Neuroscience Faculty

Research/Areas of Interest: My studies are defining novel roles of adenomatous polyposis coli (APC) and .-catenin (.-cat) proteins as key regulators of synaptic maturation and plasticity. Human genetic studies show strong correlations between dysregulation of .-cat functions and intellectual disabilities, and APC is the major negative regulator of .-cat. My work focuses on how up- or down-regulation of .-cat, in vivo, results in pathophysiological changes relevant to learning and memory. I am also identifying new roles for these proteins in regulating neuronal function through interactions with proteins such as the Fragile-X mental retardation protein (FMRP) as a means to regulate signal based mRNA translation at the synapse. The goal of my research is to provide insight into critical pathways as potential therapeutic targets for ameliorating the deficits associated with intellectual disability and autism. I am also currently working on a new disease model for CTNNB1 syndrome, a monogenic disorder that results in intellectual disabilities and muscular dystonia and spasticity in children. We are testing new generation inhibitors as preclinical proof of principle that increasing beta-catenin back to an effective range will restore the cognitive and muscle deficits we observe in our mouse model. In collaborative efforts with pediatric geneticists and the Simons Foundation, I am also currently working with human IPSCs derived from CTNNB1 syndrome patients. We will differentiate the iPSCs to both neuronal and muscle cells and test the therapeutic effectiveness of the drugs in these preclinical human cell models.

Research/Areas of Interest: My research focuses on astrocyte-neuron interactions and how astrocytic functions (glutamate clearance and K+ buffering) can modulate synaptic and somatic neuronal function. We have found novel neuronal control of astrocytic glutamate clearance kinetics with synapse specificity and fast kinetics. To investigate these questions, we use a combination of astrocyte and neuronal electrophysiology and cutting edge live imaging of glutamate, Ca2+, voltage, and other bio-sensors.

Research/Areas of Interest: Our research is focused on understanding the molecular basis of synapse function, with a focus on cell type-specific mechanisms. In particular, we are interested in the molecular mechanisms supporting function of glutamatergic synapses received by GABAergic inhibitory interneurons.

Research/Areas of Interest: My current interests are the physiology and pharmacology of channels belonging to the Cys-loop ligand-gated ion channel (LGIC) superfamily. These channels are associated with several neuropyschiatric disorders including epilepsy, anxiety, schizophrenia, depression, substance abuse and stroke. We use the patch-clamp technique to record and measure ion channel function of the following LGICs.

Research/Areas of Interest: The principal goal of my research is to understand how neurotransmission contributes to the function of neuronal networks. Neurotransmission is the most basic unit of neuronal communication. Disruption of the basic features of neurotransmission is associated with many neurological diseases. My lab aims to understand how specific properties of synaptic function contribute to network activity, and how changes in neurotransmission are involved in the pathology of disease states such as epilepsy and traumatic brain injury. We are specifically interested in astrocyte glutamate uptake, astrocyte/neuron interactions, GABAergic interneuron development, and metabolic control of neuronal activity. Using advanced neurotransmitter imaging, electrophysiological techniques, and more, my lab aims to answer questions about how neuronal network function is shaped by some of the most basic parameters of neurotransmission. We hope to contribute new understanding and novel therapies to treat epilepsy, traumatic brain injury, and other devastating neurological diseases.

Research/Areas of Interest: It is increasingly apparent that synapses are tripartite structures. In addition to the pre- and postsynaptic terminal, the astrocyte (a sub-type of glial cell) acts as a third element that wraps around the synaptic structure to control synapse formation and function. The goal of my laboratory is to identify the mechanisms by which astrocytes regulate synaptic transmission, neuronal circuits and their critical role in controlling behavior. Our recent studies also focus on the roles of these glial cells in disorders of the nervous system.

Research/Areas of Interest: Research in the Jackson lab is currently focused on exploring roles for glial cells (astrocytes) in modulating behavior, using the fruit fly Drosophila as a model. We are particularly interested in glial-neuron communication and its relevance to behavior, with emphasis on sleep and circadian behavior. Genetic or environmental insults affecting the circadian system result in alterations of sleep, seasonal depression and other neurological disorders. Our lab employs classical genetic approaches combined with genome-wide expression profiling, cellular imaging and behavioral studies to understand the neural circuitry controlling rhythmic behaviors. We have shown that glial astrocytes of the Drosophila brain are critical for normal rhythmicity and that they regulate the circadian neuronal circuitry (Suh and Jackson, 2007); Ng et al, 2011, 2015, 2016). In several studies, we have performed genome-wide translational profiling of adult fly astrocytes and conducted RNA interference (RNAi)-based genetic screens to identify specific glial factors that are required for circadian behavior or sleep (Huang et al, 2015; Ng et al, 2016). One such factor is a small secreted Ig-domain protein that is required in both astrocytes and neurons for normal sleep patterns (Sengupta et al., 2019). In other studies, we have identified microRNAs (miRNAs) and putative target mRNAs that are required in astrocytes for normal rhythmic behavior (You et al., 2018). In a recent study, we defined the 'rhythmic translatome' of astrocytes and demonstrated that certain rhythmic glial mRNAs encoding innate immune factors are required for normal sleep (You et al. 2021). Lab research continues to be focused on understanding the neural circuits and cellular pathways through which astrocytes and specific glial factors regulate behavior.

