REGEHR LAB                                                         
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SYNAPSES
A major focus of the lab is to understand how the connections between neurons, the synapses, work. It is known that when an action potential invades a presynaptic bouton it opens voltage-gated calcium channels. This results in the local elevation of calcium that causes synaptic vesicles to fuse with the plasma membrane and release their contents.  The resulting release of neurotransmitter activates receptors on the postsynaptic cell resulting in an electrical signal that influences the firing of that cell.  We are examining the mechanisms that regulate neurotransmiter release. 
                

SHORT-TERM SYNAPTIC PLASTICITY
Presynaptic forms of short-term synaptic plasticity can reduce synaptic strength for hundreds of milliseconds to seconds (depression), or enhance it for hundreds of milliseconds (facilitation) to minutes (augmentation and post-tetanic potentiation, PTP). In addition, synaptic strength can be regulated on rapid timescales by activating presynaptic ionotropic receptors and metabotropic receptors. 
These forms of short-term plasticity allow synapses and circuits to perform computations, and proteins involved in short-term synaptic plasticity have been implicated in a variety of neurological disorders. Chemical messengers can also regulate neurotransmitter release by activating either ionotropic or metabotropic receptors. A major goal of our research is to determine the mechansisms and functional consequences of short-term synaptic plasticity.  

     








CIRCUITS
It is important to consider the properties of synapses in the context of a synaptic circuits.  We are studying sereral simple circuits in the cerebellum and in the thalamus. These studies focus on feed-forward and feed-back inhibition.

CLINICAL RELEVANCE
Dysfunctional synaptic plasticity has been implicated in numerous brain disorders, including depression, dementia, ataxia, anxiety disorders and addiction.  Our research contributes to a basic understanding of synaptic plasticity that provides a foundation for understanding these brain disorders.  Cerebellar studies provide insight into Golgi cells and their circuitry, which can give rise to ataxia. Studies of retrograde signaling by endocannabinoids provide insight into a widespread phenomenon that is involved in addiction and pain. Studies of the connections between the basal ganglia and the thalamus provide crucial information an important circuit that is involved in obsessive-compulsive disorder (OCD), Tourette’s syndrome, and attention-deficit hyperactivity disorder, Huntington’s and Parkinson’s disease.





WADE REGEHR                                                          DEPARTMENT OF NEUROBIOLOGY                                     HARVARD MEDICAL SCHOOL