Astrocytic dysfunction: insights on the role in neurodegeneration.
For decades, astrocytes have been regarded as passive partners of neurons in central nervous system (CNS) function. Studies of the last 20 years, however, challenged this view by demonstrating that astrocytes possess functional receptors for neurotransmitters and respond to their stimulation via release of gliotransmitters, including glutamate. Notably, astrocytes react to synaptically released neurotransmitters with intracellular calcium ([Ca(2+)]) elevations, which result in the release of glutamate via regulated exocytosis and, possibly, other mechanisms. These findings have led to a new concept of neuron-glia intercommunication where astrocytes play an unsuspected dynamic role by integrating neuronal inputs and modulating synaptic activity. The additional observation that glutamate release from astrocytes is controlled by molecules linked to inflammatory reactions, such as the cytokine tumor necrosis factor alpha (TNFalpha) and prostaglandins (PGs), suggests that glia-to-neuron signalling may be sensitive to changes in the production of these mediators occurring in pathological conditions. Indeed, a local, parenchymal brain inflammatory reaction (neuroinflammation) characterized by astrocytic and microglial activation has been reported in several neurodegenerative disorders, including AIDS dementia complex, Alzheimer's disease and amyotrophic lateral sclerosis. This transition may be accompanied by functional de-regulation and even degeneration of the astrocytes with the consequent disruption of the cross-talk normally occurring between these cells and neurons. Incorrect neuron-astrocyte interactions may be involved in neuronal derangement and contribute to disease development. The findings reported in this review suggest that a better comprehension of the glutamatergic interplay between neurons and astrocytes may provide information about normal brain function and also highlight potential molecular targets for therapeutic interventions in pathology.
Rossi
Daniela
D
Department of Pharmacological Sciences, Center of Excellence on Neurodegenerative Diseases, University of Milan, 20133 Milan, Italy. daniela.rossi@unimi.it
Volterra
Andrea
A
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology*; D002118:Calcium / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology
D018698:Glutamic Acid; D002118:Calcium