Research

Molecular mechanisms of synaptic plasticity
           Changes in the strength of synaptic connections are thought to be essential for various brain functions, including: developmental plasticity, learning and memory, and drug addiction. The best understood models of synaptic plasticity are long-term potentiation (LTP) and long-term depression (LTD). Most details of the cellular and molecular mechanisms underlying LTP and LTD are known from studies using in vitro hippocampal slice preparations. Previous studies have provided clear evidence that LTP and LTD in the CA1 region of the hippocampus is dependent on postsynaptic modification of AMPA receptors. Theses changes involve phosphorylation of AMPA receptor subunits and targeting receptors to synaptic locations. Our laboratory is interested in understanding the role and function of AMPA receptor phosphorylation in mediating synaptic plasticity. In addition to understanding the basic mechanisms of LTP and LTD, we are investigating how these mechanisms change as the animals develop into adults.
Model: Mechanisms of AMPA receptor regulation during synaptic plasticity.
Molecular mechanisms of global plasticity in visual cortex
 

Anu's experiment room.

           It is known that visual cortex function can be altered by neural activity driven by visual experience. Research on the cellular mechanisms of visual cortical plasticity has focused mainly on activity-dependent changes that occur rapidly (on the order of minutes) and locally at specific synapses, such as LTP and LTD. However, theoretical considerations indicate that the maintenance of stability in neural networks requires additional global mechanisms of plasticity that operate at a slower time scale (hours to days). Two proposed mechanisms that can mediate global plasticity to homeostatically regulate synaptic strength are "synaptic scaling" and "sliding threshold". Such global changes in synaptic weight are especially important in periods of enhanced plasticity, such as during postnatal development. We are currently determining the molecular mechanisms that mediate global synaptic plasticity in the visual cortex, especially focusing on the role of AMPA receptor regulation.  
Whole-cell recording in brain slices.
   
Synaptic physiology and plasticity in BACE1 (beta-site APP cleavage enzyme 1) knockout mice: A model for the treatment of Alzheimer's disease?
 
Visualization of phosphorylated AMPA receptors in hippocampal slices using immunohistochemical labeling.
            Alzheimer's disease is a progressive neurodegenerative disorder that starts as a pure loss of memory that later results in severe cognitive deficits in elderly patients. This disease is characterized by the deposition of beta-amyloid and neurofibrillary tangles in the brain. Beta-amyloid peptides are formed by proteolytic cleavage of amyloid precursor proteins (APPs) by beta- and gamma-secretases. BACE1 is the principal neuronal beta-secretase required for the generation of beta-amyloid peptides. Therefore, inhibition of BACE activity has surfaced as a potential therapeutic technique for blocking beta-amyloid peptide production, and hence the progression of Alzheimer's disease. In order to use BACE inhibitors to effectively treat Alzheimer's disease, it is pertinent to understand the function of BACE. To this end, we are examining the role of BACE1 in synaptic physiology and plasticity using BACE1 knockout mice generated by Dr. Philip Wong's laboratory at the Johns Hopkins School of Medicine.

Kaiwen preps for an experiment.