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1.
iScience ; 26(1): 105728, 2023 Jan 20.
Article in English | MEDLINE | ID: mdl-36582822

ABSTRACT

In Neurodevelopmental Disorders, alterations of synaptic plasticity may trigger structural changes in neuronal circuits involved in cognitive functions. This hypothesis was tested in mice carrying the human R451C mutation of Nlgn3 gene (NLG3R451C KI), found in some families with autistic children. To this aim, the spike time dependent plasticity (STDP) protocol was applied to immature GABAergic Mossy Fibers (MF)-CA3 connections in hippocampal slices from NLG3R451C KI mice. These animals failed to exhibit STD-LTP, an effect that persisted in adulthood when these synapses became glutamatergic. Similar results were obtained in mice lacking the Nlgn3 gene (NLG3 KO mice), suggesting a loss of function. The loss of STD-LTP was associated with a premature shift of GABA from the depolarizing to the hyperpolarizing direction, a reduced BDNF availability and TrkB phosphorylation at potentiated synapses. These effects may constitute a general mechanism underlying cognitive deficits in those forms of Autism caused by synaptic dysfunctions.

2.
Proc Natl Acad Sci U S A ; 118(47)2021 11 23.
Article in English | MEDLINE | ID: mdl-34799447

ABSTRACT

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.


Subject(s)
Axons/metabolism , Hippocampus/metabolism , Homeostasis , Action Potentials/physiology , Animals , Neuronal Plasticity , Neurons/metabolism , Pyramidal Cells/metabolism , Rats , Rats, Wistar , Synapses/metabolism , Synaptic Transmission/physiology
3.
Nat Commun ; 6: 10163, 2015 Dec 10.
Article in English | MEDLINE | ID: mdl-26657943

ABSTRACT

In the mammalian brain, synaptic transmission usually depends on presynaptic action potentials (APs) in an all-or-none (or digital) manner. Recent studies suggest, however, that subthreshold depolarization in the presynaptic cell facilitates spike-evoked transmission, thus creating an analogue modulation of a digital process (or analogue-digital (AD) modulation). At most synapses, this process is slow and not ideally suited for the fast dynamics of neural networks. We show here that transmission at CA3-CA3 and L5-L5 synapses can be enhanced by brief presynaptic hyperpolarization such as an inhibitory postsynaptic potential (IPSP). Using dual soma-axon patch recordings and live imaging, we find that this hyperpolarization-induced AD facilitation (h-ADF) is due to the recovery from inactivation of Nav channels controlling AP amplitude in the axon. Incorporated in a network model, h-ADF promotes both pyramidal cell synchrony and gamma oscillations. In conclusion, cortical excitatory synapses in local circuits display hyperpolarization-induced facilitation of spike-evoked synaptic transmission that promotes network synchrony.


Subject(s)
Axons/physiology , Membrane Potentials/physiology , Presynaptic Terminals , Sodium Channels/metabolism , Animals , Animals, Newborn , Brain/cytology , Brain/physiology , Calcium/metabolism , Computer Simulation , Female , Male , Models, Biological , Nerve Net/physiology , Neurons , Rats
4.
Eur J Neurosci ; 41(3): 293-304, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25394682

ABSTRACT

Synaptic transmission usually depends on action potentials (APs) in an all-or-none (digital) fashion. Recent studies indicate, however, that subthreshold presynaptic depolarization may facilitate spike-evoked transmission, thus creating an analog modulation of spike-evoked synaptic transmission, also called analog-digital (AD) synaptic facilitation. Yet, the underlying mechanisms behind this facilitation remain unclear. We show here that AD facilitation at rat CA3-CA3 synapses is time-dependent and requires long presynaptic depolarization (5-10 s) for its induction. This depolarization-induced AD facilitation (d-ADF) is blocked by the specific Kv1.1 channel blocker dendrotoxin-K. Using fast voltage-imaging of the axon, we show that somatic depolarization used for induction of d-ADF broadened the AP in the axon through inactivation of Kv1.1 channels. Somatic depolarization enhanced spike-evoked calcium signals in presynaptic terminals, but not basal calcium. In conclusion, axonal Kv1.1 channels determine glutamate release in CA3 neurons in a time-dependent manner through the control of the presynaptic spike waveform.


