Homeostatic Regulation of Intrinsic Excitability and Synaptic Transmission in a Developing Visual Circuit

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.

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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.

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Major Role For Tonic GABAA Conductances in Anesthetic Suppression of Intrinsic Neuronal Excitability

Journal of Neurophysiology ◽

10.1152/jn.00223.2004 ◽

2004 ◽

Vol 92 (3) ◽

pp. 1658-1667 ◽

Cited By ~ 86

Author(s):

Mark C. Bieda ◽

M. Bruce MacIver

Keyword(s):

Synaptic Transmission ◽

Neuronal Excitability ◽

Brain Slices ◽

Pyramidal Cells ◽

Intrinsic Excitability ◽

High Potassium ◽

Ca1 Neurons ◽

Adult Rat ◽

Adult Rat Brain ◽

Sites Of Action

Anesthetics appear to produce neurodepression by altering synaptic transmission and/or intrinsic neuronal excitability. Propofol, a widely used anesthetic, has proposed effects on many targets, ranging from sodium channels to GABAA inhibition. We examined effects of propofol on the intrinsic excitability of hippocampal CA1 neurons (primarily interneurons) recorded from adult rat brain slices. Propofol strongly depressed action potential production induced by DC injection, synaptic stimulation, or high-potassium solutions. Propofol-induced depression of intrinsic excitability was completely reversed by bicuculline and picrotoxin but was strychnine-insensitive, implicating GABAA but not glycine receptors. Propofol strongly enhanced inhibitory postsynaptic currents (IPSCs) and induced a tonic GABAA-mediated current. We pharmacologically differentiated tonic and phasic (synaptic) GABAA-mediated inhibition using the GABAA receptor antagonist SR95531 (gabazine). Gabazine (20 μM) completely blocked both evoked and spontaneous IPSCs but failed to block the propofol-induced depression of intrinsic excitability, implicating tonic, but not phasic, GABAA inhibition. Glutamatergic synaptic responses were not altered by propofol (≤30 μM). Similar results were found in both interneurons and pyramidal cells and with the chemically unrelated anesthetic thiopental. These results suggest that suppression of CA1 neuron intrinsic excitability, by these anesthetics, is largely due to activation of tonic GABAA conductances; although other sites of action may play important roles in affecting synaptic transmission, which also can produce strong neurodepression. We propose that for some anesthetics, suppression of intrinsic excitability, mediated by tonic GABAA conductances, operates in conjunction with effects on synaptic transmission, mediated by other mechanisms, to depress hippocampal function during anesthesia.

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Homeostatic Regulation of the Efficacy of Synaptic Transmission

Neurophysiology ◽

10.1023/b:neph.0000008804.39342.b7 ◽

2003 ◽

Vol 35 (3/4) ◽

pp. 322

Author(s):

S. Y. Ivanova ◽

P. G. Kostyuk

Keyword(s):

Synaptic Transmission ◽

Homeostatic Regulation

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Nicotine Exposure during Adolescence Leads to Changes of Synaptic Plasticity and Intrinsic Excitability of Mice Insular Pyramidal Cells at Later Life

International Journal of Molecular Sciences ◽

10.3390/ijms23010034 ◽

2021 ◽

Vol 23 (1) ◽

pp. 34

Author(s):

Hiroki Toyoda ◽

Kohei Koga

Keyword(s):

Synaptic Transmission ◽

Insular Cortex ◽

Pyramidal Cells ◽

Later Life ◽

Brain Regions ◽

Spike Timing ◽

Intrinsic Excitability ◽

Nicotine Exposure ◽

Cellular Mechanisms ◽

Layer V

To find satisfactory treatment for nicotine addiction, synaptic and cellular mechanisms should be investigated comprehensively. Synaptic transmission, plasticity and intrinsic excitability in various brain regions are known to be altered by acute nicotine exposure. However, it has not been addressed whether and how nicotine exposure during adolescence alters these synaptic events and intrinsic excitability in the insular cortex in adulthood. To address this question, we performed whole-cell patch-clamp recordings to examine the effects of adolescent nicotine exposure on synaptic transmission, plasticity and intrinsic excitability in layer V pyramidal neurons (PNs) of the mice insular cortex five weeks after the treatment. We found that excitatory synaptic transmission and potentiation were enhanced in these neurons. Following adolescent nicotine exposure, insular layer V PNs displayed enhanced intrinsic excitability, which was reflected in changes in relationship between current strength and spike number, inter-spike interval, spike current threshold and refractory period. In addition, spike-timing precision evaluated by standard deviation of spike timing was decreased following nicotine exposure. Our data indicate that adolescent nicotine exposure enhances synaptic transmission, plasticity and intrinsic excitability in layer V PNs of the mice insular cortex at later life, which might contribute to severe nicotine dependence in adulthood.

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Reduced Synaptic and Intrinsic Excitability of a Subtype of Pyramidal Neurons in the Medial Prefrontal Cortex in a Mouse Model of Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-210585 ◽

2021 ◽

pp. 1-12

Author(s):

Xiao-Qin Zhang ◽

Le Xu ◽

Si-Yu Yang ◽

Lin-Bo Hu ◽

Fei-Yuan Dong ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Prefrontal Cortex ◽

Synaptic Transmission ◽

Pyramidal Neurons ◽

Intrinsic Excitability ◽

Rodent Models ◽

Morphological Complexity ◽

Sholl Analysis ◽

Model Of Alzheimer’S Disease

Background: Abnormal morphology and function of neurons in the prefrontal cortex (PFC) are associated with cognitive deficits in rodent models of Alzheimer’s disease (AD), particularly in cortical layer-5 pyramidal neurons that integrate inputs from different sources and project outputs to cortical or subcortical structures. Pyramidal neurons in layer-5 of the PFC can be classified as two subtypes depending on the inducibility of prominent hyperpolarization-activated cation currents (h-current). However, the differences in the neurophysiological alterations between these two subtypes in rodent models of AD remain poorly understood. Objective: To investigate the neurophysiological alterations between two subtypes of pyramidal neurons in hAPP-J20 mice, a transgenic model for early onset AD. Methods: The synaptic transmission and intrinsic excitability of pyramidal neurons were investigated using whole-cell patch recordings. The morphological complexity of pyramidal neurons was detected by biocytin labelling and subsequent Sholl analysis. Results: We found reduced synaptic transmission and intrinsic excitability of the prominent h-current (PH) cells but not the non-PH cells in hAPP-J20 mice. Furthermore, the function of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels which mediated h-current was disrupted in the PH cells of hAPP-J20 mice. Sholl analysis revealed that PH cells had less dendritic intersections in hAPP-J20 mice comparing to control mice, implying that a lower morphological complexity might contribute to the reduced neuronal activity. Conclusion: These results suggest that the PH cells in the medial PFC may be more vulnerable to degeneration in hAPP-J20 mice and play a sustainable role in frontal dysfunction in AD.

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