Dendritic branch structure compartmentalizes voltage-dependent calcium influx in cortical layer 2/3 pyramidal cells

Article activity feed

1. 

   Version published to 10.7554/elife.76993 on eLife

   Mar 23, 2022
2. 

   eLife

   Mar 14, 2022

   Author Response:

   Reviewer #1:

   The authors image local voltage and calcium influx in the dendrites of mouse superficial cortical pyramidal neurons while simulating synaptic input using glutamate uncaging. They show that both the degree of amplification of local calcium influx observed during back-propagating action potentials and the calcium influx evoked by the action potentials themselves vary widely across dendritic branches but are poorly correlated. The signals due to APs vary by dendritic branch. They go on to show convincingly that the reason some dendrites show smaller signals is that the APs are attenuated at some branch points leading to a failure to exceed the threshold for calcium channel activation. In contrast, since calcium influx through NMDA receptors has a less steep voltage dependence (Fig. 8A) they are less …

   Author Response:

   Reviewer #1:

   The authors image local voltage and calcium influx in the dendrites of mouse superficial cortical pyramidal neurons while simulating synaptic input using glutamate uncaging. They show that both the degree of amplification of local calcium influx observed during back-propagating action potentials and the calcium influx evoked by the action potentials themselves vary widely across dendritic branches but are poorly correlated. The signals due to APs vary by dendritic branch. They go on to show convincingly that the reason some dendrites show smaller signals is that the APs are attenuated at some branch points leading to a failure to exceed the threshold for calcium channel activation. In contrast, since calcium influx through NMDA receptors has a less steep voltage dependence (Fig. 8A) they are less affected by the attenuation, leading to decorrelation.

   This is a very thorough and well done analysis of a set of issues that have implications for the ways in which dendritic morphology affect plasticity "rules." The underlying principles are largely previously understood, but their implications (e.g. the difference between voltage dependence of calcium channel and NMDA receptor calcium influx) are not widely appreciated and yet have important effects on the resulting integration. In addition, the study is valuable because various alternative explanations (e.g. lack of calcium channels in some dendrites) have been convincingly ruled out. The results are likely to be of interest to neuroscientists and biophysicists concerned with neuronal plasticity and dendritic computation.

   Thank you for the kind words and careful summary of the work.

   Reviewer #2:

   Landau and colleagues use an impressive set of techniques, including somatic and dendritic electrical recordings and dendritic Ca2+ and voltage imaging, to study the effect of dendritic morphology on dendritic Ca2+ signaling associated with backpropagating APs (bAPs). The authors aim to test the hypothesis that the amplitudes of bAP-dependent spine Ca2+ signals depend on the branch pattern complexity of the dendritic domain that the dendrite or spine is part of. The novelty is that their approach highlights the role of the branching patterns proximal AND distal to the dendrite of interest. This is an important refinement of findings in past studies that have described that the amplitudes of bAP-dependent dendritic Ca2+ signals decrease as a function of the electrotonic distance of the soma. The authors begin in fact by replicating this well-documented result. However, they emphasize the variability of these Ca2+ signals when comparing dendrites/spine that are part of different dendritic branches but matched for distance to the soma. To go after the reason for this variability, the paper first defines two types of dendrites/dendritic spines based on the Ca2+ signal amplitude associated with a single bAP, dendrites/spines with high bAP Ca2+ signals (high delta Ca2+) and those with low bAP Ca2+ (low delta Ca2+) signals. These two groups of dendrites will be contrasted throughout the paper, but how the amplitude value separating these groups was found remains unclear. Next, a set of experiments excludes differences in voltage-gated calcium channel (VGCC) density or differences in the ability of bAPs to invade specific dendritic branches in the absence of synaptic input as potential sources for this difference. Instead, using computational modeling and detailed morphological analyses, the paper concludes is that the bAP amplitude is more attenuated in the low delta Ca2+ branches because low delta Ca2+ dendritic branches are surrounded by more elaborate branching patterns leading to a smaller overall impedance. Lower impedance leads to an increased bAP attenuation and smaller bAP-associated Ca2+ signals due to decreased VGCC opening. Overall, this manuscript is written and organized in an intuitive way, and this study is an impressive technical tour-de-force. However, one way or another, most findings of this study recapitulate or refine previous results, as mentioned by the authors themselves (e.g., Water et al, 2003; Magee and Johnston, 1997) and/or can be predicted based on cable theory.

