Thursday, November 21, 2024
11/21/2024
DESCRIPTION (provided by applicant): Neuroligins are cell-surface proteins expressed postsynaptically at excitatory and inhibitory synapses, and mutations in the genes coding for these proteins and their binding partners have been found in autism spectrum disorders. These disorders are characterized by impaired social interactions, and several mice with either knockout of neuroliginl or knock-in of a mutation found in autistic patients are known to have impaired social behavior. Recent studies have found mutations in many activity-dependent genes in autistic patients, and it is possible that the neuroligins are important in activity-dependent synaptic plasticity. The objective of this study is to investigate the role of neuroligins in synaptic plasticity at excitatory and inhibitory synapses, in order to better understand the role of neuroligins in physiology and pathophysiology. Neuroliginl (NL1) is believed to recruit NMDA receptors (NMDA R) to synapses. Long-term potentiation (LTP) of NMDA R current has been demonstrated at the mossy fiber-CA3 synapse in acute hippocampal slices. To test whether NL1 is necessary for this plasticity, acute hippocampal slices will be prepared from NL-1 knockout mice and their wild-type littermates. Whole cell recordings will be made from CAS neurons while stimulating the mossy fiber pathway to induce NMDA R LTP. The basal NMDA Rexcitatory postsynaptic current (EPSC) will also be measured in WT and KO animals. To determine the region of NL1 necessary for this plasticity, various deletion constructs of NL1 will be delivered via stereotactic injection of viral vectors to try to rescue the NMDA R LTP in the NL1-KO. To determine the specificity of the NL isoform necessary for the LTP, the NL2 and NL3-KO mice will also be tested. Neuroligin2 (NL2) appears to recruit GABAA receptors postsynaptically. Insulin application and NMDA application have been shown to cause insertion of GABAA receptors in hippocampal neurons. These drugs will be applied individually to acute hippocampal slices from NL2 KO mice and their WT littermates, while monitoring inhibitory postsynaptic currents (IPSCs) via whole cell recording from CA1 pyramidal cells. In addition, recordings will be performed in which the pipette solution will contain either the activated form of Protein Kinase B/Akt, which mediates the effect of insulin, or calcium/calmodulin to activate CaM Kinase II, the effector of the NMDA response, while monitoring elPSCs in WT and NL2-KO slices. Synaptic plasticity is believed to underlie learning and memory, the basis for behavior. Neuroligins are synaptic proteins that have been implicated by genetic studies in autism spectrum disorders. This proposal strives to determine the role of neuroligins in synaptic plasticity in the brain.
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