Biology subjects

Inglebert, Y.

Publications and source records attributed to Inglebert, Y..

8 recordsLinked to original sources

bioRxiv2025

The astroglial protein S100β regulates axon initial segment plasticity

One key regulator of neuronal excitability is the axon initial segment (AIS), a highly specialized axonal region, enriched in ion channels, where action potentials are initiated. The AIS can undergo significant morphological changes to fine-tune neuronal excitability in response to external perturbations. Long considered solely a homeostatic mechanism operating over long timescales (hours to days) to adjust excitability, we show here that this phenomenon can also occur rapidly, within minutes, following a brief period of high activity in layer 5 pyramidal neurons of the visual cortex. Because astrocytes have been known to regulate neuronal excitability, we explored the effects of gliotransmitters on this process and identified the calcium-binding protein S100{beta} from astrocytes to be required for the rapid reorganization of the AIS. O_FIG O_LINKSMALLFIG WIDTH=169 HEIGHT=200 SRC="FIGDIR/small/667937v3_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1765348org.highwire.dtl.DTLVardef@155bf98org.highwire.dtl.DTLVardef@95c300org.highwire.dtl.DTLVardef@356376_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

neuroscience↗

bioRxiv2025

The gliotransmitter S100β regulates synaptic plasticity in the visual cortex

Synaptic plasticity is a fundamental mechanism of memory storage in the brain. Among the various rules governing changes in synaptic strength, Spike Timing-Dependent Plasticity (STDP) stands out for its strong physiological relevance in vivo. Ubiquitous across brain regions and neuronal types, STDP is a complex and multifactorial process influenced by factors such as neuromodulation, extracellular calcium levels, and activity patterns. However, one relatively understudied factor is the role of astrocytes, despite their well-established involvement in regulating synaptic transmission and neuronal excitability through gliotransmitter release. While some factors have garnered significant attention, others, like S100{beta}, have remained relatively underexplored despite their potential importance in regulating synaptic plasticity. S100{beta} is a calcium-binding protein, allowing it to influence extracellular Ca{superscript 2} concentration and potentially all Ca2+-dependent plasticity processes. Building on our previous research in the visual cortex, where we examined the regulation of neuronal excitability by S100{beta}, we chose to further investigate the role of astrocytes and S100{beta} in synaptic plasticity at layer 2/3-layer 5 synapses in the visual cortex. We demonstrated that S100{beta} is an important gliotransmitter to consider, capable of regulating long-term potentiation.

neuroscience↗

bioRxiv2023

Synaptopodin is required for long-term depression at Schaffer collateral-CA1 synapses

Synaptopodin (SP), an actin-associated protein found in telencephalic neurons, affects synaptic and structural plasticity. While being required for longterm depression (LTD) mediated by metabotropic glutamate receptor (mGluR-LTD), little is known about its role in other forms of LTD induced by low frequency stimulation (LFS-LTD) or spike-timing dependent plasticity (STDP). Using SP-deficient mice (SPKO), we have here demonstrated that the presence of SP is mandatory for normal LTD expression. On the contrary, long-term potentiation (LTP), albeit diminished in SPKO, is still present and can be easily recovered by increasing the stimulation frequency. Our study shows, for the first time, the role of SP in a more physiological form of induction of synaptic plasticity.

neuroscience↗

bioRxiv2023

Loss of synaptopodin impairs mGluR5 and protein synthesis dependent mGluR-LTD at CA3-CA1 synapses

Metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) is an important form of synaptic plasticity that occurs in many regions of the CNS and is the underlying mechanism for several learning paradigms. In the hippocampus, mGluR-LTD is manifested by the weakening of synaptic transmission and elimination of dendritic spines. Interestingly, not all spines respond or undergo plasticity equally in response to mGluR-LTD. A subset of dendritic spines containing synaptopodin (SP), an actin-associated protein, are critical for mGluR-LTD and protect spines from elimination through mGluR1 activity. The precise cellular function of SP is still enigmatic and it is still unclear how SP contributes to the functional aspect of mGluR-LTD despite of its modulation on the structural plasticity. In the present study, we show that the lack of SP impairs mGluR-LTD by negatively affecting the mGluR5-dependent activity. Such impairment of mGluR5 activity is accompanied by a significant decrease of surface mGluR5 level in SP knockout (SPKO) mice. Intriguingly, the remaining mGluR-LTD becomes a protein synthesis-independent process in the SPKO and is mediated instead by endocannabinoid signaling. These data show for the first time that the postsynaptic protein SP can regulate the locus of expression of mGluR-LTD and provide insight to our understanding of spine/synapse-specific plasticity. Significance statementHippocampal group I metabotropic glutamate receptor dependent long-term depression (mGluR-LTD), a form of learning and memory, is misregulated in many murine models of neurodevelopmental disorders. Despite extensive studies there is a paucity of information on the molecular mechanism underlying mGluR-LTD. Previously, we reported that loss of synaptopodin, an actin-associated protein found in a subset of mature dendritic spines, impairs mGluR-LTD. In the current study, we uncover the molecular and cellular deficits involved. We find that synaptopodin is required for the mGluR5-Homer interaction and uncover synaptopodin as a molecular switch for mGluR-LTD expression, as mGluR-LTD becomes protein synthesis-independent and relies on endocannabinoid signaling in synaptopodin knock-out. This work provides insight into synaptopodin as a gatekeeper to regulate mGluR-LTD at hippocampal synapses.

