Homeostatic regulation of intrinsic excitability in hippocampal neurons: response to chronic depolarisation

AbstractHomeostatic plasticity of intrinsic excitability goes hand-in-hand with homeostatic plasticity of synaptic transmission. However, the mechanisms linking the two forms of homeostatic regulation have not been identified so far. Using electrophysiological, imaging and immunohistochemical techniques, we show here that blockade of excitatory synaptic receptors for 2-3 days induces an up-regulation of synaptic strength at CA3-CA3 connexions and intrinsic excitability of CA3 pyramidal neurons. Activity-deprived connexions were found to express a high release probability, an insensitivity to dendrotoxin, and a lack of depolarization-induced presynaptic facilitation, indicating a loss of presynaptic Kv1.1 function. The down-regulation of Kv1.1 channels in activity-deprived neurons was confirmed by their broader action potentials measured in the axon that were insensitive to dendrotoxin. We conclude that regulation of axonal Kv1.1 channel constitutes a unique mechanism linking intrinsic excitability and synaptic strength that accounts for the functional synergy existing between homeostatic regulation of intrinsic excitability and synaptic transmission.

Download Full-text

ADAM22 and ADAM23 modulate the targeting of the Kv1 channel-associated protein LGI1 to the axon initial segment

10.1101/311365 ◽

2018 ◽

Cited By ~ 1

Author(s):

Bruno Hivert ◽

Laurène Marien ◽

Komlan Nassirou Agbam ◽

Catherine Faivre-Sarrailh

Keyword(s):

Hippocampal Neurons ◽

Live Cell Imaging ◽

Initial Segment ◽

Cell Imaging ◽

Autosomal Dominant ◽

Neurological Diseases ◽

Axon Initial Segment ◽

Intrinsic Excitability ◽

Missense Mutant ◽

Combinatorial Expression

AbstractThe distribution of voltage-gated potassium channels Kv1 at the axon initial segment (AIS), along the axon and at presynaptic terminals influences intrinsic excitability and transmitter release. Kv1.1/1.2 subunits are associated with cell adhesion molecules (CAMs), including Caspr2 and LGI1 that are implicated in autoimmune and genetic neurological diseases with seizures. In particular, mutations in the LGI1 gene cause autosomal dominant lateral temporal lobe epilepsy (ADTLE). In the present study, we used rat hippocampal neurons in culture to assess whether interplay between distinct Kv1-associated CAMs contributes to targeting at the AIS. Strikingly, LGI1 was highly restricted to the AIS surface when transfected alone, whereas the missense mutant LGI1S473L associated with ADLTE was not. Next, we showed that ADAM22 and ADAM23 acted as chaperones to promote axonal vesicular transport of LGI1 reducing its density at the AIS. Moreover, live-cell imaging of fluorescently labelled CAMs indicated that LGI1 was co-transported in axonal vesicles with ADAM22 or ADAM23. Finally, we showed that ADAM22 and ADAM23 also associate with Caspr2 and TAG-1 to be selectively targeted within different axonal sub-regions. The combinatorial expression of Kv1-associated CAMs may be critical to tune intrinsic excitability in a physiological or an epileptogenic context.

Download Full-text

Conventional measures of intrinsic excitability are poor estimators of neuronal activity under realistic synaptic inputs

PLoS Computational Biology ◽

10.1371/journal.pcbi.1009378 ◽

2021 ◽

Vol 17 (9) ◽

pp. e1009378

Author(s):

Adrienn Szabó ◽

Katalin Schlett ◽

Attila Szücs

Keyword(s):

