a1 adrenergic receptor - PKC - Pyk2 - Src signaling boosts L-type Ca2+ channel Cav1.2 activity and long-term potentiation in rodents
- University of California, Davis, United States
- University of Iowa, United States
Abstract
The cellular mechanisms mediating norepinephrine functions in brain to result in behaviors are unknown. We identified the L-type Ca2+ channel (LTCC) CaV1.2 as a principal target for Gq-coupled a1-adrenergic receptors (ARs). a1AR signaling increased LTCC activity in hippocampal neurons. This regulation required PKC-mediated activation of the tyrosine kinases Pyk2 and, downstream, Src. Pyk2 and Src were associated with CaV1.2. In model neuroendocrine PC12 cells, stimulation of PKC induced tyrosine phosphorylation of CaV1.2, a modification abrogated by inhibition of Pyk2 and Src. Upregulation of LTCC activity by a1AR and formation of a signaling complex with PKC, Pyk2, and Src suggests that CaV1.2 is a central conduit for signaling by norepinephrine. Indeed, a form of hippocampal LTP in young mice requires both the LTCC and a1AR stimulation. Inhibition of Pyk2 and Src blocked this LTP, indicating that enhancement of CaV1.2 activity via a1AR - Pyk2 - Src signaling regulates synaptic strength.
Data availability
Raw datasets are available on Dryad (https://doi.org/10.25338/B86G9K).
Article and author information
Author details
Madeline Nieves-Cintron
Funding
National Institutes of Health (R01 MH097887)
- Johannes W Hell
National Institutes of Health (RF1 AG055357)
- Johannes W Hell
National Institutes of Health (R01 HL098200)
- Manuel F Navedo
National Institutes of Health (R01 HL121059)
- Manuel F Navedo
National Institutes of Health (T32 GM099608)
- Peter B Henderson
National Institutes of Health (R01 NS123050)
- Madeline Nieves-Cintron
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All procedures followed NIH guidelines and had been approved by the Institutional Animal Care and Use Committees (IACUC) at UC Davis (Protocol #20673 and #22403).
Copyright
© 2023, Man et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 934
- views
-
- 147
- downloads
-
- 2
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
a1 adrenergic receptor - PKC - Pyk2 - Src signaling boosts L-type Ca2+ channel Cav1.2 activity and long-term potentiation in rodents
eLife 12:e79648.
https://doi.org/10.7554/eLife.79648
Further reading
-
- Neuroscience
Recognizing and responding to threat cues is essential to survival. Freezing is a predominant threat behavior in rats. We have recently shown that a threat cue can organize diverse behaviors beyond freezing, including locomotion (Chu et al., 2024). However, that experimental design was complex, required many sessions, and had rats receive many foot shock presentations. Moreover, the findings were descriptive. Here, we gave female and male Long Evans rats cue light illumination paired or unpaired with foot shock (8 total) in a conditioned suppression setting, using a range of shock intensities (0.15, 0.25, 0.35, or 0.50 mA). We found that conditioned suppression was only observed at higher foot shock intensities (0.35 mA and 0.50 mA). We constructed comprehensive temporal ethograms by scoring 22,272 frames across 12 behavior categories in 200-ms intervals around cue light illumination. The 0.50 mA and 0.35 mA shock-paired visual cues suppressed reward seeking, rearing, and scaling, as well as light-directed rearing and light-directed scaling. The shock-paired visual cue further elicited locomotion and freezing. Linear discriminant analyses showed that ethogram data could accurately classify rats into paired and unpaired groups. Using complete ethogram data produced superior classification compared to behavior subsets, including an Immobility subset featuring freezing. The results demonstrate diverse threat behaviors – in a short and simple procedure – containing sufficient information to distinguish the visual fear conditioning status of individual rats.
-
- Neuroscience
Evidence accumulation models (EAMs) are the dominant framework for modeling response time (RT) data from speeded decision-making tasks. While providing a good quantitative description of RT data in terms of abstract perceptual representations, EAMs do not explain how the visual system extracts these representations in the first place. To address this limitation, we introduce the visual accumulator model (VAM), in which convolutional neural network models of visual processing and traditional EAMs are jointly fitted to trial-level RTs and raw (pixel-space) visual stimuli from individual subjects in a unified Bayesian framework. Models fitted to large-scale cognitive training data from a stylized flanker task captured individual differences in congruency effects, RTs, and accuracy. We find evidence that the selection of task-relevant information occurs through the orthogonalization of relevant and irrelevant representations, demonstrating how our framework can be used to relate visual representations to behavioral outputs. Together, our work provides a probabilistic framework for both constraining neural network models of vision with behavioral data and studying how the visual system extracts representations that guide decisions.
