Biology subjects

Incontro, S.

Publications and source records attributed to Incontro, S..

8 recordsLinked to original sources

bioRxiv2026

Persistent enhancement of intrinsic neuronal excitability induced by transient divalent cation depletion

Fluctuations in external calcium concentration [Ca2+]e occur during the wake and sleep cycle and during intense neuronal activity. However, the incidence of these fluctuations on neuronal excitability is not precisely known. We show here that reducing divalent cation (Ca2+ and Mg2+) concentrations from 1.3/0.8 to 0.6/0.4 mM during 15-30 minutes induces long-term potentiation of intrinsic excitability (LTP-IE) in CA1 pyramidal neurons. LTP-IE induced by low divalent cations is associated with a hyperpolarization of the action potential threshold and constitutes a positive feed-back of brain activity. This plasticity requires Ca2+-sensing receptor (CaSR), IP3 receptor (IP3R) and calcium-calmodulin kinase II (CaMKII). In fact, LTP-IE was occluded in the presence of the calcilytic NPS-2143 and absent in CRISPR CaSR neurons. In addition, inhibiting IP3R with 2-APB and CaMKII with kin considerably reduced LTP-IE magnitude. LTP-IE and synaptic potentiation (LTP) induced by spike-timing-dependent plasticity (STDP) protocol were also found to depend on CaSR as they were totally absent in CRISPR CaSR neurons. Spontaneous excitatory synaptic activity was found to be reduced by [~]35% following LTP induced by STDP. Importantly, this drop of spontaneous activity was not observed in CRISPR CaSR neurons. Taken together, these results show that CaSR plays a critical role in LTP-IE induced by low [Ca2+]e and [Mg2+]e and as well as in LTP of synaptic transmission and intrinsic excitability induced by STDP.

neuroscience↗

bioRxiv2025

Divalent cation depletion enhances neuronal excitability through CaSR-dependent modulation of threshold channels

External calcium ([Ca{superscript 2}]{square}) and magnesium ([Mg{superscript 2}]{square}) concentrations fluctuate across physiological and pathological brain states. For example, [Ca{superscript 2}]{square} decreases during intense neuronal activity and epilepsy, whereas it rises during sleep. Similarly, [Mg{superscript 2}]{square} varies with the sleep/wake cycle and is reduced in epilepsy. Lowering either [Ca2+]e or [Mg2+]e increases intrinsic excitability and hyperpolarizes the action potential (AP) threshold, yet the underlying mechanisms remain unclear. Here, we confirm that reducing [Ca2+]e or [Mg2+]e enhances intrinsic excitability and hyperpolarizes the AP threshold of CA1 pyramidal neurons. Physiological reductions in [Mg{superscript 2}]{square} (0.8 [->] 0.4 mM) have minimal effect, whereas decreases from supraphysiological levels (2.0 [->] 0.4 mM) robustly increase excitability. Using pharmacology and CRISPR/Cas9 gene editing, we identify the calcium-sensing receptor (CaSR) as a key mediator of these effects. The calcilytic NPS-2143 mimics and largely occludes both the intrinsic excitability increase and the AP-threshold hyperpolarization, while genetic reduction of CaSR produces similar outcomes. We further show that AP-threshold hyperpolarization induced by low divalent cations involves both Kv1 and Nav1.2 channels. Together, these findings reveal CaSR as a critical link between external divalent cation levels and intrinsic neuronal excitability through the modulation of Kv1 and Nav channels.

neuroscience↗

bioRxiv2025

Somatostatin released by single O-LM interneurons slowly inhibits intrinsic neuronal excitability in a paracrine and autocrine manner

Somatostatin (SST) is a neuropeptide known to inhibit both neuronal excitability and excitatory synaptic transmission in principal neurons. While SST is expressed in some GABAergic interneurons such as Oriens-Lacunosum Moleculare (O-LM) cells, the precise conditions governing SST release remain poorly defined. We show here that, in the presence of GABAA receptor antagonist, single O-LM interneurons of CA1 are able to inhibit pyramidal neuron excitability when O-LM cells fire at frequencies above 20 Hz. This inhibition is suppressed by the SST receptor antagonist cyclo-SST and is absent when the O-LM interneuron is located more than 150 {micro}m from the pyramidal cell. Likewise, a single O-LM cell was also able to inhibit the intrinsic excitability of another O-LM cell, provided the two cells are in proximity. Exogeneous application of SST transiently inhibits excitatory synaptic transmission and intrinsic excitability in O-LM interneurons through SST1 and SST2, respectively. Notably, this transient inhibition became sustained when clathrin-dependent endocytosis of SST receptors was blocked. Blocking of SST receptors reduced NMDA receptor-mediated responses, prevented induction of both synaptic and intrinsic potentiation in pyramidal neurons and reduced the coherence of theta oscillations. These findings reveal that SST released by O-LM interneurons constitutes an additional inhibitory mechanism, modulating both synaptic excitation and intrinsic excitability beyond the transient inhibition mediated by GABA release.

neuroscience↗

bioRxiv2025

Distinct Electrophysiological Signatures Define Neuronal Subtypes in the Fasciola Cinereum

