Faculty Bibliography

Astrocytes constitute approximately 30% of the cells in the mammalian central nervous system (CNS). They are integral to brain and spinal-cord physiology and perform many functions important for normal neuronal development, synapse formation, and proper propagation of action potentials. We still know very little, however, about how these functions change in response to immune attack, chronic neurodegenerative disease, or acute trauma. In this review, we summarize recent studies that demonstrate that different initiating CNS injuries can elicit at least two types of "reactive" astrocytes with strikingly different properties, one type being helpful and the other harmful. We will also discuss new methods for purifying and investigating reactive-astrocyte functions and provide an overview of new markers for delineating these different states of reactive astrocytes. The discovery that astrocytes have different types of reactive states has important implications for the development of new therapies for CNS injury and diseases.

APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-beta pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-alpha (TNF-alpha) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-alpha. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an epsilon4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-beta pathology with symptomatic Alzheimer disease who usually have tau pathology, epsilon4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-beta pathology. ApoE4 exerts a 'toxic' gain of function whereas the absence of ApoE is protective.

The calcium-binding protein calbindin-D28k is critical for hippocampal function and cognition, but its expression is markedly decreased in various neurological disorders associated with epileptiform activity and seizures. In Alzheimer's disease (AD) and epilepsy, both of which are accompanied by recurrent seizures, the severity of cognitive deficits reflects the degree of calbindin reduction in the hippocampal dentate gyrus (DG). However, despite the importance of calbindin in both neuronal physiology and pathology, the regulatory mechanisms that control its expression in the hippocampus are poorly understood. Here we report an epigenetic mechanism through which seizures chronically suppress hippocampal calbindin expression and impair cognition. We demonstrate that DeltaFosB, a highly stable transcription factor, is induced in the hippocampus in mouse models of AD and seizures, in which it binds and triggers histone deacetylation at the promoter of the calbindin gene (Calb1) and downregulates Calb1 transcription. Notably, increasing DG calbindin levels, either by direct virus-mediated expression or inhibition of DeltaFosB signaling, improves spatial memory in a mouse model of AD. Moreover, levels of DeltaFosB and calbindin expression are inversely related in the DG of individuals with temporal lobe epilepsy (TLE) or AD and correlate with performance on the Mini-Mental State Examination (MMSE). We propose that chronic suppression of calbindin by DeltaFosB is one mechanism through which intermittent seizures drive persistent cognitive deficits in conditions accompanied by recurrent seizures.

Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease, but their role is poorly understood. Here we show that a subtype of reactive astrocytes, which we termed A1, is induced by classically activated neuroinflammatory microglia. We show that activated microglia induce A1 astrocytes by secreting Il-1alpha, TNF and C1q, and that these cytokines together are necessary and sufficient to induce A1 astrocytes. A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when the formation of A1 astrocytes is blocked. Finally, we show that A1 astrocytes are abundant in various human neurodegenerative diseases including Alzheimer's, Huntington's and Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. Taken together these findings help to explain why CNS neurons die after axotomy, strongly suggest that A1 astrocytes contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders, and provide opportunities for the development of new treatments for these diseases.

Blind source separation-the extraction of independent sources from a mixture-is an important problem for both artificial and natural signal processing. Here, we address a special case of this problem when sources (but not the mixing matrix) are known to be nonnegative-for example, due to the physical nature of the sources. We search for the solution to this problem that can be implemented using biologically plausible neural networks. Specifically, we consider the online setting where the data set is streamed to a neural network. The novelty of our approach is that we formulate blind nonnegative source separation as a similarity matching problem and derive neural networks from the similarity matching objective. Importantly, synaptic weights in our networks are updated according to biologically plausible local learning rules.

During embryogenesis, neural progenitors in the ganglionic eminences give rise to diverse GABAergic interneuron subtypes that populate all forebrain regions. The extent to which these cells are genetically predefined or determined by postmigratory environmental cues remains unknown. To address this question, we performed homo- and heterotopic transplantation of early postnatal MGE-derived cortical and hippocampal interneurons. Grafted cells migrated, and displayed neurochemical, electrophysiological, morphological, and neurochemical profiles similar to endogenous interneurons. Our results indicate that the host environment regulates the proportion of interneuron classes in the brain region. However, some specific interneuron subtypes retain characteristics representative of their donor brain regions.

Glioblastoma (GBM) stem cells (GSCs) reside in both hypoxic and vascular microenvironments within tumors. The molecular mechanisms that allow GSCs to occupy such contrasting niches are not understood. We used patient-derived GBM cultures to identify GSC subtypes with differential activation of Notch signaling, which co-exist in tumors but occupy distinct niches and match their metabolism accordingly. Multipotent GSCs with Notch pathway activation reside in perivascular niches, and are unable to entrain anaerobic glycolysis during hypoxia. In contrast, most CD133-expressing GSCs do not depend on canonical Notch signaling, populate tumors regardless of local vascularity and selectively utilize anaerobic glycolysis to expand in hypoxia. Ectopic activation of Notch signaling in CD133-expressing GSCs is sufficient to suppress anaerobic glycolysis and resistance to hypoxia. These findings demonstrate a novel role for Notch signaling in regulating GSC metabolism and suggest intratumoral GSC heterogeneity ensures metabolic adaptations to support tumor growth in diverse tumor microenvironments.

Psychiatric disorders are amongst the most prevalent and impairing conditions in childhood and adolescence. Unfortunately, it is well known that general practitioners (GPs) and other frontline health providers (i.e., child protection workers, public health nurses, and pediatricians) are not adequately trained to address these ubiquitous problems (Braddick et al. Child and Adolescent mental health in Europe: infrastructures, policy and programmes, European Communities, 2009; Levav et al. Eur Child Adolesc Psychiatry 13:395-401, 2004). Advances in technology may offer a solution to this problem with clinical decision support systems (CDSS) that are designed to help professionals make sound clinical decisions in real time. This paper offers a systematic review of currently available CDSS for child and adolescent mental health disorders prepared according to the PRISMA-Protocols (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols). Applying strict eligibility criteria, the identified studies (n = 5048) were screened. Ten studies, describing eight original clinical decision support systems for child and adolescent psychiatric disorders, fulfilled inclusion criteria. Based on this systematic review, there appears to be a need for a new, readily available CDSS for child neuropsychiatric disorder which promotes evidence-based, best practices, while enabling consideration of national variation in practices by leveraging data-reuse to generate predictions regarding treatment outcome, addressing a broader cluster of clinical disorders, and targeting frontline practice environments.