We are interested in the organization and dynamics of biological circuits underlying the assembly of functional neural circuits in the mammalian brain. We employ a “bottom-up” approach to tackle this problem, based on the investigation of genes and pathways at the level of individual synapses, intact neural circuits and behavioral outcomes. Our research is multidisciplinary, combining transgenic mouse models with cutting-edge live-cell imaging, chemical genetics, protein chemistry, electrophysiology and behavior. Current projects in the lab focus on: (i) the interaction of the endoplasmic reticulum with excitatory synapses, (ii) mitochondrial dynamics in neural circuits implicated in schizophrenia, (iii) micro-RNAs and the synaptic transcriptome, and (iv) mechanisms of cellular self-assembly.
(i). Signaling from the endoplasmic reticulum to the synapse
(Collaboration with Profs. Zoe Bichler (NNI) and Saji Sreedhaaran (NUS)).
The endoplasmic reticulum (ER) is a continuous and dynamic network of tubular membranes that extends throughout the axon and dendrites, protruding into large dendritic spines. The ER has long been associated with various forms of synaptic plasticity, but little is known as to how this organelle communicates with synapses and instructs specific synaptic modifications. Electron microscopy studies from the 1960's showed that the ER makes close contacts with the plasma membrane (PM) in neurons. We are exploring the role of these ER-PM contact sites in synaptic physiology. We are particularly interested in the ER-resident STIM proteins, which sense Ca2+ concentration in the ER and migrate to ER-PM junctions upon ER Ca2+ depletion. STIMs (STIM1 and STIM2 in mammals) regulate store operated Ca2+ entry in non-excitable cells, but their function in the brain is largely unknown. We have generated forebrain-specific STIM1, STIM2 and double STIM1/STIM2 cKO mouse models, which we are using to explore the impact of STIMs on synaptic transmission in neural circuits underlying learning/memory, as well as social behaviors.
(ii). Mitochondrial dynamics in neural circuits implicated in mood disorders.
(Collaboration with Prof. Kozo Kaibuchi, Kyoto Univ.)
DISC1 (Disrupted-in-Schizophrenia-1) is now considered one of the most probable susceptibility gene for psychiatric illness, but the impact of this gene on synaptic circuits underlying cognitive (dys)functions remains poorly understood. Using a DISC1 KO mouse (generated by Kozo Kaibuchi's lab) and a combination of optical and electrophysiological measurement of synaptic properties, we are evaluating the impact of DISC1 on synaptic transmission/plasticity in the hippocampus, a region of the brain strongly implicated in schizophrenia and other mental illnesses. We are also exploring the relationship between DISC1 and mitochondrial dynamics in the context of synaptic functions.
(iii). Micro-RNAs in presynaptic function
(Collaboration with Prof. Mathijs Voorhoeve, NUS)
Using an array of synapse-based imaging assays in combination with a bioinformatics approach, we are screening for micro-RNAs (miRs) that regulate distinct aspects of presynaptic assembly and function, from the formation of a functional active zone to neurotransmitter release. Our results indicate that several key steps in synaptic transmission are under the control of a network of miRs. The identification of these miRs synaptic targets is under way.
In an effort to quantitatively analyze the global impact of miRs on synapse composition, we are analyzing the synapse transcriptome in a dicer cKO mouse model using nanoString technologies. We are particularly interested in mapping changes in the synapse transcriptome in response to different synaptic activationand behavioral paradigms.
(iv). Cellular self-assembly
(Collaboration with Prof. Takanari Inoue, Johns Hopkins.)
The ability of cells to spontaneously self-organize is central to a variety of important biological outcomes, such as cell migration, neuronal polarization, tissue patterning and regeneration. We are interested in mapping the signaling network that enables migratory cells (fibroblasts) to self-polarize and initiate a migratory response in the absence of spatial cues. We are using chemical genetics in combination with quantitative live-cell imaging to address this issue. We have recently identified a self-perpetuating signaling circuit, comprised of HRas and PI3K, which is required for the initiation and maintenance of cell movement (Mol. Cell. Biol. 2013. July;(24):2228-37) (PDF).