Synaptic pathology in multiple sclerosis: a role for Nogo-A signaling in astrocytes?

Astrocytes, the most abundant glial cells in the mammalian brain, are critical regulators of brain development and physiology through dynamic and often bidirectional interactions with neuronal synapses. Despite the clear importance of astrocytes for the establishment and maintenance of proper synaptic connectivity, our understanding of their role in brain function is still in its infancy. We propose that this is at least in part due to large gaps in our knowledge of the cell biology of astrocytes and the mechanisms they use to interact with synapses. In this review, we summarize some of the seminal findings that yield important insight into the cellular and molecular basis of astrocyte-neuron communication, focusing on the role of astrocytes in the development and remodeling of synapses. Furthermore, we will pose some pressing questions that need to be addressed to advance our mechanistic understanding of the role of astrocytes in regulating synaptic development.

Multiple sclerosis (MS) has long been regarded as a chronic inflammatory disease of the white matter that leads to demyelination and eventually to neurodegeneration. In the past decade, several aspects of MS pathogenesis have been challenged, and degenerative changes of the grey matter, which are independent of demyelination, have become a topic of interest. CNS inflammation in MS and experimental autoimmune encephalomyelitis (EAE; a disease model used to study MS in rodents) causes a marked imbalance between GABAergic and glutamatergic transmission, and a loss of synapses, all of which leads to a diffuse 'synaptopathy'. Altered synaptic transmission can occur early in MS and EAE, independently of demyelination and axonal loss, and subsequently causes excitotoxic damage. Inflammation-driven synaptic abnormalities are emerging as a prominent pathogenic mechanism in MS-importantly, they are potentially reversible and, therefore, represent attractive therapeutic targets. In this Review, we focus on the connection between inflammation and synaptopathy in MS and EAE, which sheds light not only on the pathophysiology of MS but also on that of primary neurodegenerative disorders in which inflammatory processes contribute to disease progression.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system, leading to memory impairment in up to 65% of patients. Memory dysfunction in MS has been associated with loss of synapses in the hippocampus, but its molecular basis is unknown. Accumulating evidence suggests that components of the complement system, C1q and C3, can mediate elimination of synapses.