Research/Areas of Interest: Autism spectrum disorders (ASD) and intellectual disabilities (ID) are highly prevalent developmental brain disorders. Knowledge of the underlying pathophysiological changes is essential for developing therapeutic strategies. Emerging evidence from human genetic studies suggests that several of the risk genes for ASD, ID, and seizures (pediatric epileptic encephalopathies) converge on the adenomatous polyposis coli protein (APC), .-catenin (.-cat), canonical Wnt signaling pathway. However, direct tests that malfunction of this pathway can cause these disorders, and knowledge of the underlying mechanisms, are largely lacking. To address this important question, we have generated several novel mutant mouse lines with gain- or loss- of function in this pathway in neurons of the brain. We are determining the pathophysiological changes on behavioral, molecular, synaptic, and circuit levels. Additionally, we are using pharmacological approaches to test novel molecular targets with potential to ameliorate ID, ASD and seizures and thereby advance the design of effective therapeutic interventions. Our studies have identified APC as a key regulator of excitatory synaptic maturation and plasticity in both peripheral and central neurons. APC's synaptic functions were undefined prior to our work. Our current findings are identifying additional new roles for APC and .-cat in synaptic plasticity required for learning and memory formation. Our results are providing critical insights into molecular etiologies that cause learning impairments of different severities, autism-like behaviors and chronic seizures. To gain insights into the underlying pathophysiological changes, we have generated an APC conditional knock-out (cKO) mouse with APC deletion targeted to neurons during synaptic differentiation. APC cKO mice, compared with wild-type littermates, exhibit learning impairments, autism-like behaviors, reduced hearing and chronic seizures (pediatric epileptic encephalopathies) (Mohn et al, 2014; Hickman et al, 2015; Pirone et al, 2017, 2018).

Research/Areas of Interest: Alzheimer's disease (AD) accounts for approximately 70% of all cases of dementia. Currently, no cure or prevention for AD exists. During my predoctoral career, I conducted innovative studies on sporadic and familial AD mouse models aimed to elucidate the role of cerebellum in this pathology. Since I joined Dr. G. Tesco laboratory, I have been trying to comprehend the function of the protein GGA3 in both healthy and AD brains. I developed and advanced an innovative live cell imaging approach to investigate GGA3 trafficking in hippocampal neurons. I recently demonstrated that not only does GGA3 reside in axons, but fundamentally that this protein is essential for BACE1 trafficking regulation and homeostasis. Our current data demonstrate that GGA3 genetic deletion results in the accumulation of BACE1 in the axon of hippocampal neurons. Furthermore, we observed a general disruption of BACE1 axonal trafficking in GGA3 null neurons together with its accumulation in axonal swellings. We have also identified a novel AD-linked GGA3 loss of function mutation in late-onset AD patients. Altogether, our data demonstrate that GGA3 loss of function and consequent axonal accumulation of BACE1 initiate a cascade of events leading to AD-like axonopathy. Our studies provide a proof-of-concept that drugs aimed to preserve GGA3 function could be beneficial for AD treatment and/or prevention. Recently, I have been developing a new experimental approach to differentiate human neurons from iPSC derived from patient carrying familial AD mutations. I have already established a successful protocol to differentiate 2D iPSC-derived neuronal culture from these lines. Currently, I am collaborating with Dr. D. Kaplan to grow these neurons in silk-collagen protein scaffolds. This model is highly innovative. Differentiating neurons will grow in a donut-shaped porous silk sponge within an optically cleared collagen-filled central region which will allow, for the first time, live in vivo studies of a human Alzheimer's brain-like tissue during ageing under controlled experimental conditions.