Subject(s)
Action Potentials/physiology , CA3 Region, Hippocampal/physiology , Kv1.1 Potassium Channel/metabolism , Synaptic Transmission/physiology , Action Potentials/drug effects , Animals , CA3 Region, Hippocampal/drug effects , Calcium/metabolism , Calcium Chelating Agents/pharmacology , Egtazic Acid/pharmacology , Glutamic Acid/metabolism , Kv1.1 Potassium Channel/antagonists & inhibitors , Models, Neurological , Patch-Clamp Techniques , Peptides/pharmacology , Potassium Channel Blockers/pharmacology , Pyramidal Cells/drug effects , Pyramidal Cells/physiology , Rats, Wistar , Sodium/metabolism , Synapses/drug effects , Synapses/physiology , Synaptic Transmission/drug effects , Time , Tissue Culture Techniques
5.
Nat Rev Neurosci ; 14(1): 63-9, 2013 01.
Article in English | MEDLINE | ID: mdl-23187813

ABSTRACT

Synaptic transmission in the brain generally depends on action potentials. However, recent studies indicate that subthreshold variation in the presynaptic membrane potential also determines spike-evoked transmission. The informational content of each presynaptic action potential is therefore greater than initially expected. The contribution of this synaptic property, which is a fast (from 0.01 to 10 s) and state-dependent modulation of functional coupling, has been largely underestimated and could have important consequences for our understanding of information processing in neural networks. We discuss here how the membrane voltage of the presynaptic terminal might modulate neurotransmitter release by mechanisms that do not involve a change in presynaptic Ca(2+) influx.


Subject(s)
Brain/cytology , Calcium/metabolism , Neurotransmitter Agents/metabolism , Presynaptic Terminals/physiology , Signal Transduction/physiology , Animals , Brain/physiology , Humans
6.
J Physiol ; 589(Pt 15): 3753-73, 2011 Aug 01.
Article in English | MEDLINE | ID: mdl-21624967

ABSTRACT

Hyperpolarization-activated cyclic nucleotide modulated current (I(h)) sets resonance frequency within the θ-range (5­12 Hz) in pyramidal neurons. However, its precise contribution to the temporal fidelity of spike generation in response to stimulation of excitatory or inhibitory synapses remains unclear. In conditions where pharmacological blockade of I(h) does not affect synaptic transmission, we show that postsynaptic h-channels improve spike time precision in CA1 pyramidal neurons through two main mechanisms. I(h) enhances precision of excitatory postsynaptic potential (EPSP)--spike coupling because I(h) reduces peak EPSP duration. I(h) improves the precision of rebound spiking following inhibitory postsynaptic potentials (IPSPs) in CA1 pyramidal neurons and sets pacemaker activity in stratum oriens interneurons because I(h) accelerates the decay of both IPSPs and after-hyperpolarizing potentials (AHPs). The contribution of h-channels to intrinsic resonance and EPSP waveform was comparatively much smaller in CA3 pyramidal neurons. Our results indicate that the elementary mechanisms by which postsynaptic h-channels control fidelity of spike timing at the scale of individual neurons may account for the decreased theta-activity observed in hippocampal and neocortical networks when h-channel activity is pharmacologically reduced.


