Astrocyte development—More questions than answers

The past 15–20 years has seen a remarkable shift in our understanding of astrocyte contributions to central nervous system (CNS) function. Astrocytes have emerged from the shadows of neuroscience and are now recognized as key elements in a broad array of CNS functions. Astrocytes comprise a substantial fraction of cells in the human CNS. Nevertheless, fundamental questions surrounding their basic biology remain poorly understood. While recent studies have revealed a diversity of essential roles in CNS function, from synapse formation and function to blood brain barrier maintenance, fundamental mechanisms of astrocyte development, including their expansion, migration, and maturation, remain to be elucidated. The coincident development of astrocytes and synapses highlights the need to better understand astrocyte development and will facilitate novel strategies for addressing neurodevelopmental and neurological dysfunction. In this review, we provide an overview of the current understanding of astrocyte development, focusing primarily on mammalian astrocytes and highlight outstanding questions that remain to be addressed. We also include an overview of Drosophila glial development, emphasizing astrocyte-like glia given their close anatomical and functional association with synapses. Drosophila offer an array of sophisticated molecular genetic tools and they remain a powerful model for elucidating fundamental cellular and molecular mechanisms governing astrocyte development. Understanding the parallels and distinctions between astrocyte development in Drosophila and vertebrates will enable investigators to leverage the strengths of each model system to gain new insights into astrocyte function

Calpain mediates proteolysis of the voltage-gated sodium channel alpha-subunit

Alterations in the expression, molecular composition, and localization of voltage-gated sodium channels play major roles in a broad range of neurological disorders. Recent evidence identifies sodium channel proteolysis as a key early event after ischemia and traumatic brain injury, further expanding the role of the sodium channel in neurological diseases. In this study, we investigate the protease responsible for proteolytic cleavage of voltage-gated sodium channels (NaChs). NaCh proteolysis occurs after protease activation in rat brain homogenates, pharmacological disruption of ionic homeostasis in cortical cultures, and mechanical injury using an in vitro model of traumatic brain injury. Proteolysis requires Ca2+ and calpain activation but is not influenced by caspase-3 or cathepsin inhibition. Proteolysis results in loss of the full-length {alpha}-subunits, and the creation of fragments comprising all domains of the channel that retain interaction even after proteolysis. Cell surface biotinylation after mechanical injury indicates that proteolyzed NaChs remain in the membrane before noticeable evidence of neuronal death, providing a mechanism for altered action potential initiation, propagation, and downstream signaling events after Ca2+ elevation

Habituation Learning Is a Widely Affected Mechanism in Drosophila Models of Intellectual Disability and Autism Spectrum Disorders

BACKGROUND: Although habituation is one of the most ancient and fundamental forms of learning, its regulators and its relevance for human disease are poorly understood. METHODS: We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and we tested these models in light-off jump habituation. We dissected neuronal substrates underlying the identified habituation deficits and integrated genotype-phenotype annotations, gene ontologies, and interaction networks to determine the clinical features and molecular processes that are associated with habituation deficits. RESULTS: We identified >100 genes required for habituation learning. For 93 of these genes, a role in habituation learning was previously unknown. These genes characterize ID disorders with macrocephaly and/or overgrowth and comorbid ASD. Moreover, individuals with ASD from the Simons Simplex Collection carrying damaging de novo mutations in these genes exhibit increased aberrant behaviors associated with inappropriate, stereotypic speech. At the molecular level, ID genes required for normal habituation are enriched in synaptic function and converge on Ras/mitogen-activated protein kinase (Ras/MAPK) signaling. Both increased Ras/MAPK signaling in gamma-aminobutyric acidergic (GABAergic) neurons and decreased Ras/MAPK signaling in cholinergic neurons specifically inhibit the adaptive habituation response. CONCLUSIONS: Our work supports the relevance of habituation learning to ASD, identifies an unprecedented number of novel habituation players, supports an emerging role for inhibitory neurons in habituation, and reveals an opposing, circuit-level-based mechanism for Ras/MAPK signaling. These findings establish habituation as a possible, widely applicable functional readout and target for pharmacologic intervention in ID/ASD