Hippocampal Neurons ◽

Intrinsic Excitability ◽

High Yield ◽

Kinetic Properties ◽

Dynamic Clamp ◽

Synaptic Inputs ◽

Proportional Relationship ◽

Activity Dependent ◽

K Currents ◽

Synaptic Responses

Activity-dependent regulation of intrinsic excitability has been shown to greatly contribute to the overall plasticity of neuronal circuits. Such neuroadaptations are commonly investigated in patch clamp experiments using current step stimulation and the resulting input-output functions are analyzed to quantify alterations in intrinsic excitability. However, it is rarely addressed, how such changes translate to the function of neurons when they operate under natural synaptic inputs. Still, it is reasonable to expect that a strong correlation and near proportional relationship exist between static firing responses and those evoked by synaptic drive. We challenge this view by performing a high-yield electrophysiological analysis of cultured mouse hippocampal neurons using both standard protocols and simulated synaptic inputs via dynamic clamp. We find that under these conditions the neurons exhibit vastly different firing responses with surprisingly weak correlation between static and dynamic firing intensities. These contrasting responses are regulated by two intrinsic K-currents mediated by Kv1 and Kir channels, respectively. Pharmacological manipulation of the K-currents produces differential regulation of the firing output of neurons. Static firing responses are greatly increased in stuttering type neurons under blocking their Kv1 channels, while the synaptic responses of the same neurons are less affected. Pharmacological blocking of Kir-channels in delayed firing type neurons, on the other hand, exhibit the opposite effects. Our subsequent computational model simulations confirm the findings in the electrophysiological experiments and also show that adaptive changes in the kinetic properties of such currents can even produce paradoxical regulation of the firing output.

Download Full-text

Reduced Hyperpolarization-Activated Current Contributes to Enhanced Intrinsic Excitability in Cultured Hippocampal Neurons from PrP−/− Mice

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2016.00074 ◽

2016 ◽

Vol 10 ◽

Cited By ~ 10

Author(s):

Jing Fan ◽

Patrick L. Stemkowski ◽

Maria A. Gandini ◽

Stefanie A. Black ◽

Zizhen Zhang ◽

...

Keyword(s):

Hippocampal Neurons ◽

Intrinsic Excitability ◽

Hyperpolarization Activated Current ◽

Cultured Hippocampal Neurons

Download Full-text

Homeostatic regulation of axonal Kv1.1 channels accounts for both synaptic and intrinsic modifications in the hippocampal CA3 circuit

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2110601118 ◽

2021 ◽

Vol 118 (47) ◽

pp. e2110601118

Author(s):

Mickaël Zbili ◽

Sylvain Rama ◽

Maria-José Benitez ◽

Laure Fronzaroli-Molinieres ◽

Andrzej Bialowas ◽

...

Keyword(s):

Synaptic Transmission ◽

Pyramidal Neurons ◽

Homeostatic Plasticity ◽

Intrinsic Excitability ◽

Homeostatic Regulation ◽

Major Mechanism ◽

Hippocampal Ca3 ◽

Synaptic Receptors ◽

Intrinsic Plasticity ◽

Immunohistochemical Techniques

Homeostatic plasticity of intrinsic excitability goes hand in hand with homeostatic plasticity of synaptic transmission. However, the mechanisms linking the two forms of homeostatic regulation have not been identified so far. Using electrophysiological, imaging, and immunohistochemical techniques, we show here that blockade of excitatory synaptic receptors for 2 to 3 d induces an up-regulation of both synaptic transmission at CA3–CA3 connections and intrinsic excitability of CA3 pyramidal neurons. Intrinsic plasticity was found to be mediated by a reduction of Kv1.1 channel density at the axon initial segment. In activity-deprived circuits, CA3–CA3 synapses were found to express a high release probability, an insensitivity to dendrotoxin, and a lack of depolarization-induced presynaptic facilitation, indicating a reduction in presynaptic Kv1.1 function. Further support for the down-regulation of axonal Kv1.1 channels in activity-deprived neurons was the broadening of action potentials measured in the axon. We conclude that regulation of the axonal Kv1.1 channel constitutes a major mechanism linking intrinsic excitability and synaptic strength that accounts for the functional synergy existing between homeostatic regulation of intrinsic excitability and synaptic transmission.

Download Full-text