Biology subjects

Xapelli, S.

Publications and source records attributed to Xapelli, S..

4 recordsLinked to original sources

bioRxiv2024

Cleavage of the TrkB-FL Receptor During Epileptogenesis: Insights from a Kainic Acid-Induced Model of Epilepsy and Human Samples

AO_SCPLOWBSTRACTC_SCPLOWBrain-derived neurotrophic factor (BDNF) is essential for neuronal survival, differentiation, and plasticity. In epilepsy, BDNF exhibits a dual role, exerting both antiepileptic and pro-epileptic effects. The cleavage of its main receptor, full-length tropomyosin-related kinase B (TrkB-FL), was suggested to occur in status epilepticus (SE) in vitro. Moreover, under excitotoxic conditions, TrkB-FL was found to be cleaved, resulting in the formation of a new intracellular fragment, TrkB-ICD. Thus, we hypothesized that TrkB-FL cleavage and TrkB-ICD formation could represent an uncovered mechanism in epilepsy. We used a rat model of mesial temporal lobe epilepsy (mTLE) induced by kainic acid (KA) to investigate TrkB-FL cleavage and TrkB-ICD formation during SE and established epilepsy (EE). Animals treated with 10 mg/kg of KA exhibited TrkB-FL cleavage during SE, with hippocampal levels of TrkB-FL and TrkB-ICD correlating with seizure severity. Notably, TrkB-FL cleavage and TrkB-ICD formation were also detected in animals with EE, which exhibited spontaneous recurrent convulsive seizures, neuronal death, mossy fiber sprouting, and long-term memory impairment. Importantly, hippocampal samples from patients with refractory epilepsy also showed TrkB-FL cleavage with increased TrkB-ICD levels. Additionally, overexpression of TrkB-ICD in the hippocampus of healthy rodents resulted in long-term memory impairment. Our findings suggest that TrkB-FL cleavage and the subsequent TrkB-ICD production occur throughout epileptogenesis, with the extent of cleavage correlating positively with seizure occurrence. Moreover, we found that TrkB-ICD impairs memory. This work uncovers a novel mechanism in epileptogenesis that could serve as a potential therapeutic target in mTLE, with implications for preserving cognitive function.

neuroscience↗

bioRxiv2024

Brain-derived neurotrophic factor and adenosine A2A receptor interaction modulates oligodendrogenesis derived from postnatal SVZ neural stem cells

Oligodendrocytes (OLs) are vital for myelin formation in the Central Nervous System. OLs can be produced by the maturation of oligodendrocyte precursor cells (OPCs) present throughout the brain parenchyma or from the differentiation of subventricular zone-derived neural stem cells (SVZ-NSCs). Importantly, efficient differentiation from SVZ-NSCs remains a significant area of research due to its potential for remyelination in demyelinating disorders. In this work, we studied the role of brain-derived neurotrophic factor (BDNF) and adenosine A2A receptors (A2ARs), as well as the putative crosstalk between these two modulatory mechanisms, in regulating oligodendrogenesis from SVZ-NSCs. Using a neurosphere culture system, we observed that BDNF significantly increased the mRNA expression levels of OPC cell markers after 2 days in vitro (DIV), an effect blocked by the A2AR antagonist ZM 241385. This early transcriptional regulation by BDNF was followed by changes in the percentage of both OPCs and mature OLs in culture at DIV 7 and 14. Interestingly, blocking A2ARs prevented the potentiating effect of BDNF on the percentage of OLs at DIV 14. Concerning the morphology of mature OLs, BDNF influenced their maturation by reducing branching near the soma at DIV 7, an effect that was not observed at 14 DIV, when all treatments resulted in similar OL morphology. Overall, our results establish BDNF as a regulator of OL formation from SVZ-NSCs, with A2AR-BDNF interaction modulating the differentiation process.

neuroscience↗

bioRxiv2023

Unravelling a novel role for Cannabidivarin in the modulation of subventricular zone postnatal neurogenesis

Postnatal neurogenesis has been shown to rely on the endocannabinoid system. Here we aimed at unravelling the role of Cannabidivarin (CBDV), a non-psychoactive cannabinoid, with high affinity for the non-classical cannabinoid receptor TRPV1, on subventricular zone (SVZ) postnatal neurogenesis. Using the neurosphere assay, SVZ-derived neural stem/progenitor cells (NSPCs) were incubated with CBDV and/or 5-Iodoresinferotoxin (TRPV1 antagonist), and their role on cell viability, proliferation, and differentiation were dissected. CBDV was able to promote, through a TRPV1-dependent mechanism, cell survival, cell proliferation and neuronal differentiation. Furthermore, pulse-chase experiments revealed that CBDV-induced neuronal differentiation was a result of cell cycle exit of NSPCs. Regarding oligodendrocyte differentiation, CBDV inhibited oligodendrocyte differentiation and maturation. Since our data suggested that the CBDV-induced modulation of NSPCs acted via TRPV1, a sodium-calcium channel, and that intracellular calcium levels are known regulators of NSPCs fate and neuronal maturation, single cell calcium imaging was performed to evaluate the functional response of SVZ-derived cells. We observed that CBDV-responsive cells displayed a two-phase calcium influx profile, being the initial phase dependent on TRPV1 activation. Taken together, this work unveiled a novel and untapped neurogenic potential of CBDV via TRPV1 modulation. These findings pave the way to future neural stem cell biological studies and repair strategies by repurposing this non-psychoactive cannabinoid as a valuable therapeutic target.

neuroscience↗

bioRxiv2023

Cannabinoid type 2 receptor inhibition enhances the antidepressant and proneurogenic effects of physical exercise after chronic stress

Chronic stress is a major risk factor of neuropsychiatric conditions such as depression. Adult hippocampal neurogenesis (AHN) has emerged as a promising target to counteract stress-related disorders given the ability of newborn neurons to facilitate endogenous plasticity. Recent data sheds light on the interaction between cannabinoids and neurotrophic factors underlying the regulation of AHN, with important effects upon cognitive plasticity and emotional flexibility. Since physical exercise (PE) is known to enhance neurotrophin levels, we hypothesized that PE could engage with cannabinoids to influence AHN and that this would result in beneficial effects under stressful conditions. We therefore investigated the actions of modulating cannabinoid type 2 receptors (CB2R), which are devoid of psychotropic effects, in combination with PE in chronically stressed animals. We found that CB2R inhibition, but not CB2R activation, in combination with PE significantly ameliorated stress-evoked emotional changes and cognitive deficits. Importantly, this combined strategy critically shaped stress-induced changes in AHN dynamics, leading to a significant increase in the rates of cell proliferation and differentiation of newborn neurons, and an overall reduction in neuroinflammation. Together, these results show that CB2Rs are crucial regulators of the beneficial effects of PE in countering the effects of chronic stress. Our work emphasizes the importance of understanding the mechanisms behind the actions of cannabinoids and PE and provides a framework for future therapeutic strategies to treat stress-related disorders that capitalize on lifestyle interventions complemented with endocannabinoid pharmacomodulation.

neuroscience↗