Potential Role of Drebrin A, an F-Actin Binding Protein, in Reactive Synaptic Plasticity after Pilocarpine-Induced Seizures: Functional Implications in Epilepsy

Several neurological disorders characterized by cognitive deficits, including Alzheimer's disease, down syndrome, and epilepsy exhibit abnormal spine density and/or morphology. Actin-based cytoskeleton network dynamics is critical for the regulation of spine morphology and synaptic function. In this paper, I consider the functions of drebrin A in cell shaping, spine plasticity, and synaptic function. Developmentally regulated brain protein (drebrin A) is one of the most abundant neuron-specific binding proteins of F-actin and its expression is increased in parallel with synapse formation. Drebrin A is particularly concentrated in dendritic spines receiving excitatory inputs. Our recent findings point to a critical role of DA in dendritic spine structural integrity and stabilization, likely via regulation of actin cytoskeleton dynamics, and glutamatergic synaptic function that underlies the development of spontaneous recurrent seizures in pilocarpine-treated animals. Further research into this area may provide useful insights into the pathology of status epilepticus and epileptogenic mechanisms and ultimately may provide the basis for future treatment options

A New Role for TIMP-1 in Modulating Neurite Outgrowth and Morphology of Cortical Neurons

BACKGROUND:Tissue inhibitor of metalloproteinases-1 (TIMP-1) displays pleiotropic activities, both dependent and independent of its inhibitory activity on matrix metalloproteinases (MMPs). In the central nervous system (CNS), TIMP-1 is strongly upregulated in reactive astrocytes and cortical neurons following excitotoxic/inflammatory stimuli, but no information exists on its effects on growth and morphology of cortical neurons. PRINCIPAL FINDINGS:We found that 24 h incubation with recombinant TIMP-1 induced a 35% reduction in neurite length and significantly increased growth cones size and the number of F-actin rich microprocesses. TIMP-1 mediated reduction in neurite length affected both dendrites and axons after 48 h treatment. The effects on neurite length and morphology were not elicited by a mutated form of TIMP-1 inactive against MMP-1, -2 and -3, and still inhibitory for MMP-9, but were mimicked by a broad spectrum MMP inhibitor. MMP-9 was poorly expressed in developing cortical neurons, unlike MMP-2 which was present in growth cones and whose selective inhibition caused neurite length reductions similar to those induced by TIMP-1. Moreover, TIMP-1 mediated changes in cytoskeleton reorganisation were not accompanied by modifications in the expression levels of actin, betaIII-tubulin, or microtubule assembly regulatory protein MAP2c. Transfection-mediated overexpression of TIMP-1 dramatically reduced neuritic arbour extension in the absence of detectable levels of released extracellular TIMP-1. CONCLUSIONS:Altogether, TIMP-1 emerges as a modulator of neuronal outgrowth and morphology in a paracrine and autrocrine manner through the inhibition, at least in part, of MMP-2 and not MMP-9. These findings may help us understand the role of the MMP/TIMP system in post-lesion pre-scarring conditions

Unpublished Mediterranean and Black Sea records of marine alien, cryptogenic, and neonative species

To enrich spatio-temporal information on the distribution of alien, cryptogenic, and neonative species in the Mediterranean and the Black Sea, a collective effort by 173 marine scientists was made to provide unpublished records and make them open access to the scientific community. Through this effort, we collected and harmonized a dataset of 12,649 records. It includes 247 taxa, of which 217 are Animalia, 25 Plantae and 5 Chromista, from 23 countries surrounding the Mediterranean and the Black Sea. Chordata was the most abundant taxonomic group, followed by Arthropoda, Mollusca, and Annelida. In terms of species records, Siganus luridus, Siganus rivulatus, Saurida lessepsianus, Pterois miles, Upeneus moluccensis, Charybdis (Archias) longicollis, and Caulerpa cylindracea were the most numerous. The temporal distribution of the records ranges from 1973 to 2022, with 44% of the records in 2020–2021. Lethrinus borbonicus is reported for the first time in the Mediterranean Sea, while Pomatoschistus quagga, Caulerpa cylindracea, Grateloupia turuturu, and Misophria pallida are first records for the Black Sea; Kapraunia schneideri is recorded for the second time in the Mediterranean and for the first time in Israel; Prionospio depauperata and Pseudonereis anomala are reported for the first time from the Sea of Marmara. Many first country records are also included, namely: Amathia verticillata (Montenegro), Ampithoe valida (Italy), Antithamnion amphigeneum (Greece), Clavelina oblonga (Tunisia and Slovenia), Dendostrea cf. folium (Syria), Epinephelus fasciatus (Tunisia), Ganonema farinosum (Montenegro), Macrorhynchia philippina (Tunisia), Marenzelleria neglecta (Romania), Paratapes textilis (Tunisia), and Botrylloides diegensis (Tunisia).peer-reviewe

