Cholinergic modulation shifts the response of CA1 pyramidal cells to depolarizing ramps via TRPM4 channels with potential implications for place field firing
- Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, United States
- Department of Cell Biology and Anatomy, School of Medicine, Louisiana State University Health Sciences Center, United States
Figures
Figure 1 with 2 supplements
Carbachol shifts the center of mass of firing in response to depolarizing current ramps.
(A) Somatic recording, control. (A1) Voltage trace for a two second triangular current ramp (represented below) injected in the soma. (A2) Instantaneous frequency for example in A1 as it changes …
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Figure 1—source data 1
Carbachol shifts the center of mass of firing in response to depolarizing current ramps.
- https://cdn.elifesciences.org/articles/84387/elife-84387-fig1-data1-v2.xlsx
Figure 1—figure supplement 1
Plots of instantaneous frequency versus current injection showing different effects of carbachol on firing rate adaptation.
(A and B) Two examples of somatic recordings where the firing rate adaptation in control is reversed in the presence of CCh, such that the clockwise hysteresis becomes counter-clockwise. (C and D) …
Figure 1—figure supplement 2
Effects of the membrane potential, injected current and input resistance on the adaptation index.
(A) Adaptation index as a function of membrane potential. Index values for each trial for all neurons are plotted against the membrane potential measured just before the current injection ramp for …
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Figure 1—figure supplement 2—source data 1
Carbachol shifts the center of mass of firing in response to depolarizing current ramps.
- https://cdn.elifesciences.org/articles/84387/elife-84387-fig1-figsupp2-data1-v2.xlsx
Figure 2
Cholinergic modulation of the response to electrical stimulation of Schaffer collaterals, recorded at the soma.
(A) Top, synaptic response in control conditions to an input frequency that increases and decreases symmetrically, from 6.7 to 25 Hz, as denoted by the pulses, labeled stim. Bottom, Raster plot of …
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Figure 2—source data 1
Cholinergic modulation of the response to electrical stimulation of Schaffer collaterals, recorded at the soma.
- https://cdn.elifesciences.org/articles/84387/elife-84387-fig2-data1-v2.xlsx
Figure 3
Modulation of responses to symmetric ramps by acetylcholine is concentration dependent.
(A) Voltage trace recorded in the soma for a two second triangular current ramp injected in the soma in control. Current traces and instantaneous frequency plots are just below the voltage traces. (B…
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Figure 3—source data 1
Modulation of responses to symmetric ramps by acetylcholine is concentration dependent.
- https://cdn.elifesciences.org/articles/84387/elife-84387-fig3-data1-v2.xlsx
Figure 4
Cholinergic-associated shift in the timing of firing on ramp is mediated by TRP channels, but notably not TRPC channels.
(A) Somatic recordings for a two second triangular current ramp injected in the soma in control (A1), CCh (2 µM) (A2), and CCh + FFA (100 µM) (A3) applied subsequently to the same cell. Current …
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Figure 4—source data 1
Cholinergic-associated shift in the timing of firing on ramp is mediated by TRP channels, but notably not TRPC channels.
- https://cdn.elifesciences.org/articles/84387/elife-84387-fig4-data1-v2.xlsx
Figure 5
Cholinergic-mediated shift in the center of mass of firing is mediated by TRPM4 channels.
(A) Somatic recordings for a two second triangular current ramp injected in the soma in control (A1), CCh (2 µM) (A2), and CCh + CBA (50 µM) (A3) applied subsequently to the same cell. Current …
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Figure 5—source data 1
Cholinergic-associated shift in the timing of firing on ramp is mediated by TRP channels, but notably not TRPC channels.
- https://cdn.elifesciences.org/articles/84387/elife-84387-fig5-data1-v2.xlsx
Figure 6
Pharmacological block of IP3Rs or RyRs has no effect on CCh-mediated shift in firing along ramp.
(A) Somatic recordings during intracellular dialysis with Xestospongin C (2 µM), for a two second triangular current ramp injected in the soma before (A1), and during superfusion with CCh (2 µM) (A2)…
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Figure 6—source data 1
Pharmacological block of IP3Rs or RyRs has no effect on CCh-mediated shift in firing along ramp.
- https://cdn.elifesciences.org/articles/84387/elife-84387-fig6-data1-v2.xlsx
Figure 7
Simulated voltage responses to triangular current ramp injections, and underlying mechanisms.
(A) Simulated control response to triangular current ramp. (A1) Top. Simplified model calcium handling schematic. For simplicity, only one annulus (shell) is shown, and the rest are represented as …
Figure 8
The model explains how simulated TRPM4 channel activation can reverse the adaptation mediated by long-term inactivation of NaV1.6 channels.