Research/Areas of Interest: Research in the Maguire lab takes a systems physiology approach to studying the mechanisms contributing to neurological and neuropsychiatric diseases, with a focus on epilepsy and mood disorders. Our research has explored the impact of the neuroendocrine system on the comorbidity of epilepsy and depression as well as the role in postpartum depression. Working from the vantage point of synaptic changes, such as GABAergic dysregulation, to circuit dysfunction between the prefrontal cortex and the amygdala, to in vivo changes in excitability and behavior, we have explored many mechanistic levels contributing to neurological and neuropsychiatric diseases. We have incorporated cutting edge tools into our research program, where appropriate, to study the contribution of specific cell types and circuits in mediating physiological and pathological processes. Based on our discovery of neurosteroid-mediated alterations in GABAA receptor subunit expression during pregnancy and the postpartum period and our theory for a potential role in postpartum depression, a company designing neurosteroid-based treatment approaches embarked on a series of successful clinical trials for the treatment of postpartum depression. Our discoveries have also generated two useful mouse models of postpartum depression, leading to a collaboration with SAGE Therapeutics to perform preclinical studies on the underlying mechanisms and treatment options for postpartum depression. Our basic research program is also actively investigating the mechanisms of hypothalamic-pituitary-adrenal (HPA) axis regulation during the peripartum period and the contribution of dysregulation of the HPA axis in abnormal postpartum behaviors. Our research has also discovered a novel mechanism contributing to epilepsy progression and associated comorbidities, involving dysfunction in the regulation of the HPA axis. This work has carved out a niche in the field, establishing our lab as experts in this area. This work also earned two competitive research grants (RO1s) from the National Institutes of Health to fund this work. Our lab is presenting investigating the pathological consequences of seizure-induced activation of the HPA axis, focusing on the role of hypercortisolism in seizure susceptibility and associated comorbidities. Our research and technical expertise has led to collaborations with numerous faculty members within the Neuroscience Department at Tufts University School of Medicine (Steve Moss, Leon Reijmers, Maribel Rios), in other departments within the Tufts University School of Medicine (Carol Kumamoto, Larry Feig, Alain Charest), at Tufts University (Klaus Miczek), Tufts Medical Center (Jonas Galper, Julian Wu), and outside institutions (Bernard Luscher, Pennsylvania State University; Sue Paradis, Brandeis University).

Research/Areas of Interest: Research in my lab focuses on the receptors that mediate the actions of gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the vertebrate nervous system. GABA receptors are also critical drug targets for anti-convulsants, sedatives and anesthetics. We are interested in understanding how neurons regulate the accumulation of these critical inhibitory receptors on the neuronal surface in addition to their functional properties. Given that altered GABA receptor function plays critical roles in a number of neuropsychiatric disorders, the results may lead to new insights and therapeutic strategies for such debilitating disorders as epilepsy, anxiety, schizophrenia, depression and substance abuse.

Research/Areas of Interest: Our laboratory studies how neurons store a memory. Transgenic mice are used to tag neurons that are activated during memory encoding. The tag can be used to image, analyze and manipulate these neurons. Imaging tagged neurons in various brain regions provides important information on how circuits of neurons support memory storage and erasure. Tagged neurons can be analyzed for changes in gene expression, thereby elucidating molecular mechanisms of memory storage. Selective manipulation of tagged neurons can be used to control behavioral expression of a memory.

Research/Areas of Interest: Our laboratory uses molecular, biochemical, electrophysiological, behavioral and genetic tools to ascertain the role of brain-derived neurotrophic factor (BDNF) in the modulation of energy homeostasis and affective behavior. For this, we generate and study mice with central or site-specific deletion of the BDNF gene. Our efforts are focused on defining neural circuits in the brain modulated by BDNF to control appetite and affective states and the cellular and molecular mechanisms underlying the actions of this neurotrophin.

Research/Areas of Interest: My research investigates neurobiological mechanisms that underlie susceptibility to the onset of affective disorders, with an emphasis on adolescent maturation of the brain. In particular, my work focusses on limbic and prefrontal neural circuits, neuromodulator and transmitter dynamics, and behaviours of emotional regulation and decision-making. These analyses are conducted through a combination of technical approaches, including ex vivo electrophysiology, anatomical tracing and immunostaining, behavioural testing, and in vivo physiological measurements and manipulations.

Research/Areas of Interest: Josh's research interests include characterizing endogenous GABA A receptor subunit composition, investigating how this can influence receptor-interacting proteins, and how this dictates the pharmacology and sub-cellular localization of receptor sub-types. This work involves the development of large data-rich 'omic' technologies and bioinformatic analyses for the identification of novel GABA A receptor-related targets for neurological diseases.

Research/Areas of Interest: Alzheimer's disease (AD) is a devastating neurodegenerative disorder that results in loss of memory and cognitive function, eventually leading to dementia. A key neuropathological event in AD is the cerebral accumulation of senile plaques formed by aggregates of amyloid-beta-peptides derived from serial proteolysis of the amyloid precursor protein by BACE1 and gamma-secretase. Our studies have revealed a novel mechanism of BACE1 regulation mediated by the BACE1-interacting molecule GGA3. We are probing the molecular mechanisms with a long range goal of understanding AD pathogenesis.

Research/Areas of Interest: Astroglia is the most abundant non-neuronal cell type in mammalian central nervous system (CNS), actively participating in many CNS physiology and pathology. The main areas of research in the lab center on neuron to (astro)glial signaling in postnatal development and pathological conditions, including neurodegenerative diseases AD and ALS, neurodevelopmental disorders FXS, and others. These include the molecular mechanisms that regulate functional astroglial maturation during postnatal development, especially the role of neuronal signals; exosome-mediated communication between neurons and glia, and mechanisms of astroglial dysfunction in neurological diseases/disorders.