The fasciola cinereum (FC) is a small, conserved hippocampal subregion whose cellular properties remain poorly understood. Anatomically positioned between dorsal CA1 and the third ventricle, the FC receives diverse cortical and subcortical inputs but is often excluded from hippocampal circuit models. Here, we performed ex vivo whole-cell patch-clamp recordings in mouse hippocampal slices to define the intrinsic and synaptic properties of FC neurons. We find that FC neurons are electrophysiologically and morphologically distinct from neighboring CA1 and CA2 pyramidal cells, exhibiting reduced intrinsic excitability, delayed spike initiation, and enhanced afterhyperpolarizations. These properties are strongly shaped by potassium conductances, with Kv2 (KCNB) and Kv7 (KCNQ) channels contributing to the suppression of firing. We find that FC neurons span a continuum of intrinsic excitability which is structured by variability in potassium channel-mediated conductances and is inversely coordinated with excitatory synaptic input, such that less excitable neurons receive stronger synaptic drive. Together, these findings establish a mechanistic framework in which intrinsic membrane properties and synaptic input are co-organized across the FC population, providing new insight into how this understudied hippocampal region may contribute to the regulation of neural excitability. Key PointsO_LIThe fasciola cinereum (FC) is a small and poorly understood hippocampal subregion that has recently been implicated in hippocampal related function and seizure activity. C_LIO_LIHere we show that neurons in the FC are morphologically and functionally distinct from cells in neighboring CA1 and CA2 hippocampal subregions, and find substantial physiological diversity of FC neurons, including differences in firing behavior, membrane properties, and intrinsic excitability. C_LIO_LIPharmacological analyses show that Kv2 and Kv7 potassium channels play a key role in shaping the intrinsic properties of FC neurons. C_LIO_LILess excitable FC neurons receive stronger excitatory synaptic input, revealing an inverse relationship between intrinsic membrane excitability and synaptic drive. C_LIO_LIThese findings identify the FC as a physiologically specialized hippocampal subregion and provide a foundation for understanding its role in hippocampal function and neurological disease. C_LI

neuroscience↗

bioRxiv2023

Visual activity enhances neuronal excitability in thalamic relay neurons

The dorsal lateral geniculate nucleus (dLGN) has long been held to act as a basic relay for visual information travelling from the retina to cortical areas, but recent findings suggest a largely underestimated functional plasticity of dLGN neurons. However, the cellular mechanisms supporting this functional plasticity have not been yet explored. In particular, it remains to elucidate whether intrinsic neuronal excitability change upon visual stimuli. We show here that monocular deprivation for 10 days reduces the intrinsic excitability of dorsal LGN relay cells. Furthermore, dLGN neurons exhibit long-term potentiation of their intrinsic excitability (LTP-IE) when suprathreshold afferent retinal inputs are stimulated at 40 Hz or when spikes are induced with direct somatic current injection to reproduce patterns of retinal activity. LTP-IE is observed after eye opening and requires calcium influx mediated by L-type calcium channels. It involves activation of PKA and is expressed through the down-regulation of Kv1 potassium channels. In conclusion, our study provides the first evidence for intrinsic plasticity in dLGN relay cells, thus further pointing the role of thalamic neurons in activity-dependent visual plasticity and amblyopia.

neuroscience↗

bioRxiv2023

Contrasting synaptic roles of MDGA1 and MDGA2

Neurodevelopmental disorders are frequently linked to mutations in synaptic organizing molecules. MAM domain containing glycosylphosphatidylinositol anchor 1 and 2 (MDGA1 and MDGA2) are a family of synaptic organizers suggested to play an unusual role as synaptic repressors, but studies offer conflicting evidence for their localization. Using epitope-tagged MDGA1 and MDGA2 knock-in mice, we found that native MDGAs are expressed throughout the brain, peaking early in postnatal development. Surprisingly, endogenous MDGA1 was enriched at excitatory, but not inhibitory, synapses. Both shRNA knockdown and CRISPR/Cas9 knockout of MDGA1 resulted in cell-autonomous, specific impairment of AMPA receptor- mediated synaptic transmission, without affecting GABAergic transmission. Conversely, MDGA2 knockdown/knockout selectively depressed NMDA receptor-mediated transmission but enhanced inhibitory transmission. Our results establish that MDGA2 acts as a synaptic repressor, but only at inhibitory synapses, whereas both MDGAs are required for excitatory transmission. This nonoverlapping division of labor between two highly conserved synaptic proteins is unprecedented. TeaserMDGAs 1 and 2 independently localize to and modulate excitatory and inhibitory hippocampal synapses by different mechanisms.

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

Long-lasting reduction of intrinsic excitability in O-LM interneurons is mediated by endocannabinoid-dependent up-regulation of Kv7 channels

KCNQ-Kv7 channels are found at the axon initial segment of pyramidal neurons where they control cell firing and membrane potential. In oriens lacunosum moleculare (O-LM) interneurons, these channels are mainly expressed in the dendrites, suggesting a peculiar function of Kv7 channels in these neurons. The physiology of Kv7 channels is well characterized today but the precise contribution of these channels to neuronal plasticity is still unknown. Here, we show that Kv7 channel activity is up-regulated following induction of presynaptic long-term synaptic depression (LTD) in O-LM interneurons, thus resulting in a synergistic long-term depression of intrinsic neuronal excitability (LTD-IE). Both LTD and LTD-IE involve endocannabinoid (eCB) biosynthesis for their induction. Molecular modeling shows strong interaction of eCBs with Kv7.2/3 channel, suggesting a persistent action of these lipids on Kv7 channel activity. Our data thus unveil a major role for eCB synthesis in triggering both synaptic and intrinsic depression in O-LM interneurons.

neuroscience↗