Glial Regulation of Synaptic Function in Plasticity and Disease
Astrocytes are the most abundant cell type in the human brain, yet we still do not fully understand the impact of astrocytes on human disease. We have begun to uncover the role of astrocytes in regulating cortical plasticity using several new technologies, including quantitative mass spectroscopy and microfluidic chambers that I have developed to rapidly identify additional astrocyte factors released in response to paracrine signals that impact plasticity and affect both the developing and adult brain. Additionally, we are taking advantage of the outstanding stem cell work here at UCSF to ask whether astrocytes derived from somatic cells from individuals on the autism spectrum secrete altered levels of synaptogenic factors using a combined microfluidic chamber and imaging system. These studies have the potential uncover the role of glial cells in normal plasticity and disease.
Molecular Mechanisms Regulating Synapse Formation and Function
What molecular signals impact the number and function of synapses? We have used our unique cell culture systems to screen for genes and small RNAs that impact synaptic transmission. In one ongoing project, we have identified the miRNA pathway as an important regulator of a variety of neuronal and synaptic processes. Alterations of miRNA expression both at the global level and the single miRNA level can profoundly affect synaptic function. Currently we are investigating several miRNAs and newly discovered small RNAs that regulate neuronal function. In another project, we have identified regulators of cell adhesion as important for the proper establishment of functional connections. These regulators are members of the Wint, Disheveled, Catenin signaling pathway and this pathway may be linked to Autism Spectrum Disorders.
Activity-Dependent Regulation of Synaptic Circuits
Activity has long been known to play a critical role in the establishment of precise connections in the mammalian nervous system. How activity does this is still not completely understood. We have developed a number of transgenic mice that allow us to manipulate activity and synaptic transmission in a defined population of CNS neurons and determine how precise functional connections are changed. These studies allow us to further screen for molecular regulators of synaptic connections within these defined neuronal populations and identify mechanisms that lead to remodeling of CNS connections.