The overall goal of this research program is to better understand the role of kalirin-7 in excitatory synaptic transmission and plasticity and how disruption of the function of this protein might be involved in complex neuropsychiatric disorders such as schizophrenia and Alzheimer's disease. The applicant for this K99/R00 Pathway to Independence Award, Dr. Bruce Herring, is a postdoctoral fellow with Dr. Roger Nicoll at UCSF. Dr. Herring's long-term career goal is to lead an independent research laboratory in basic neuroscience research as a tenure-track principle investigator in an academic research institution. Dr. Herring's long-term research goal is to use a combination of cellular, molecular, electrophysiological, imaging, biochemical and genetic approaches to elucidate the cellular and synaptic level mechanisms that govern synaptic transmission, underlie synaptic plasticity and give rise to neuropsychiatric disease. Though etiological mechanisms underlying schizophrenia remain largely unknown, a convergence of pharmacologic, genetic and morphological data implicates a dysregulation of spine stability, excitatory transmission and synaptic plasticity in tis disease. Kalirin-7 has been shown to have a critical role in spino- and synaptogenesis and maintenance, is regulated by DISC1, a protein heavily implicated in schizophrenia, and several mutations in the KALRN gene have been identified as possible genetic risk factors for this disease. Furthermore, phosphorylation of an N-terminal threonine residue (T95) by CaMKII augments kalirin-7's ability to activate small GTPases that are involved in regulating synapse morphology. CaMKII is critical in the induction of long-term potentiation (LTP), a phenomenon thought to be one of the primary mechanisms underlying synaptic plasticity and generally regarded as the cellular basis of learning and memory. However, the targets of CaMKII phosphorylation responsible for giving rise to LTP have not been identified. Given kalirin-7's potential role in LTP, coupled with the implication of this protein in dendritic spine maintenance and a number of neuropsychiatric diseases, may indicate that kalirin-7 represents a key point of convergence between the molecular mechanisms underlying learning, memory and neuropsychiatric disorders. Using a combination of innovative genetic approaches allowing endogenous kalirin to be replaced with recombinant kalirin-7 mutants in individual neurons, Dr. Herring proposes a systematic investigation into the role of kalirin-7 phosphorylation by CaMKII in excitatory synaptic morphology, function and learning and memory. By combining his training in molecular and cellular biology, pharmacology and synaptic electrophysiology, Dr. Herring will pursue additional training in imaging and biochemical methods to address the following specific aims: 1) Determine the role kalirin-7 phosphorylation plays in the regulation of excitatory synapses, learning and memory;2) Identify whether kalirin-7 and Trio represent redundant pathways supporting LTP;3) Identify functionally relevant protein-protein interactions involving kalirin-7. Successful completion of this application will identify new mechanisms and new proteins underlying and modulating LTP and will open new frontiers for the development of disease-modifying therapeutic approaches for schizophrenia and other neuropsychiatric disorders. Furthermore, the training period afforded by the K99/R00 Award will provide Dr. Herring with a powerful toolbox for his independent career investigating the molecular mechanisms underlying synaptic transmission, plasticity and disease.
Given kalirin-7's potential role in synaptic plasticity, coupled with the implication of this protein in dendritic spine maintenance and a number of neuropsychiatric diseases, may indicate that kalirin-7 represents a key point of convergence between the molecular mechanisms underlying learning, memory and neuropsychiatric disorders. I propose the use of innovative strategies to precisely identify how kalirin-7 regulatio impacts synaptic transmission, plasticity and learning and memory. A detailed understanding of kalirin-7's role in synaptic morphology and function will provide critical insights that may lead t the identification of novel molecular targets for therapeutic intervention and drug development.
|Sadybekov, Anastasiia; Tian, Chen; Arnesano, Cosimo et al. (2017) An autism spectrum disorder-related de novo mutation hotspot discovered in the GEF1 domain of Trio. Nat Commun 8:601|