Subject(s)
Cyclic Nucleotide-Gated Cation Channels/physiology , Excitatory Postsynaptic Potentials/physiology , Inhibitory Postsynaptic Potentials/physiology , Neocortex/physiology , Neurons/physiology , Potassium Channels/physiology , Pyramidal Cells/physiology , Animals , Cyclic Nucleotide-Gated Cation Channels/metabolism , Electric Stimulation/methods , Electrophysiology/methods , Evoked Potentials/drug effects , Evoked Potentials/physiology , Excitatory Postsynaptic Potentials/drug effects , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels , Inhibitory Postsynaptic Potentials/drug effects , Neocortex/drug effects , Neurons/drug effects , Potassium Channels/metabolism , Pyramidal Cells/drug effects , Pyrimidines/pharmacology , Rats , Synapses/drug effects , Synapses/physiology , Synaptic Transmission/drug effects , Synaptic Transmission/physiology
7.
Physiol Rev ; 91(2): 555-602, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21527732

ABSTRACT

Axons are generally considered as reliable transmission cables in which stable propagation occurs once an action potential is generated. Axon dysfunction occupies a central position in many inherited and acquired neurological disorders that affect both peripheral and central neurons. Recent findings suggest that the functional and computational repertoire of the axon is much richer than traditionally thought. Beyond classical axonal propagation, intrinsic voltage-gated ionic currents together with the geometrical properties of the axon determine several complex operations that not only control signal processing in brain circuits but also neuronal timing and synaptic efficacy. Recent evidence for the implication of these forms of axonal computation in the short-term dynamics of neuronal communication is discussed. Finally, we review how neuronal activity regulates both axon morphology and axonal function on a long-term time scale during development and adulthood.


Subject(s)
Axons/physiology , Action Potentials/physiology , Animals , Axons/pathology , Cell Proliferation , Channelopathies/pathology , Electrophysiological Phenomena , Humans , Ion Channels/physiology , Neuronal Plasticity/physiology , Signal Transduction/physiology , Synaptic Transmission/physiology
8.
Neuron ; 67(2): 268-79, 2010 Jul 29.
Article in English | MEDLINE | ID: mdl-20670834

ABSTRACT

Acidification of synaptic vesicles by the vacuolar proton ATPase is essential for loading with neurotransmitter. Debated findings have suggested that V-ATPase membrane domain (V0) also contributes to Ca(2+)-dependent transmitter release via a direct role in vesicle membrane fusion, but the underlying mechanisms remain obscure. We now report a direct interaction between V0 c-subunit and the v-SNARE synaptobrevin, constituting a molecular link between the V-ATPase and SNARE-mediated fusion. Interaction domains were mapped to the membrane-proximal domain of VAMP2 and the cytosolic 3.4 loop of c-subunit. Acute perturbation of this interaction with c-subunit 3.4 loop peptides did not affect synaptic vesicle proton pump activity, but induced a substantial decrease in neurotransmitter release probability, inhibiting glutamatergic as well as cholinergic transmission in cortical slices and cultured sympathetic neurons, respectively. Thus, V-ATPase may ensure two independent functions: proton transport by a fully assembled V-ATPase and a role in SNARE-dependent exocytosis by the V0 sector.


Subject(s)
Neurons/metabolism , Neurotransmitter Agents/metabolism , Synapses/physiology , Synaptic Vesicles/metabolism , Vacuolar Proton-Translocating ATPases/metabolism , Animals , Animals, Newborn , Calcium/metabolism , Cell Membrane/metabolism , Cerebral Cortex/cytology , Enzyme Inhibitors/pharmacology , Enzyme-Linked Immunosorbent Assay/methods , Excitatory Postsynaptic Potentials/drug effects , In Vitro Techniques , Liposomes/metabolism , Macrolides/pharmacology , Mutation/genetics , Neurons/drug effects , Neurons/ultrastructure , Neurotransmitter Agents/pharmacology , Peptides/metabolism , Peptides/pharmacology , Protein Binding/drug effects , Protein Binding/physiology , Protein Subunits/genetics , Protein Subunits/metabolism , Proteolipids/metabolism , Rats , Rats, Wistar , SNARE Proteins/metabolism , Sequence Alignment/methods , Two-Hybrid System Techniques , Vacuolar Proton-Translocating ATPases/chemistry , Vesicle-Associated Membrane Protein 2/genetics , Vesicle-Associated Membrane Protein 2/metabolism
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