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In the mammalian central nervous system, reactive oxygen species (ROS) generation is counterbalanced by antioxidant defenses. When large amounts of ROS accumulate, antioxidant mechanisms become overwhelmed and oxidative cellular stress may occur. Therefore, ROS are typically characterized as toxic molecules, oxidizing membrane lipids, changing the conformation of proteins, damaging nucleic acids, and causing deficits in synaptic plasticity. High ROS concentrations are associated with a decline in cognitive functions, as observed in some neurodegenerative disorders and age-dependent decay of neuroplasticity. Nevertheless, controlled ROS production provides the optimal redox state for the activation of transductional pathways involved in synaptic changes. Since ROS may regulate neuronal activity and elicit negative effects at the same time, the distinction between beneficial and deleterious consequences is unclear. In this regard, this review assesses current research and describes the main sources of ROS in neurons, specifying their involvement in synaptic plasticity and distinguishing between physiological and pathological processes implicated.

We investigated whether fluoxetine, a widely prescribed medication for treatment of depression, restores neuronal plasticity in the adult visual system of the rat. We found that chronic administration of fluoxetine reinstates ocular dominance plasticity in adulthood and promotes the recovery of visual functions in adult amblyopic animals, as tested electrophysiologically and behaviorally. These effects were accompanied by reduced intracortical inhibition and increased expression of brain-derived neurotrophic factor in the visual cortex. Cortical administration of diazepam prevented the effects induced by fluoxetine, indicating that the reduction of intracortical inhibition promotes visual cortical plasticity in the adult. Our results suggest a potential clinical application for fluoxetine in amblyopia as well as new mechanisms for the therapeutic effects of antidepressants and for the pathophysiology of mood disorders.

Immunotherapy is changing the therapeutic landscape of many hematologic diseases, with immune checkpoint inhibitors, bispecific antibodies, and CAR-T therapies being its greatest expression. Unfortunately, immunotherapy in acute myeloid leukemia (AML) has given less brilliant results up to now, and the only approved drug is the antiCD33 antibody-drug conjugate gemtuzumab ozogamicin. A promising field of research in AML therapy relies on anti-leukemic vaccination to induce remission or prevent disease relapse. In this review, we analyze recent evidence on AML vaccines and their biological mechanisms. The principal proteins that have been exploited for vaccination strategies and have reached clinical experimental phases are Wilm’s tumor 1, proteinase 3, and RHAMM. the majority of data deals with WT1-base vaccines, given also the high expression and mutation rates of WT1 in AML cells. Stimulators of immune responses such as TLR7 agonist and interleukin-2 have also proven anti-leukemic activity both in vivo and in vitro. Lastly, cellular vaccines mainly based on autologous or allogeneic off-the-shelf dendritic cell-based vaccines showed positive results in terms of T-cell response and safety, also in elderly patients. Compared to other immunotherapeutic strategies, anti-AML vaccines have the advantage of being a less toxic and a more manageable approach, applicable also to elderly patients with poorer performance status, and may be used in combination with currently available therapies. As for the best scenario in which to use vaccination, whether in a therapeutic, prophylactic, or preemptive setting, further studies are needed, but available evidence points to poorer results in the presence of active or high-burden disease. Given the poor prognosis of relapsed/refractory or high-risk AML, further research is urgently needed to better understand the biological pathways that sustain its pathogenesis. In this setting, research on novel frontiers of immunotherapy-based agents, among which vaccines represent important actors, is warranted to develop new and efficacious strategies to obtain long-term disease control by immune patrolling.

Loss of visual acuity caused by abnormal visual experience during development (amblyopia) is an untreatable pathology in adults. We report that environmental enrichment in adult amblyopic rats restored normal visual acuity and ocular dominance. These effects were due to reduced GABAergic inhibition in the visual cortex, accompanied by increased expression of BDNF and reduced density of extracellular-matrix perineuronal nets, and were prevented by enhancement of inhibition through benzodiazepine cortical infusion.

Models of firing rate homeostasis such as synaptic scaling and the sliding synaptic plasticity modification threshold predict that decreasing neuronal activity (for example, by sensory deprivation) will enhance synaptic function. Manipulations of cortical activity during two forms of visual deprivation, dark exposure (DE) and binocular lid suture, revealed that, contrary to expectations, spontaneous firing in conjunction with loss of visual input is necessary to lower the threshold for Hebbian plasticity and increase miniature excitatory postsynaptic current (mEPSC) amplitude. Blocking activation of GluN2B receptors, which are upregulated by DE, also prevented the increase in mEPSC amplitude, suggesting that DE potentiates mEPSCs primarily through a Hebbian mechanism, not through synaptic scaling. Nevertheless, NMDA-receptor-independent changes in mEPSC amplitude consistent with synaptic scaling could be induced by extreme reductions of activity. Therefore, two distinct mechanisms operate within different ranges of neuronal activity to homeostatically regulate synaptic strength.

[...]many neurological diseases and neuropsychiatric disorders are today interpreted as alterations in plasticity mechanisms. Using in vivo recordings and genetic manipulations, they show that cortical plasticity accompanying behavioral habituation occurs across seconds, minutes, and days of repeated stimulus experience. [...]they characterized the role of NMDA receptors and parvalbumin-positive interneurons in such processes, identifying a range of mechanistically separable forms of plasticity occurring at different timescales in the same learning mouse. dos Santos Cardoso et al., focus on the analysis of the potentially beneficial effect of photobiomodulation (transcranial near-infrared laser treatment) on the aging brain. By investigating the expression and activation of distinct intracellular signaling proteins in the cerebral cortex and hippocampus of aged rats treated with the transcranial near-infrared laser, they identify that this experimental approach improves intracellular signaling pathways linked to cell survival, memory, and glucose metabolism.

