism for cPCDH inhibition of Kv3.3 channels. My work is the first to show that the cPCDH clusters cooperate in PC dendrite self-avoidance, and that the cPCDHs can regulate the firing properties of a neuron, as well as PC-specific behavioural output.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".