There are an estimated hundred billion neurons in the human brain and they are connected to each other via physical contact points called synapses. Synapses enable neurons to communicate with each other. The hundreds of trillions of synapses in our brain establish neural circuitries that guide how we think, move and feel. More than a thousand different proteins are found at synapses and they form complex protein networks. Paradoxically, synapses are both insoluble and yet also plastic. On the one hand, synapses are isolated biochemically as the ‘triton-insoluble' fraction. Yet on the other hand, in vivo, synapses come and go. Synapses grow ‘weaker' and ‘stronger', as their adhesive properties and their ability to transmit signals change. Significantly, properties of synapses also appear to change as a function of their activity. External stimuli such as events triggering memory and learning, stress, and exposure to chemicals such as drugs of abuse, anti-depressants and anti-psychotics, all seem to affect synapses and the connections they form. Many different neuropsychiatric disorders and neurodegenerative disorders are increasingly being referred to as ‘synaptopathies', emphasizing the role of disrupted synaptic structure and function in the pathogenesis of these disorders. By unraveling how the many different synaptic proteins interact with each other and form complex protein networks, we hope to not only gain fundamental insight into how neurons communicate with each other enabling the brain to function, but also to discover new potential therapeutic targets.
Our laboratory is particularly fascinated by the complex protein networks in the synaptic cleft found at chemical synapses, i.e. the 250 Å space between the ‘pre-synaptic' membrane which hosts the exocytosis machinery for synaptic vesicles and the ‘post-synaptic' membrane which hosts machinery responding to the transmitted chemical signals. We are studying a number of synaptic adhesion molecules and synaptic organizers to understand their role in mediating synapse formation, maintenance, and plasticity. One family of synaptic adhesion molecules that we have studied extensively is the family of neurexins. Neurexins play a role in synapse organization and adhesion. Mutations and lesions in neurexins have recently been implicated in autism spectrum disorder, schizophrenia and mental retardation. Excitingly, not only neurexins, but also many of their direct protein partners in the synaptic cleft are implicated in these diseases as well (Fig. 1). Neurexins and their partners must touch fundamental biological processes that are involved in the pathogenesis of these disorders, but it is not clear which processes these are and the exact role that neurexins and their partners play in these processes.
Fig. 1: Synaptic interactome centered around neurexin 1alpha. Alpha-neurexin splice forms (blue ovals)interact directly with a number of different synaptic proteins including neuroligins, LRRTMs, neurexophilins, alpha-dystroglycan, and GABAA-receptors, while CASK and SHANK are recruited (directly and indirectly) in the cytosol as well. Alpha-neurexins and many of their partners are implicated in autism spectrum disorder, schizophrenia and mental retardation (underlined in red), and strikingly, these same genes contribute to multiple disorders.
Our laboratory is working to understand on a molecular level how neurexins, their partners, as well as a number of other synaptic organizers recognize, bind, and arrange different synaptic partners in the synaptic cleft impacting synaptic function. By understanding the molecular mechanisms of these molecules, we will be able to not only further delineate their role at synapses but also understand why these molecules, when disrupted, contribute to neurological disorders. We use biochemical and biophysical techniques as well as protein crystallography (Fig. 2).
Fig. 2: Understanding how proteins look in three dimensions (their chemical formula) by solving their structure helps us understand how these proteins work at the synapse and carry out their function.
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