Role of drebrin A in dendritic spine plasticity and synaptic function: Implications in neurological disorders

Drebrin A is one of the most abundant neuron-specific binding proteins of F-actin and its expression is increased in parallel with synapse formation. Drebrin A is particularly concentrated in dendritic spines, postsynaptic sides of excitatory glutamatergic synapses. More recently, Ferhat and colleagues reported the functional role of drebrin A in regulating synaptic transmission. Indeed, our study showed that overexpression of drebrin A induced an increase of glutamatergic but not GABAergic synapses and resulted in the alteration of the normal excitatory-inhibitory ratio in favor of excitation in mature hippocampal neurons. Downregulation of drebrin A expression by antisense oligonucleotides resulted in the decrease of both miniature- glutamatergic and GABAergic synaptic activities without affecting the excitatory-inhibitory ratio. Studies performed in heterologous cells revealed that drebrin A reorganized the actin filaments and stabilized them and that these effects are depend upon its actin-binding domain. These results suggest that drebrin A regulates dendritic spine morphology, size and density, presumably via regulation of actin cytoskeleton remodeling and dynamics. These data demonstrate for the first time that an actin-binding protein such as drebrin A regulates both glutamatergic and GABAergic synaptic transmissions, probably through an increase of active synaptic site density for glutamatergic transmission and through homeostatic mechanisms for the GABAergic one

Drebrin A expression is altered after pilocarpine-induced seizures: time course of changes is consistent for a role in the integrity and stability of dendritic spines of hippocampal granule cells

International audienceWe used a pathophysiological model of temporal lobe epilepsy induced by pilocarpine in adult rats in order to assess the in vivo role of drebrin A (DA), one of the major regulators of F-actin. This model displays a dynamic reorganization of the glutamatergic network including neo-spinogenesis, morphogenesis, and neo-synaptogenesis associated with an aberrant sprouting of granule cell axons in the dentate gyrus (DG). This reactive plasticity contributes in dentate granule-cell hyperexcitability that could lead to the emergence of recurrent spontaneous seizures. We investigated the hippocampal DA expression changes in pilocarpine animals using immunohistochemical, Western blot, and in situ hybridization analyses. We showed that DA immunoreactivity was decreased in the inner molecular layer (IML) and in the hilus (H) of the DG, at latent stage, when spinogenesis and morphogenesis occur. Western blot analysis confirmed these overall hippocampal decreases of DA protein expression. At chronic stage, when newly formed glutamatergic synapses are being established, the levels of immunolabeling for DA in the H and the IML were similar to control rats. This recovery is likely due to the increase of DA mRNA in perikarya of hilar and granule cells. Interestingly, our data showed that the changes pattern of labeling for Bassoon, a specific marker for presynaptic active zone, in the IML of pilocarpine-treated animals paralleled those found for DA at all time points examined. Furthermore, our double and triple immunofluorescence studies showed that the recovery in DA levels in the IML occurred within the dendritic spines involved in glutamatergic active synapses of presumed granule cells. Altogether, our results indicate that in vivo DA is not critical for spinogenesis and morphogenesis but instead is consistent with an involvement in synaptic structural integrity, stabilization, and function. Thus, DA appears as a novel modulator of reactive synaptic plasticity associated with epilepsy

