From the dynamic synapse to synaptopathies

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There is increasing evidence that the dynamic regulation of synapse structure and function within neuronal circuits is an essential component of normal cognitive function. Multiple studies have demonstrated that changes in the number and shape of dendritic spines are key to the acquisition of learned behaviours. These actin rich dendritic protrusions are the sites for the majority of excitatory synapses within the mammalian forebrain, and contain a vast number of synaptic proteins, including glutamate receptors. The precise control of structural and functional plasticity is, therefore, critical for normal cognitive function. This is further emphasized by increasing evidence that alterations in the expression or function of key proteins that regulate these parameters are strongly associated with a range of neuropsychiatric and neurodegenerative disorders. Therefore, there is increasing interest in understanding whether modulation of structural and functional plasticity may offer a therapeutic avenue for the treatment of neuropsychiatric or neurodegenerative disorders.
The Srivastava lab is interested in understanding the molecular mechanisms underlying the dynamic regulation of structural and functional plasticity at excitatory synapses in response to extrinsic and intrinsic signals. Furthermore, the lab is interested in how these mechanisms are perturbed in a number of neurodevelopmental, psychiatric and neurodegenerative diseases, and how alteration in excitatory synaptic function may contribute to the pathophysiology of disease. Moreover, we are interested in whether it is possible to mimic how dendritic spines are regulated under physiological conditions, in order to ‘normalize’ aberrant synaptic structure and/or function. In this talk, I will highlight some recent work from our group that aims to understand how estrogens dynamically regulate synaptic structure and function. Estrogens are powerful regulators of cognition in both male and females, however, the precise mechanisms that underlie these effects are not well understood. Critically, recent clinical studies have indicated that estrogenic-based compounds have beneficial or neuroprotective effects in schizophrenia and Alzheimer’s disease. However, again, our understanding of how these effects occur are limited. Using a range of in vitro approaches, including primary cell cultures as well as neurons differentiated from patient-specific induced pluripotent stem cells to recapitulate synaptic pathology seen in disease, we find that estrogens are still capable of modulating synapse structure and function. Thus, we propose that the beneficial effects that estrogenic-based compounds exert are in part driven by their ability to modulate synaptic structure and function.