(A) Voltage traces from 7A1 and B1 overlaid; control (in black), CCh (in magenta). The triangular current injection ramps are shown below. (B) Occupancy of NaV1.6 channel in the open state (O) in …
Figure 9
The model explains how activation of TRPM4 channels affects the firing pattern in response to triangular ramps that evoke similar firing frequencies.
(A) Simulated voltage traces (top) during a two second triangular current ramp (just below voltage traces). Insets show the reciprocal of the interspike interval (ISI) plotted as the instantaneous …
Figure 10
A high concentration of BAPTA is required to interfere with CCh-mediated shift in firing along ramp.
(A) Somatic recordings during intracellular dialysis with 10 mM BAPTA, for a two second triangular current ramp injected in the soma before (A1), and during superfusion with CCh (2 µM) (A2). Current …
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Figure 10—source data 1
A high concentration of BAPTA is required to interfere with CCh-mediated shift in firing along ramp.
- https://cdn.elifesciences.org/articles/84387/elife-84387-fig10-data1-v2.xlsx
Figure 11 with 1 supplement
Model Schematics.
(A) Reconstructed morphology ported to NEURON simulation program, with somatic current injection site labeled. (B) Equivalent circuit diagram, with the reversal potentials for each channel indicated …
Figure 11—figure supplement 1
Old model in which the source of Ca2+ with privileged access to the nanodomain required to activated TRPM4 channels is IP3R.
This model captures the responses seen with cholinergic activation in the experiments. (A) Simulated somatic recordings in control (low IP3). (A1) Voltage traces and current ramp. (A2) Nanomolar Ca2+…
Tables
Key resources table
| Reagent type (species) or resource | Designation | Source or reference | Identifiers | Additional information |
|---|---|---|---|---|
| Strain, strain background | Male Sprague Dawley rats | Envigo (Inovit) | Hsd:Sprague Dawley SD | 7–12 weeks old when sacrificed for experiments |
| Chemical compound, drug | NBQX | Alomone Labs | cat# N-186 | AMPA receptor antagonist |
| Chemical compound, drug | DL-APV | HelloBio | cat# HB0252 | NMDA receptor antagonist |
| Chemical compound, drug | Gabazine | Alomone Labs | cat# G-216 | GABAA receptor antagonist |
| Chemical compound, drug | CGP55845 | Abcam | cat# ab120337 | GABAB receptor antagonist |
| Chemical compound, drug | Carbachol | Tocris | cat# 2810 | Acetylcholine receptor agonist |
| Chemical compound, drug | Acetylcholine | Sigma-Aldrich | cat# A6625 | Ligand for acetylcholine receptors |
| Chemical compound, drug | flufenamic acid | Sigma-Aldrich | cat# F9005 | TRP channel antagonist |
| Chemical compound, drug | SKF96365 | Alomone Labs | cat# S-175 | TRPC channel antagonist |
| Chemical compound, drug | CBA | Tocris | cat# 6724 | TRPM4 channel antagonist |
| Chemical compound, drug | 9-phenanthrol | Tocris | cat# 4999 | TRPM4 channel antagonist |
| Chemical compound, drug | Xestospongin C | Abcam | cat# ab120914 | IP3R antagonist |
| Chemical compound, drug | low molecular weight heparin | Sigma-Aldrich | cat# H3149 | IP3R antagonist |
| Chemical compound, drug | D-myo-IP3 | Cayman Chemical | cat# 60960 | IP3R agonist |
| Chemical compound, drug | Adenophostin A | MilliporeSigma | cat# 115500 | IP3R agonist |
| Chemical compound, drug | Ryanodine | HelloBio | cat# HB1320 | RyR antagonist at [µM] |
| Chemical compound, drug | Ruthenium red | Tocris | cat# 1439 | RyR antagonist |
| Chemical compound, drug | Dantrolene | Tocris | cat# 0507 | RyR antagonist |
| Chemical compound, drug | caffeine | Tocris | cat# 2793 | RyR agonist |
| Chemical compound, drug | Thapsigargin | Alomone Labs | cat# T-650 | SERCA inhibitor |
| Chemical compound, drug | BAPTA tetra-potassium salt (K4-BAPTA) | Sigma-Aldrich | cat# A9801 | fast Ca2+ chelator |
| Software, algorithm | MAXCHELATOR, WEBMAXC EXTENDED | https://somapp.ucdmc.ucdavis.edu/pharmacology/bers/maxchelator/webmaxc/webmaxcE.htm | Online free metal calculator | |
| Software, algorithm | SPSS | IBM | RRID:SCR_002865 | Statistics software |
| Software, algorithm | NEURON | Hines and Carnevale, 1997; Carnevale and Hines, 2006 | doi:doi.org/10.1162/neco.1997.9.6.1179; doi.org/10.1017/CBO9780511541612 | Computational modelling and simulation software |
| Other | Laerd Statistics | https://statistics.laerd.com/ | Online tutorial and software guide |