Neurotensin and Neurotensin Receptors in Stress-related Disorders: Pathophysiology & Novel Drug Targets

Abstract: Neurotensin (NT) is a 13-amino acid neuropeptide widely distributed in the CNS that has been involved in the pathophysiology of many neural and psychiatric disorders. There are three known neurotensin receptors (NTSRs), which mediate multiple actions, and form the neurotensinergic system in conjunction with NT. NTSR1 is the main mediator of NT, displaying effects in both the CNS and the periphery, while NTSR2 is mainly expressed in the brain and NTSR3 has a broader expression pattern. In this review, we bring together up-to-date studies showing an involvement of the neuroten- sinergic system in different aspects of the stress response and the main stress-related disorders, such as depression and anxiety, post-traumatic stress disorder (PTSD) and its associated symptoms, such as fear memory and maternal separation, ethanol addiction, and substance abuse. Emphasis is put on gene, mRNA, and protein alterations of NT and NTSRs, as well as behavioral and pharmacological studies, leading to evidence-based suggestions on the implicated regulating mechanisms as well as their therapeutic exploitation. Stress responses and anxiety involve mainly NTSR1, but also NTSR2 and NTSR3. NTSR1 and NTSR3 are primarily implicated in depression, while NTSR2 and secondari- ly NTSR1 in PTSD. NTSR1 is interrelated with substance and drug abuse and NTSR2 with fear memory, while all NTSRs seem to be implicated in ethanol consumption. Some of the actions of NT and NTSRs in these pathological settings may be driven through interactions between NT and cortico- trophin releasing factor (CRF) in their regulatory contribution, as well as by NT’s pro-inflammatory mediating actions

Effects of tenascin-C in cultured hippocampal astrocytes: NCAM and fibronectin immunoreactivity changes.

International audienceTenascin-C is an extracellular matrix glycoprotein with trophic and repulsive properties on neuronal cells, involved in migratory processes of immature neurons. Previous reports demonstrated that this molecule is produced and secreted by astrocytes, in vitro after activation by bFGF or in vivo after CNS lesion. In injured brain the expression of tenascin-C has been correlated with the glial reaction since it was observed in regions suffering a dramatic glial proliferation and hypertrophy. In this report we show that the treatment of cultured hippocampal astrocytes with tenascin-C results in an increased fibronectin and NCAM immunoreactivities. In addition, treated astrocytes form longer extensions than control ones. The number of cells as well as the levels of GFAP mRNA and protein immunoreactivity are not modified after tenascin-C treatment. The present changes may, therefore, be related to the modification of the adhesive properties of astrocytes to the substrate. These observations are compatible with the hypothesis that tenascin-C may contribute to the glial scarring process

Pilocarpine-Induced Status Epilepticus in the Rat Hippocampus is Associated with Reactive Glia and Concomitant Increased Expression of CD31, PDGFRβ and Collagen IV in Endothelial Cells and Pericytes of the Blood Brain Barrier

Temporal lobe epilepsy (TLE) is associated with reorganization of neuronal networks, gliosis, neuroinflammation, loss of integrity of the blood brain barrier (BBB) in the hippocampus in humans and animal models. More than 30% of epilepsies remain intractable and characterization of the molecular mechanisms involved in BBB dysfunction is essential to the identification of new therapeutic strategies. In this work, we induced status epilepticus in rats by injection of the proconvulsant drug pilocarpine that leads to TLE. Using RT-qPCR, double immunohistochemistry and confocal imaging, we studied at different time points of epileptogenesis (latent phase, 3, 7, 14 days; chronic phase, 1 and 3 months) the regulation of reactive glia and vascular markers. In the hippocampus, increased expression of mRNA encoding the glial proteins GFAP and Iba1 confirmed neuroinflammatory status. We report for the first time the concomitant induction in endothelial cells, pericytes and basal membrane of the BBB of specific proteins CD31, PDGFR and ColIV, that peaks at the same time points as inflammation. The altered expression of these proteins occurs early in TLE, during the latent phase, suggesting that they could be associated with early rupture and pathogenicity of the BBB that will contribute to the chronic phase of epilepsy