Synapses

Function of individual synapses

Glutamatergic synapses formed onto projection neurons are typically associated with the head of a dendritic spine.  Using imaging and electrophysiological approaches, we are examining the signaling cascades that are active in individual dendritic spines and that regulate the activity of the associated postsynaptic terminal.  We have found an extraordinary complexity within active spines by which cascades of ion channels and kinases modulate synapse structure and function on rapid time scales.

 

Interplay between activity and synapse formation

During postnatal development, there is an explosion of synaptogenesis and spinogenesis in many brain areas, including cerebral cortex and striatum.  We are using molecular, pharmacological, and electrophysiological approaches to determine the triggers and regulators of activity-dependent synapse formation in the mammalian brain.

 

Synapses and disease

Many neuropsychiatric diseases are caused by mutations in proteins that are at or associated with synapses.  How do these mutations lead to the manifestations of the disease?  This is a particular perplexing question for autism and autism-spectrum disorders for which there is no clear relationship or connection between many of the genes associated with the disorder.  Our current focus is on the Tuberous Sclerosis Complex proteins, which regulate the mTOR pathway, as well as on the synaptically localized cell-adhesion molecules of the Neuroligin family. Our research has shown that the TSC pathway is required for the expression of metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD). Thus, despite both syndromes being commonly associated with autism, proteins necessary for Fragile-X syndrome and Tuberous Sclerosis Complex have opposite effects on this form of synaptic plasticity.

 

Regulation by neuromodulators

Changes in behavioral state trigger the release of neuromodulators such as acetylcholine and dopamine in the brain.  Our goal is to understand the consequences of release of these molecules on neuron and synapse function.  In the process of performing these experiments we have found that many classic neuromodulatory neurons also release fast-acting neurotransmitters such as GABA and glutamate.

 

Neurotransmission by peptides

Many neurons in the mammalian brain express and release neuropeptides such as opioids (enkephalin, dynorphin…), substance P, cholecystikinin, and neuropeptide Y.  Although differential expression of these peptides is often used to distinguish cell types, the function of these peptides is unclear.  We are developing and using photoactivatable peptides to determine and understand the effects neuropeptides release on cells and circuits.

July 15th, 2011

Howard Hughes Medical Institute
Harvard Medical School