Research areas
Understanding our focus
Mechanisms of estrogen modulation of neural circuitry
The neurosteroid estrogen is fast emerging as a key regulator of synaptic plasticity, but how estrogen achieves this is still unclear.
So far the Srivastava lab has:
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Identified key signalling pathways involved in estrogenic-modulation of synaptic plasticity.
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Identified a novel form of spine plasticity, whereby estrogen “prime” neurons to respond to subsequent synaptic-activity stimuli with greater efficacy. This is achieved by estrogen acutely modulating spine structure and functional plasticity in neural circuits.
We are now focused on dissecting the molecular mechanisms and signalling pathways that underlie this novel form of plasticity in vitro as well as in vivo.
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This will provide a mechanistic understanding of how this neurosteroid controls structural and functional plasticity and how this regulation may be relevant for its effects on cognition.
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Additionally, we are using neurons generated from patient specific induced pluripotent stem cells (iPSCs) to investigate the potential therapeutic value, and underlying mechanisms, of estrogen-based compounds in treatment of schizophrenia.
Recent work in the lab has focused on:
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Using human neural stem cells as an additional cellular model to further elucidate mechanisms that are critical for the development of neurodevelopmental disorders.
Utilizing this approach, as well as neurons differentiated from human induced pluripotent stem cells (hiPSC-neurons).
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We have investigated the biological function of ZNF804a, the first gene to be identified by GWAS studies as a risk factor for schizophrenias, bi-polar and more recently, autism spectrum disorders.
This work has identified that ZNF804a regulates early development of neuronal morphology, and moreover, is required for the maintenance of synapse number.
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We are also utilized patient specific hiPSC-neurons from individuals diagnosed with schizophrenia or autism spectrum disorders (ASDs), to investigate the mechanisms that contribute to the emergence of these disorders.
Translating genetic susceptibility into cellular functions
Work in this area has focused on determining the role of disease associated factors on different aspects of synaptic biology.
Modelling disease using patient-specific iPSCs
In collaboration with clinical researchers, psychiatrists and pharmaceutical companies.
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We will continue examining the mechanisms underlying the development of neurodevelopmental disorders using multiple cellular systems.
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Moreover, we will establish whether manipulating neuromodualtory signalling can be utilized to rescue specific cognitive deficits, such as working memory and depression, which are a principal symptom of disorders such as schizophrenia.
Critically, the work that we are currently undertaking using patient derived iPSCs, places us in an ideal situation to:
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model disease progression and elucidate the key molecular players involved in the emergence of disease.
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In addition, we will be able to use this cellular system to help develop and screen potential small molecule compounds, aimed for the treatment of neurodevelopmental disorders.
Excitingly, we would also be well placed to undertake projects in which we would be able to:
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Follow specific patients through a series of diagnostics screenings, genomics, functional imaging, and pharmaceutical interventions, whilst being able to model the ongoing cellular and molecular events in iPSC-neurons.
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Ultimately, this will aid in the development of more effective, efficient and personalised treatments for patients with these devastating disorders.
In a number of disorders, key synaptic proteins are thought to be mislocalized, indicating that the mechanisms underlying their targeting and/or trafficking maybe compromised.
In order to investigate mechanism relevant for the localization and/or trafficking of key synaptic proteins required for normal neuronal function.
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We have investigated the function of 2 scaffold proteins, afadin and X-11 in these processes.
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We have discovered that afadin, a target of the small GTPase Rap1, directly binds GluA1 and 2-subunits of AMPA receptors and is key in determining their synaptic targeting and maintenance under basal conditions.
Recently we have also demonstrated that:
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X11, a protein implicated in Alzheimer’s disease.
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X11 is a dynamic protein within post-synaptic compartments.
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Moreover, it regulates the trafficking and targeting of key synaptic protein from golgi-outposts to synapses.
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Protein trafficking & metabolism at the Synapse
An emerging theme is that the precise localization and trafficking of proteins to and from specific sub-cellular compartments is key in determine a protein’s function.
Fig. 9 (VanLeeuwen et al. 2014)