Exploring synaptic function and activity-dependent synapse-to-nucleus signaling

An important question in neuroscience is how does neuronal activity alter neuronal connectivity. This question is critically important since changes in connectivity and transmission underlie higher order brain functions such as learning and memory and likely play a role in the cognitive deficits observed in many neurological diseases. To explore this question, we employ proteomics and mass spectrometry, which provide us with a global overview of synaptic and nuclear complexity and allow us to explore their dynamics. Using these methods, we found that a number of synaptic components can shuttle to the neuronal nucleus in response to synaptic activity. These include PRR7 and AIDA-1, which binds to NMDA receptors (NMDAR) and links synaptic activity to nuclear functions. Recent studies implicate AIDA-1 in diverse psychiatric and developmental disorders including schizophrenia and Autism spectrum disorders. A single nucleotide polymorphism (SNP) in the AIDA-1 gene (ANKS1b) is associated with response to antipsychotics, suggesting AIDA-1 may play a role in schizophrenia. Moreover copy number variations (CNVs) and SNPs of AIDA-1 have been identified in patients with autism and correlate positively with impaired play skills in ASD. Moreover we have recently found that AIDA-1 can regulate the metabolism of the Amyloid Precursor Protein (APP) in neurons. AIDA-1 can promote the generation of amyloid beta peptides by regulating APP internalization, and may therefore it may play an important role in Alzheimer’s disease.

Moreover we found that certain RNA binding proteins (RNABPs) shuttle back into synaptic junctions in response to neuronal activity. We have recently shown that one of these proteins, Sam68, regulates the synaptic and dendritic expression of beta-actin and is crucial for proper spine morphology and synaptic function. Sam68 has been recently implicated in Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), which is a neurodegenerative disorder caused by mutations upstream of the FMR1 gene. We are therefore investigating if Sam68-dependent protein translation of cytoskeletal components can affect synaptic function and plasticity and ultimately behavior. We believe Sam68 plays a role in the generation and refining of neuronal networks. Understanding precisely how neurons regulate specific connections amongst their many thousand inputs is a central question in neuroscience. Therefore our lab employs broad-based proteomics methods to understand how synapses relay fast synaptic information to the nucleus and back, what are the key players in this process, and what role do these molecules play in brain pathologies.