Dr. Jason Pugh's lab is interested in understanding how synaptic properties are fine-tuned to function within specific circuits and process information.
To address these questions, our lab works on synapses in the cerebellar circuit, a brain region primarily involved in motor learning and motor coordination (though involvement in cognitive functions have also been demonstrated).
We study synaptic transmission in the cerebellar circuit because the underlying neural circuity is relatively simple and highly regular throughout the cerebellum, making it possible to correlate synaptic properties with specific circuit functions and even behavioral output.
We primarily use patch clamp electrophysiology, to measure postsynaptic currents and potentials, and two-photon calcium imaging, to measure pre- or postsynaptic calcium influx and cell morphology.
Our lab is currently focused on two projects:
1) Function of presynaptic GABAA and GABAB receptors. Parallel fiber synapses (the primary excitatory synapses in the cerebellum) express GABAA and GABAB receptors in their presynaptic boutons. Previous work has shown that GABAA receptors enhance release of neurotransmitter while GABAB receptors inhibit release of neurotransmitter. However, these two receptors are activated by the same ligand (GABA) and are therefore likely to be co-activated in vivo. Do the opposing effects of these receptors cancel one another out? Does one receptor effect dominate over the other? Or do differences in the kinetics and affinities of these receptors allow them to be selectively activated in some conditions?
2) Role of dystrophin in cerebellar function. Muscular dystrophy is caused by mutations in the gene for dystrophin, a protein highly expressed in muscle tissue that acts as a linker between the intracellular cytoskeleton and the extracellular matrix. Dystrophin is also expressed in the central nervous system and many individuals with muscular dystrophy show cognitive deficits, suggesting dystrophin may also play a role in neuronal function. Dystrophin is most highly expressed in Purkinje cells of the cerebellum, specifically at inhibitory synapses onto these cells. They hypothesize that dystrophin mutations disrupt cerebellar function which contributes to the loss of motor and cognitive function observed in muscular dystrophy. They are addressing these questions using patch-clamp electrophysiology to measure synaptic function and firing in the cerebellar circuit of mouse models of muscular dystrophy and creating a Purkinje cell specific knock-out of dystrophin for behavioral testing.
Pugh, J.R., and Jahr, C.E. (2013) Activation of axonal receptors by GABA spillover increases somatic firing. J Neurosci. In Press
Pugh, J.R., and Jahr, C.E. (2011) Axonal GABAA receptors increase cerebellar granule cell excitability and synaptic activity. J Neurosci. 31: 565 - 574
Pugh, J.R., and Jahr, C.E. (2011) NMDA receptor agonists fail to alter release from cerebellar basket cells. J Neurosci. 31(46): 16550-55.