The ability of synapses to change their functional and structural properties in response to activity, called synaptic plasticity, is essential for experience-dependent adjustments of brain function. A widely expressed mechanism of synaptic plasticity in the CNS involves long-term changes in neurotransmitter release. Dysregulation of presynaptic plasticity has been implicated in the pathophysiology of a number of neuropsychiatric conditions, including cognitive disorders, autism spectrum disorders (ASD), intellectual developmental disabilities, mood disorders, schizophrenia, epilepsy and drug addiction. Despite significant advancements in the molecular basis of neurotransmission, exactly how transmitter release is modified in a long-term manner remains largely unknown. Here, we hypothesize that local presynaptic translation is a highly regulated, activity-dependent process that mediates functional and structural presynaptic plasticity at both excitatory and inhibitory synapses in the mature mammalian brain. To test our hypothesis we will utilize a number of complementary approaches that specifically target the presynaptic neuron. As a model system, we will focus on rodent hippocampal synapses that express mechanistically similar forms of presynaptic plasticity. We seek to determine the identity of presynaptic mRNAs that undergo translation and demonstrate their presence in axons, as well as visualize local protein synthesis in axon terminals (Aim 1). In addition, we will determine the requirements and main properties of activity-dependent presynaptic remodeling implicated in long-term presynaptic plasticity, including the translational pathways involved and the role of actin cytoskeletal dynamics (Aim 2). Though mRNA transcripts can be found in axons, how their translation is controlled remains poorly understood. We will test the hypothesis that presynaptic FMRP regulates both structural and functional presynaptic plasticity presumably by controlling local presynaptic protein synthesis (Aim 3). Lastly, we will visualize and characterize BDNF release from axon terminals and test the hypothesis that BDNF/TrkB signaling mediates structural and functional plasticity and promotes local protein synthesis in axons. Successful completion of these aims will likely provide substantial insights and may establish general principles into the mechanisms underlying presynaptic plasticity and its dysregulation in brain disorders.
Experience-dependent adjustments of brain function, as it happens during learning and memory, critically rely on activity-dependent modifications of neural circuits that mainly occur at synapses. Alterations of this process is thought to underlie several brain diseases such as autism, epilepsy and major psychiatric disorders. The proposed studies seek to demonstrate a role for local protein synthesis in activity-dependent remodeling of the presynaptic compartment and long-term changes in neurotransmitter release.
