Departments & Divisions
Currently seeking M.S. & Ph.D. students
Jason Pugh, Ph.D.
Cellular and Integrative Physiology
A fundamental question in neuroscience is how neurons receive, process, and transmit signals, transforming sensory input to behavioral output. At the cellular level, neurons transmit signals and store information primarily through synaptic connections between neurons. Synapses are remarkably diverse in the transmitters used, receptors express (both pre- and postsynaptic), kinetics, and ability to undergo short-term and long-term changes in strength. Each of these properties influences how information is transmitted and stored at a particular synapse. We are interested in understanding how synaptic properties are fine-tuned to function within specific circuits and process information.
To address these questions, we work 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. We hypothesize that dystrophin mutations disrupt cerebellar function which contributes to the loss of motor and cognitive function observed in muscular dystrophy. We 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.
Research & Grants
We are interested in understanding how synaptic properties are fine-tuned to function within specific circuits and process information. 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.
Diseases Associated: Ataxia, Muscular Dystrophy, Autism, Epilepsy
Techniques Used: Patch-clamp electrophysiology, calcium imaging, two-photon laser scanning microscopy, optogenetics
Howell, R.D, and Pugh, J.R. (2016) Biphasic modulation of parallel fiber synaptic transmission by co-activation of presynaptic GABBAA and GABAB receptors in mice. J Physiol. 594(13):3651-3666.
Pugh, J.R., and Jahr, C.E. (2013) Activation of axonal receptors by GABA spillover increases somatic firing. J Neurosci. 33(43):16924-16929.
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.
Pugh, J.R. and Raman, I.M. (2009) Nothing can be coincidence: synaptic inhibition and plasticity in the cerebellar nuclei. Trends Neurosci. 32:170-177.
Bender, V.A., Pugh, J.R., Jahr, C.E. (2009) Presynaptically expressed long-term potentiation increases multivesicular release at parallel fiber synapses. J Neurosci. 29:10974-10978.
Pugh, J.R. and Raman, I.M. (2008) Mechanisms of potentiation of mossy fiber EPSCs in the cerebellar nuclei by coincident synaptic excitation and inhibition. J Neurosci. 28:10549-10560.
Pugh, J.R. and Raman, I.M. (2006) Potentiation of Mossy Fiber EPSCs in the Cerebellar Nuclei by NMDA Receptor Activation followed by Postinhibitory Rebound Current. Neuron. 51:113-123.
Pugh, J.R. and Raman, I.M. (2005) GABAA receptor kinetics in the cerebellar nuclei: Evidence for detection of transmitter from distant release sites. Biophysical Journal. 88(3):1740-54.
Helfand B.T., Mendez M.G., Pugh J., Delsert C., Goldman R.D. (2003) A role for intermediate filaments in determining and maintaining the shape of nerve cells. Mol Biol Cell. 14(12):5069-81.