University of Virginia Health System

John T. Hackett, Ph.D.
Professor

Research Description

Neurosecretion of transmitter substances is a cellular process whereby information transfer occurs in the nervous system. Thus, normal nervous system signaling and resultant behavior depend upon an orderly and closely regulated release mechanism for these transmitters. The hypothesis we wish to test is that the quantal processes of docking and fusion of neurotransmitter packets are critical sites which can be modulated by synaptic integration.

The physiological measures of quantal docking and fusion may be related to the presynaptic parameters (n) and (p), respectively. However, a comprehensive model relating these parameters to modulation of neurosecretion has not been forthcoming. To further work in this area, we have developed a computer algorithm for high resolution quantal detection and for an analysis of unbiased presynaptic parameters.

In concert with these improvements we have found that the increased efficacy of neurosecretion elicited by repetitive simulation of the lobster neuromuscular junction can be explained in terms of changes in presynaptic parameters. This explanation also includes provision for the replenishment of released quanta from a depot pool and mobilization of extra quanta to docking sites.

We wish to further explore presynaptic inhibition and other modes of enhanced neurosecretion, augmentation and potentiation, which may be the forerunners of long term memory storage. Thus, we propose that the isolation of docking and fusion steps by evaluating presynaptic parameters will reveal the mechanisms of synaptic plasticity.

 Brosius, D.C., J.T. Hackett, J.B. Tuttle (1992): Ca^2+-independent and Ca^2+-dependent stimulation of quantal release in avian ciliary ganglion neurons. J. Neurophysiol. 68 :1229-1234. [View Entrez Listing]

Sperelakis, N. Suszkiw, J.B., and Hackett, J.T. (1995) The neuromuscular junction. In: The Thorax, P. Macklem and Ch. Roussos (eds.) pp. 141-184.

Bykhovskaia, M., Worden, M.K., and J.T. Hackett (1996): An algorithm for high resolution detection of postsynaptic quantal events in extracellular records. J. of Neuroscience Methods 65 173-182

Worden, M.K., M. Bykhovskaia, and J.T. Hackett (1997): Facilitation at the Lobster Neuromuscular Junction: A Stimulus-Dependent Mobilization Model. J. Neurophysiol. 78 : 417-428.

Bykhovskaia, M., J.T. Hackett, and Worden, M.K. (Submitted). Asychrony of Quantal Events in Evoked Multiquantal Responses.

Bykhovskaia, M., J.T. Hackett, and M.K Worden (1999). Asynchrony of quantal events in evoked multiquantal responses indicates presynaptic quantal interaction. J. Neurophysiol. 81: 2234-2242.

Bykhovskaia, M., Worden, M.K., and. Hackett, J.T (1999). Presynaptic Facilitation: Quantal Analylsis and Simulations. Neurocomputing 26-27: 9-15.

Vorobieva, O.N., Hackett J. T., Worden, M.K. and Bykhovskaia, M (1999) Evaluation of quantal neurosecretion from evoked and miniature postsynaptic responses by deconvolution method. J. Neurosci. Methods 92: 91-99[View Entrez Listing]

Bykhovskaia, M., Worden, M.K., and. Hackett, J.T (2000) Stochastic modeling of facilitated neurosecretion. J Computational Neuroscience 8,113-126.[View Entrez Listing]

Bykhovskaia, M., Polagaeva, E.B., and. Hackett, J.T (2001): Hyperosmolarity reduces presynaptic facilitation by a Ca²⁺-independent mechanism: depletion of a releasable pool?  J. Physiol. 537.1: 179-190 [View Entrez Listing]

Vorob'eva ON. Polagaeva E.B. Worden MK. Hackett J.T. , and Bykhovskaia M.( 2002)     Statistical analysis of quantal events in synaptic transmission in the neuromuscular junction in lobsters Homarus americanus. Zhurnal Evoliutsionnoi Biokhimii i Fiziologii. 38(4): 341-347 [View Entrez Listing]                     

Bykhovskaia, M., Polagaeva, E and. Hackett, J. (2002).  Effect of Ca 2+ on presynaptic facilitation.Neuorcomputing 44-46: 1-5 

Bykhovskaia, M., Polagaeva, E and. Hackett, J.T (2004) Mechanisms underlying different facilitation forms at the lobster neuromuscular synapse.  Brain Res. 1019:10-21  [View Entrez Listing]

Wang K. Hackett JT. Cox ME. Van Hoek M. Lindstrom JM. Parsons SJ. Regulation of      the neuronal nicotinic acetylcholine receptor by SRC family tyrosine kinases.  Journal of Biological Chemistry. 279(10):8779-86, 2004.[View Entrez Listing]