   Thank you for this summary. We agree with the general comments and that some aspects of the work can be predicted from prior studies and cable theory. However, that dendrites exist in which the bAP amplitude falls below voltage-gated Ca channel activation yet maintains NMDA-receptor-based nonlinearities in synaptic Ca influx has not been demonstrated, as far as we know. Of course, cable theory predicts that bAPs will become smaller and wider as impedance falls in highly branching dendrites, but reproducing our findings would require a “just-so” type model in which the bAP is tailored to fall into this amplitude window. In contrast, our study starts with an empirical observation that such dendrites exist and then demonstrates the mechanism.

   Read the original source
3. 

   eLife

   Mar 14, 2022

   Evaluation Summary:

   Synaptic plasticity typically requires the conjunction of dendritic action potentials and synaptic activation. Together these signals cause nonlinear changes in calcium influx that then drive plasticity. The strength of these interactions can vary in complex ways. The authors use an elegant combination of imaging and electrophysiology to convincingly show how some of these complexities in murine cortical neurons arise from electrical properties of neuronal dendrites and synaptic NMDA receptors. This is a thorough and well done analysis of a set of issues that have implications for the ways in which dendritic morphology affect plasticity "rules." The underlying principles are largely previously understood, but their implications (e.g. the difference between voltage dependence of calcium channel and NMDA receptor …

   Evaluation Summary:

   Synaptic plasticity typically requires the conjunction of dendritic action potentials and synaptic activation. Together these signals cause nonlinear changes in calcium influx that then drive plasticity. The strength of these interactions can vary in complex ways. The authors use an elegant combination of imaging and electrophysiology to convincingly show how some of these complexities in murine cortical neurons arise from electrical properties of neuronal dendrites and synaptic NMDA receptors. This is a thorough and well done analysis of a set of issues that have implications for the ways in which dendritic morphology affect plasticity "rules." The underlying principles are largely previously understood, but their implications (e.g. the difference between voltage dependence of calcium channel and NMDA receptor calcium influx) are not widely appreciated and yet have important effects on the resulting integration.

   (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

   Read the original source
4. 

   eLife

   Mar 14, 2022

   Reviewer #1 (Public Review):

   The authors image local voltage and calcium influx in the dendrites of mouse superficial cortical pyramidal neurons while simulating synaptic input using glutamate uncaging. They show that both the degree of amplification of local calcium influx observed during back-propagating action potentials and the calcium influx evoked by the action potentials themselves vary widely across dendritic branches but are poorly correlated. The signals due to APs vary by dendritic branch. They go on to show convincingly that the reason some dendrites show smaller signals is that the APs are attenuated at some branch points leading to a failure to exceed the threshold for calcium channel activation. In contrast, since calcium influx through NMDA receptors has a less steep voltage dependence (Fig. 8A) they are less affected by …

   Reviewer #1 (Public Review):

   The authors image local voltage and calcium influx in the dendrites of mouse superficial cortical pyramidal neurons while simulating synaptic input using glutamate uncaging. They show that both the degree of amplification of local calcium influx observed during back-propagating action potentials and the calcium influx evoked by the action potentials themselves vary widely across dendritic branches but are poorly correlated. The signals due to APs vary by dendritic branch. They go on to show convincingly that the reason some dendrites show smaller signals is that the APs are attenuated at some branch points leading to a failure to exceed the threshold for calcium channel activation. In contrast, since calcium influx through NMDA receptors has a less steep voltage dependence (Fig. 8A) they are less affected by the attenuation, leading to decorrelation.

   This is a very thorough and well done analysis of a set of issues that have implications for the ways in which dendritic morphology affect plasticity "rules." The underlying principles are largely previously understood, but their implications (e.g. the difference between voltage dependence of calcium channel and NMDA receptor calcium influx) are not widely appreciated and yet have important effects on the resulting integration. In addition, the study is valuable because various alternative explanations (e.g. lack of calcium channels in some dendrites) have been convincingly ruled out. The results are likely to be of interest to neuroscientists and biophysicists concerned with neuronal plasticity and dendritic computation.

