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Dysfunctions of the neuronal-glial crosstalk and/or impaired signaling of neurotrophic factors represent key features of the maladaptive changes in the central nervous system (CNS) in neuroinflammatory as neurodegenerative disorders. Tissue plasminogen activator (tPA)/plasminogen (PA)/plasmin system has been involved in either process of maturation and degradation of nerve growth factor (NGF), highlighting multiple potential targets for new therapeutic strategies. We here investigated the role of intrathecal (i.t.) delivery of neuroserpin (NS), an endogenous inhibitor of plasminogen activators, on neuropathic behavior and maladaptive synaptic plasticity in the rat spinal cord following spared nerve injury (SNI) of the sciatic nerve. We demonstrated that SNI reduced spinal NGF expression, induced spinal reactive gliosis, altering the expression of glial and neuronal glutamate and GABA transporters, reduced glutathione (GSH) levels and is associated to neuropathic behavior. Beside the increase of NGF expression, i.t. NS administration reduced reactive gliosis, restored synaptic homeostasis, GSH levels and reduced neuropathic behavior. Our results hereby highlight the essential role of tPA/PA system in the synaptic homeostasis and mechanisms of maladaptive plasticity, sustaining the beneficial effects of NGF-based approach in neurological disorders.

Understanding the biological complexity of the central nervous system (CNS) is a frontier in neuroscience. Morphological organization of the CNS represents the basis for its functional properties underlying higher brain functions; therefore, efforts are needed to boost the comprehension of the organization of the CNS, from the ultrastructural to the functional-networks level.To date, two highly integrated and interconnected cellular networks substantiate the anatomofunctional organization of CNS: neurons and non-neuronal cells, namely glial cells. Glial cells, including astrocytes, oligodendrocytes, and microglia, actively participate in many complex functions within the CNS (immunity surveillance and inflammatory response, metabolic and synaptic homeostasis, modulation of blood-brain barrier?BBB) (Volterra and Meldolesi, 2005). Moreover, interaction with the elements of the extracellular matrix (ECM), an active player for long-term plasticity and circuit maintenance, adds another level of complexity to the modern model of the synapse structure (tetrapartite synapse) (Song and Dityatev, 2018). Therefore, if on one hand glial cells allow adaptive synaptic plasticity of CNS in several physiological conditions modulating synaptic transmission, homeostasis, and neural pathways signaling, then on the other, when activated, they boost inflammatory response and perturb neuroglial interactions, synaptic circuitry, and plasticity. This new condition, called maladaptive synaptic plasticity, may represent an early stage of neuroinflammatory processes in neurodegenerative disorders (Papa et al., 2014). Recently, it has been hypothesized that the morpho-functional heterogeneity of astrocytes in different brain regions might explain the regional diversity of astrocytic response to an external injury and the selectivity of neuronal degeneration (Cragnolini et al., 2018, 2020). Therefore, the comprehension of these mechanisms is relevant for the development of targeted therapies for clinical management of neurodegenerative disorders. Only through unraveling the complex interactions between the different cell types at the synapse, we will truly understand synaptic plasticity, higher brain functions, and how perturbations of these interactions contribute to brain diseases with dramatic clinical impact. Fil: Korai, Sohaib Ali. Università degli Studi della Campania "Luigi Vanvitelli"; Italia Fil: Sepe, Giovanna. Università degli Studi della Campania "Luigi Vanvitelli"; Italia Fil: Luongo, Livio. Università degli Studi della Campania "Luigi Vanvitelli"; Italia Fil: Cragnolini, Andrea Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina Fil: Cirillo, Giovanni. Università degli Studi della Campania "Luigi Vanvitelli"; Italia

Non-invasive low-intensity transcranial electrical stimulation (tES) of the brain is an evolving field that has brought remarkable attention in the past few decades for its ability to directly modulate specific brain functions. Neurobiological after-effects of tES seems to be related to changes in neuronal and synaptic excitability and plasticity, however mechanisms are still far from being elucidated. We aim to review recent results from in vitro and in vivo studies that highlight molecular and cellular mechanisms of transcranial direct (tDCS) and alternating (tACS) current stimulation. Changes in membrane potential and neural synchronization explain the ongoing and short-lasting effects of tES, while changes induced in existing proteins and new protein synthesis is required for long-lasting plastic changes (LTP/LTD). Glial cells, for decades supporting elements, are now considered constitutive part of the synapse and might contribute to the mechanisms of synaptic plasticity. This review brings into focus the neurobiological mechanisms and after-effects of tDCS and tACS from in vitro and in vivo studies, in both animals and humans, highlighting possible pathways for the development of targeted therapeutic applications.