Reference number : GC-2017-Q1-03264, amendment number : , agreement type : G, recipient legal name : Ramsey, Amy (University of Toronto), recipient country : CA, recipient province : nan, recipient city : Ontario, recipient postal code : nan, program name english : Discovery Grants Program - Individual, program name french : Programme de subventions à la découverte - individuelles, program purpose english : NMDA receptors (NMDARs) are a type of glutamate neurotransmitter receptor that is widely expressed in the central nervous system. NMDARs are highly conserved among mammals and are found throughout the animal kingdom. One reason for their presence in all animals is that they play a fundamental role in the process of synaptic plasticity. Synaptic plasticity refers to the process by which neurons change the strength and number of connections in the developing brain and throughout life. 
 
NMDARs are required for many forms of synaptic plasticity, and when NMDAR function is compromised, it impacts the patterns of connections that are made during development and impairs learning and memory. Interestingly, there is growing evidence that synaptic plasticity is accompanied by changes in the number and morphology of dendritic spines. Accordingly, NMDAR dysfunction leads to a loss of dendritic spines, although the molecular events that cause this have not been determined. 
 
In our laboratory, we have studied the impact of NMDAR dysfunction using a genetic mouse model. NMDAR knockdown mice have reductions in cortical and striatal spine density, and have impaired learning and memory in several cognitive tasks. We have begun to elucidate the molecular changes that occur when NMDARs are dysfunctional, and have identified changes in the RhoGTPase signal transduction pathway. This pathway is known to regulate actin cytoskeleton dynamics, and changes in Rho signaling lead to changes in spine number and morphology. Therefore, we hypothesize that the impact of NMDAR dysfunction on RhoGTPase signaling is the cause of spine loss. 
 
The overall goal of this proposal is to elucidate the molecular machinery that connects NMDAR activity to changes in spine number and morphology. In the first aim, we will study how components of the RhoGTPase pathways are affected by genetic or pharmacologic blockade of NMDARs. In the second aim of this proposal, we will manipulate the levels and activity of RhoGTPase effectors to determine whether this reverses spine deficits and cognitive impairments that are caused by NMDAR dysfunction., program purpose french : NMDA receptors (NMDARs) are a type of glutamate neurotransmitter receptor that is widely expressed in the central nervous system. NMDARs are highly conserved among mammals and are found throughout the animal kingdom. One reason for their presence in all animals is that they play a fundamental role in the process of synaptic plasticity. Synaptic plasticity refers to the process by which neurons change the strength and number of connections in the developing brain and throughout life. 
 
NMDARs are required for many forms of synaptic plasticity, and when NMDAR function is compromised, it impacts the patterns of connections that are made during development and impairs learning and memory. Interestingly, there is growing evidence that synaptic plasticity is accompanied by changes in the number and morphology of dendritic spines. Accordingly, NMDAR dysfunction leads to a loss of dendritic spines, although the molecular events that cause this have not been determined. 
 
In our laboratory, we have studied the impact of NMDAR dysfunction using a genetic mouse model. NMDAR knockdown mice have reductions in cortical and striatal spine density, and have impaired learning and memory in several cognitive tasks. We have begun to elucidate the molecular changes that occur when NMDARs are dysfunctional, and have identified changes in the RhoGTPase signal transduction pathway. This pathway is known to regulate actin cytoskeleton dynamics, and changes in Rho signaling lead to changes in spine number and morphology. Therefore, we hypothesize that the impact of NMDAR dysfunction on RhoGTPase signaling is the cause of spine loss. 
 
The overall goal of this proposal is to elucidate the molecular machinery that connects NMDAR activity to changes in spine number and morphology. In the first aim, we will study how components of the RhoGTPase pathways are affected by genetic or pharmacologic blockade of NMDARs. In the second aim of this proposal, we will manipulate the levels and activity of RhoGTPase effectors to determine whether this reverses spine deficits and cognitive impairments that are caused by NMDAR dysfunction., agreement title english : Molecular pathways connecting NMDA receptors to synapse number, agreement title french : Molecular pathways connecting NMDA receptors to synapse number, agreement number : RGPIN, agreement value : 26000.0, agreement start date : 2017-05-10, agreement end date : nan, description english : nan, description french : nan, expected results english : nan, expected results french : nan, additional information english : Grant or Award spanning more than one fiscal year. (2017-2018 to 2018-2019), additional information french : Subvention ou bourse octroyée s'appliquant à plus d'un exercice financier. (2017-2018 à 2018-2019), owner organization : nserc-crsng, owner organization title : Natural Sciences and Engineering Research Council of Canada | Conseil de recherches en sciences naturelles et en génie du Canada