Glial Cells, Maladaptive Plasticity and Neurodegeneration: Mechanisms, Targeted Therapies and Future Directions

Recent advances strongly support the role of activated glial cells (microglia and astrocytes) to the perturbation of neuroglial interactions, synaptic circuitry and plasticity. This condition, called maladaptive plasticity, may represent an early stage of neuroinflammatory processes in neurodegenerative disorders of the central nervous system (CNS). The combination of other factors, including the release of proinflammatory mediators and the resulting activation of microglia and astrocytes (reactive gliosis), the alteration of neurovascular coupling and blood brain barrier, the changes of neurotransporters and neurotransmitters homeostasis, the failure of rescue mechanisms (release/production of trophic factors, GSH/antioxidants) and the energy impairment by metabolic or mitochondrial dysfunction, may initiate a cascade of events leading to disruption of the complex neuro-glial networks underlying neural homeostasis and connectivity within brain circuits. Thus, neurodegenerative diseases might be primarily regarded as maladaptive processes of altered neuro-glial-vascular interactions, in which early and profound alterations of glial activation have a clear impact on onset, progression and outcomes of the neuropathological process. Recently, 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. 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. As such, glial cells represent a further frontier in how brain works and represent an ideal target to prevent those alterations that ultimately lead to neuronal death and onset of disorders with dramatic clinical impact.

The biological complexity of the brain requires a systems biology approach, to integrate statistical computations of digital data, network construction of preexistent findings, mathematical models and new experiments in an iterative pathway to reconstruct the “logic” beneath this “organized complexity”. In this new emerging light, neurodegenerative diseases should be then considered as system biology disorders.

The potential subtopics of this collection of articles include, but are not limited to:

• In vitro/ex vivo evidence of glial-induced perturbation of synaptic homeostasis
• Animal models of glial-induced neurodegenerative and neuroinflammatory disorders
• Gliotransmitters involved in neurodegeneration and neuroinflammation
• Advanced imaging of neuroglial networks
• Artificial tissue engineering for neurodegenerative and neuroinflammatory disorders
• Targeting glial cells and modulation of glial activation by novel molecules
• Neurotrophin signaling and neuroglial interactions
• Astrocytic-induced selective neuronal degeneration
• Morpho-functional modulation of glial cells by non-invasive brain stimulation techniques
• Big data analysis of neural networks involved in metabolic, inflammatory and neurodegenerative pathways

This Research Topic seeks contributions in the form of original research articles, reviews, perspectives, commentaries and opinions.