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 vesicles to fuse with the plasma membrane and release their contents. Neurotransmitter release 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. For example, in some cases, as in different regions of the inferior olive release is synchronous and in other cases it is asynchronous (Best and Regehr, 2009). We found that the presence or absence of fast synaptotagmin isoforms controls the kinetics of asnchronous release (Turecek and Regehr 2019).
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. We have found that the slow Ca sensor Syt7 plays a key role in synaptic facilitation (Jackman et al. 2016).
We study cells, synapses and circuits in the cerebellum. These studies include studies of different cell types including Purkinje cells (PCs), molecular layer interneurons (MLIs), unipolar brush cells (UBCs), granule cells, Golgi cells, cells in the deep cerebellar nuclei and the inferior olive. We have been studying circuit specializations of different regions of the cerebellum. The image shows shows a sagittal section of the cerebellar vermis with mGluR1 labeling ofthe brushes of a class of UBCs (pink) and synapses made by PC collaterals in green. We are currently collaborating with the Evan Macosko lab to identify different classes and subclasses of cerebellar neurons and then determine their function.
We use numerous approaches to characterize cell types and circuits in the cerebellum. These include electrophysiology, optogenetics, optical imaging and electron microscopy. EM reconstructions of circuits are performed in collaboration with the Wei-Chung Allen Lee lab as shown to the right for a Purkinje cell and an interneuron.
Cerebellar Regulation of Behavior
The cerebellum regulates a variety of motor and social behaviors. We study the effects of genetic and optogenetic cerebellar manipulations to determine how the cerebellum controls behaviors. We examine gait, conditioned eyeblink and VOR. We found that the cerebellum regulates social behaviors as revealed by differences in the 3-chamber assay and other behavioral assays (Tsai et al. 2012, Tsai et al. 2018). We found that cerebellar-specific manipulations alter anxiety and behaviors in a sex specific manner (Rudolph et al. 2019). We also found that the cerebellum regulates aggression (Jackman et al. 2020).
Most neural communication occurs either via chemical transmission (synapses) or electrical transmission (gap junctions). However, in some cases neurons can affect the firing of other neurons just through their electric fields (ephaptic coupling), resulting in incredibly rapid changes in excitability. We study how Purkinje cells are ephaptically coupled, and how this effects the entire cerebellar circuit (Han et al. 1998; Han et al. 2000).