neuroscience↗

bioRxiv2022

Synaptic and intrinsic potentiation in O-LM interneurons is induced by theta patterns of stimulation

Oriens lacunosum-moleculare (O-LM) interneurons display a non-conventional form of long-term synaptic potentiation (LTP) conferred by calcium-permeable AMPA receptors (CP-AMPAR). So far, this form of LTP has been induced in O-LM cells by physiologically unrealistic protocols. We report here the induction of both synaptic and intrinsic potentiation in O-LM interneurons following stimulation of afferent glutamatergic inputs in the theta ({theta}) frequency range. LTP is induced by synaptic activation of CP-AMPAR whereas long-term potentiation of intrinsic excitability (LTP-IE) results from the mGluR1-dependent down-regulation of Kv7 voltage-dependent potassium channel and hyperpolarization activated and cyclic nucleotide-gated (HCN) channel through the depletion of phosphatidylinositol-4,5-bi-phosphate (PIP2). LTP and LTP-IE are reversible, demonstrating that both synaptic and intrinsic changes are bidirectional in O-LM cells. We conclude that physiological stimuli such as {theta} patterns induce synaptic and intrinsic potentiation in O-LM interneurons.

neuroscience↗

bioRxiv2021

Stabilization of spine Synaptopodin by mGluR1 is required for mGluR-LTD

Dendritic spines, actin-rich protrusions forming the postsynaptic sites of excitatory synapses, undergo activity-dependent molecular and structural remodeling. Activation of group 1 metabotropic glutamate receptors - mGluR1 and mGluR5 - by synaptic or pharmacological stimulation, induces LTD but whether this is accompanied with spine elimination remains unresolved. A subset of telencephalic mushroom spines contains the spine apparatus (SA), an enigmatic organelle composed of stacks of smooth endoplasmic reticulum, whose formation depends on the expression of the actin-bundling protein Synaptopodin. Allocation of Synaptopodin to spines appears governed by cell-intrinsic mechanisms as the relative frequency of spines harboring Synaptopodin is conserved in vivo and in vitro. Here we show that expression of Synaptopodin/SA in spines is required for induction of mGluR-LTD at Schaffer collateral-CA1 synapses. Post-mGluR-LTD, mushroom spines lacking Synaptopodin/SA are selectively lost whereas spines harboring it are preserved, a process dependent on activation of mGluR1 but not mGluR5. Mechanistically, we find that mGluR1 supports physical retention of Synaptopodin within excitatory spine synapses during LTD while triggering lysosome-dependent degradation of the protein residing in dendritic shafts. Together, these results reveal a cellular mechanism, dependent on mGluR1, which enables selective preservation of stronger spines containing Synaptopodin/SA while eliminating weaker ones and potentially countering spurious strengthening by de novo recruitment of Synaptopodin. Overall our results identify spines with Synaptopodin/SA as the locus of mGluR-LTD and underscore the importance of the molecular microanatomy of spines in synaptic plasticity.

neuroscience↗

bioRxiv2020

Altered spike timing-dependent plasticity rules in physiological calcium

Like many forms of long-term synaptic plasticity, spike-timing-dependent plasticity (STDP) depends on intracellular Ca2+ signaling for its induction. Yet, all in vitro studies devoted to STDP used abnormally high external Ca2+ concentration. We measured STDP at the CA3-CA1 hippocampal synapses under different extracellular Ca2+ concentrations and found that the sign, shape and magnitude of plasticity strongly depend on Ca2+. A pre-post protocol that results in robust LTP in high Ca2+, yielded only LTD or no plasticity in the physiological Ca2+ range. LTP could be restored by either increasing the number of post-synaptic spikes or increasing the pairing frequency. A calcium-based plasticity model in which depression and potentiation depend on post-synaptic Ca2+ transients was found to fit quantitatively all the data, provided NMDA receptor-mediated non-linearities were implemented. In conclusion, STDP rule is profoundly altered in physiological Ca2+ but specific activity regimes restore a classical STDP profile.

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bioRxiv2019

Axonal Na+ channels detect and transmit levels of input synchrony in local brain circuits

Sensory processing requires mechanisms of fast coincidence-detection to discriminate synchronous from asynchronous inputs. Spike-threshold adaptation enables such a discrimination but is ineffective in transmitting this information to the network. We show here that presynaptic axonal sodium channels read and transmit precise levels of input synchrony to the postsynaptic cell by modulating the presynaptic action potential (AP) amplitude. As a consequence, synaptic transmission is facilitated at cortical synapses when the presynaptic spike is produced by synchronous inputs. Using dual soma-axon recordings, imaging, and modeling, we show that this facilitation results from enhanced AP amplitude in the axon due to minimized inactivation of axonal sodium-channels. Quantifying local circuit activity and using network modeling, we found that spikes induced by synchronous inputs produced a larger effect on network activity than spikes induced by asynchronous inputs. Therefore, this input-synchrony dependent facilitation (ISF) may constitute a powerful mechanism regulating spike transmission.

neuroscience↗