   Read the original source
5. 

   eLife

   Mar 14, 2022

   Reviewer #2 (Public Review):

   Landau and colleagues use an impressive set of techniques, including somatic and dendritic electrical recordings and dendritic Ca2+ and voltage imaging, to study the effect of dendritic morphology on dendritic Ca2+ signaling associated with backpropagating APs (bAPs). The authors aim to test the hypothesis that the amplitudes of bAP-dependent spine Ca2+ signals depend on the branch pattern complexity of the dendritic domain that the dendrite or spine is part of. The novelty is that their approach highlights the role of the branching patterns proximal AND distal to the dendrite of interest. This is an important refinement of findings in past studies that have described that the amplitudes of bAP-dependent dendritic Ca2+ signals decrease as a function of the electrotonic distance of the soma. The authors begin …

   Reviewer #2 (Public Review):

   Landau and colleagues use an impressive set of techniques, including somatic and dendritic electrical recordings and dendritic Ca2+ and voltage imaging, to study the effect of dendritic morphology on dendritic Ca2+ signaling associated with backpropagating APs (bAPs). The authors aim to test the hypothesis that the amplitudes of bAP-dependent spine Ca2+ signals depend on the branch pattern complexity of the dendritic domain that the dendrite or spine is part of. The novelty is that their approach highlights the role of the branching patterns proximal AND distal to the dendrite of interest. This is an important refinement of findings in past studies that have described that the amplitudes of bAP-dependent dendritic Ca2+ signals decrease as a function of the electrotonic distance of the soma. The authors begin in fact by replicating this well-documented result. However, they emphasize the variability of these Ca2+ signals when comparing dendrites/spine that are part of different dendritic branches but matched for distance to the soma. To go after the reason for this variability, the paper first defines two types of dendrites/dendritic spines based on the Ca2+ signal amplitude associated with a single bAP, dendrites/spines with high bAP Ca2+ signals (high delta Ca2+) and those with low bAP Ca2+ (low delta Ca2+) signals. These two groups of dendrites will be contrasted throughout the paper, but how the amplitude value separating these groups was found remains unclear. Next, a set of experiments excludes differences in voltage-gated calcium channel (VGCC) density or differences in the ability of bAPs to invade specific dendritic branches in the absence of synaptic input as potential sources for this difference. Instead, using computational modeling and detailed morphological analyses, the paper concludes is that the bAP amplitude is more attenuated in the low delta Ca2+ branches because low delta Ca2+ dendritic branches are surrounded by more elaborate branching patterns leading to a smaller overall impedance. Lower impedance leads to an increased bAP attenuation and smaller bAP-associated Ca2+ signals due to decreased VGCC opening. Overall, this manuscript is written and organized in an intuitive way, and this study is an impressive technical tour-de-force. However, one way or another, most findings of this study recapitulate or refine previous results, as mentioned by the authors themselves (e.g., Water et al, 2003; Magee and Johnston, 1997) and/or can be predicted based on cable theory.

   Read the original source
6. 

   eLife

   Mar 14, 2022

   Reviewer #3 (Public Review):

   This interesting paper examines how dendrite geometry influences back-propagating action potentials (bAPs) and their associated Ca2+ signals (∆CaAP). The authors use an elegant combination of 2-photon Ca2+ imaging, 2-photon uncaging, 1-photon voltage imaging, and modeling. They first show that different spines and dendrites can have very different ∆CaAP signals, which they divide into low and high groups. They also show that sites with low ∆CaAP still undergo large amplification when paired with uncaging EPSPs (uEPSPs). They show that the low ∆CaAP dendrites both support bAPs and have Ca2+ channels that could in principle evoke signals. However, using voltage imaging, they show that bAP amplitude is smaller in the low ∆CaAP dendrites. They show this depends on increased dendritic complexity at these …

   Reviewer #3 (Public Review):

   This interesting paper examines how dendrite geometry influences back-propagating action potentials (bAPs) and their associated Ca2+ signals (∆CaAP). The authors use an elegant combination of 2-photon Ca2+ imaging, 2-photon uncaging, 1-photon voltage imaging, and modeling. They first show that different spines and dendrites can have very different ∆CaAP signals, which they divide into low and high groups. They also show that sites with low ∆CaAP still undergo large amplification when paired with uncaging EPSPs (uEPSPs). They show that the low ∆CaAP dendrites both support bAPs and have Ca2+ channels that could in principle evoke signals. However, using voltage imaging, they show that bAP amplitude is smaller in the low ∆CaAP dendrites. They show this depends on increased dendritic complexity at these dendrites, which is associated with lower impedance. In this case, some additional voltage imaging experiments could be very useful to fully explore these ideas. Lastly, they use simulations to show how branch structure can influence both bAPs and synaptic responses. Overall, I think this is careful and well-written study that augments our understanding of dendritic signaling.

   Read the original source
7. 

   Version published to 10.1101/2022.01.11.475883v1 on bioRxiv

   Jan 12, 2022