Important functions of the prefrontal cortex (PFC) are established during early life, when neurons exhibit enhanced synaptic plasticity and synaptogenesis. This developmental stage drives the organization of cortical connectivity, responsible for establishing behavioral patterns. Serotonin (5-HT) emerges among the most significant factors that modulate brain activity during postnatal development. In the PFC, activated 5-HT receptors modify neuronal excitability and interact with intracellular signaling involved in synaptic modifications, thus suggesting that 5-HT might participate in early postnatal plasticity. To test this hypothesis, we employed intracellular electrophysiological recordings of PFC layer 5 neurons to study the modulatory effects of 5-HT on plasticity induced by theta-burst stimulation (TBS) in two postnatal periods of rats. Our results indicate that 5-HT is essential for TBS to result in synaptic changes during the third postnatal week, but not later. TBS coupled with 5-HT 2A or 5-HT 1A and 5-HT 7 receptors stimulation leads to long-term depression (LTD). On the other hand, TBS and synergic activation of 5-HT 1A , 5-HT 2A , and 5-HT 7 receptors lead to long-term potentiation (LTP). Finally, we also show that 5-HT dependent synaptic plasticity of the PFC is impaired in animals that are exposed to early-life chronic stress.

Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MCs) in extra-cutaneous organs. It could be divided into indolent SM, smoldering SM, SM with an associated hematologic (non-MC lineage) neoplasm, aggressive SM, and mast cell leukemia. SM is generally associated with the presence of a gain-of-function somatic mutation in KIT at codon 816. Clinical features could be related to MC mediator release or to uncontrolled infiltration of MCs in different organs. Whereas indolent forms have a near-normal life expectancy, advanced diseases have a poor prognosis with short survival times. Indolent forms should be considered for symptom-directed therapy, while cytoreductive therapy represents the first-line treatment for advanced diseases. Since the emergence of tyrosine kinase inhibitors (TKIs), KIT inhibition has been an attractive approach. Initial reports showed that only the rare KITD816V negative cases were responsive to first-line TKI imatinib. The development of new TKIs with activity against the KITD816V mutation, such as midostaurin or avapritinib, has changed the management of this disease. This review aims to focus on the available clinical data of therapies for SM and provide insights into possible future therapeutic targets.

Background: Blinatumomab (Blina) and inotuzumab ozogamicin (InO) has improved the outcome of relapsed/refractory B-lymphoblastic leukemia (R/R B-ALL). However, little is known about the outcome after recurrence and re-treatment with immunotherapy. Methods: We describe 71 R/R B-ALL patients treated for different relapses with Blina and InO. Blina was the first treatment in 57 patients and InO in 14. Twenty-seven patients had a previous allogeneic hematopoietic stem cell transplantation (allo-HSCT). Results: In the Blina/InO group, after Blina, 36 patients (63%) achieved a complete remission (CR), with 42% of negative minimal residual disease (MRD−); after InO, a CR was achieved in 47 patients (82%, 34 MRD−). In the InO/Blina group, after InO, 13 cases (93%) reached a CR (6 MRD−); after Blina, a CR was re-achieved in 6 cases (43%, 3 MRD−). Twenty-six patients proceeded to allo-HSCT. In the Blina/InO group, the median overall survival (OS) was 19 months; the disease-free survival (DFS) after Blina was 7.4 months (11.6 vs. 2.7 months in MRD− vs. MRD+, p = 0.03) and after InO, 5.4 months. In the InO/Blina group, the median OS was 9.4 months; the median DFS after InO was 5.1 months and 1.5 months after Blina (8.7 vs. 2.5 months in MRD− vs. MRD+, p = 0.02). With a median follow-up of 16.5 months from the start of immunotherapy, 24 patients (34%) are alive and 16 (22%) are alive in CR. Conclusion: In our series of R/R B-ALL, Blina and InO treatment demonstrate efficacy for subsequent relapses in terms of MRD response, OS and DFS, and as a bridge to allo-HSCT.

The ketogenic diet is a therapeutic strategy applied to reduce brain hyperexcitability in conditions such as epilepsy, Parkinson’s and Alzheimer’s disease, migraines, and autism. This diet reduces circulating glucose levels and increases ketone bodies, with β-hydroxybutyrate (BHB) being one of the leading promoters of the beneficial effects. BHB was previously reported as a mediator of cognitive restoration and memory formation. Herein, we investigate the effect of exogenous BHB on hippocampal neuronal excitability and synaptic plasticity mechanisms, regardless of the pathological or neurodegenerative conditions. Electrophysiological experiments were conducted to explore both passive and active neuronal properties, including action potential firing and spontaneous and evoked postsynaptic responses. Electrical stimulation along the CA3-CA1 pathway enabled the assessment of both short- and long-term synaptic plasticity, as well as the mechanisms mediated by AMPA and NMDA receptors. Experiments were conducted in hippocampal slices treated with 3-β-hydroxybutyrate glycerides (DHB) and niacin (HCAR2 agonist). Although DHB incubation did not alter passive membrane properties, it significantly increased neuronal excitability, reflected in an elevated firing rate upon depolarizing stimulation and enhanced spontaneous excitatory postsynaptic currents in CA1 pyramidal neurons, which were dependent on synaptic inputs. DHB treatment led to a reduction in long-term potentiation (LTP) in CA1 neurons, suggesting a metaplastic effect independent of NMDA receptor activation. Importantly, these DHB-induced neuronal alterations were found to be independent of HCAR2 receptor activation, supporting the involvement of distinct intracellular pathways and long-term modulatory mechanisms. Our findings indicate that DHB exerts a modulatory effect on hippocampal neural activity by enhancing excitability and concurrently promoting a compensatory reduction in LTP, suggesting a homeostatic balancing mechanism.