Translational Neuroscience Facility

Project Outlines

Purinergic signal transduction in the cochlea is being studied with regard to its involvement in the physiology and pathophysiology of hearing.

This research utilizes transgenic mouse models where particular purinergic (P2X) receptors have been knocked out. Cellular physiology is investigating how the signalling between cells in the cochlea, that is mediated by release of ATP, is affected by loss of specific receptors. Research to date indicates that this ATP signalling provides a humoral action in the cochlea which desensitises the sensory cells at high sound levels, thereby extending the ability of the cochlea to work safely under sound stress. Our auditory assessment has shown that members of the P2X receptor gene family contribute protection from age-related hearing loss (Presbycusis).



Calcium signalling in the cochlear sensory cells

Our research has recently established that a TRPC3 ion channel – which is a class of Ca2+ entry ion channel, is responsible for maintaining Ca2+ homeostasis in the cochlear hair cells. We are investigating whether we can manipulate this process to develop protection from noise-stress.



Calcium signalling in the cochlear auditory neurons

We recently published studies showing that the primary auditory neurons in the cochlea express high levels of ryanodine receptors (RyR) that mediate the release of stored calcium. We showed that these RyR were activated by entry of Ca2+ into the neurons via AMPA-type glutamate receptors. We are studying whether Ca2+ homeostasis in auditory neurons can be manipulated to improve survival.



Development and maintenance of the cochlear innervation

We are currently investigating the outgrowth and synaptic programming of the developing cochlea using transgenic models, including imaging of neuron development. This research will provide an insight into the molecular signalling between the auditory neurones and the sensory hair cells that is fundamental to neurotransmission in the cochlea, and to the regeneration of auditory synapses following injury.



Molecular Physiology of Purinergic Receptors

Given the fundamental significance of P2X receptors to neural function, we are undertaking an extensive analysis of the molecular physiology of these receptors, to look at the dynamics of expression and trafficking of these ion channel proteins within sensory, neural and supporting cells that express these ion channels.



Ca2+ entry channels in motor control and central auditory processing

We are studying whether neuronal pathways, including the auditory brainstem pathways, and the motor control circuitry of the cerebellum, are differentially influenced by alterations in Ca2+ entry via TRPC channels. Our studies include the expression of the recombinant isoforms of the channel to facilitate functional analysis by electrophysiology and Ca2+ imaging.

Staff

Research Grants

Recent Publications and Review Articles

• Morton-Jones, R.T., Cannell, M.B., Housley, G.D. (2007) Ca2+ entry via AMPA-type glutamate receptors triggers Ca2+-induced Ca2+ release from ryanodine receptors in rat spiral ganglion neurons. Cell Calcium (in press).

• Lorier, A.R., Lipski, J., Housley, G.D., Greer, J.J. , Funk, G.D. (2008) ATP sensitivity of preBotzinger complex neurones in neonatal rat in: mechanism underlying a P2 receptor-mediated increase in inspiratory frequency. Journal of Physiology. (London) (in press).

• Barclay, M., Hoya, N., Noakes, P., Ryan, A.F., Housley, G.D. (2007) Neuronal expression of peripherin, a type III intermediate filament protein, in the mouse hindbrain. Histochemistry Cell Biology 128(6), 541-50.

• Huang, L-C., Thorne, P.R., Housley, G.D., Montgomery, J.M. (2007). Spatiotemporal definition of neurite outgrowth, refinement and retraction in the developing mouse cochlea. Development 134, 2925-2933.

• Hedlund, M., Tangvoranuntakul, P., Takematsu, H., Long, J., Housley, G.D., Kozutsumi, Y., Suzuki, A., Wynshaw-Boris, A., Ryan, A.F., Gallo, R., Varki, N., Varki, A. (2007) N-glycolylneuraminic acid deficiency in mice: Implications for human biology and evolution. Molecular and Cellular Biology (MCB) 27, 4340-4346.

• Greenwood, D., Jagger, D.J., Huang, L-C., Hoya, N., Thorne, P.R., Wildman, S.S, King, B.F., Pak, K., Ryan, A.F. Housley, G.D. (2007) P2X receptor signaling inhibits BDNF-mediated spiral ganglion neurite development in the neonatal rat cochlea. Development 134, 1407-1417.

• Schwander, M., Sczaniecka, A., Grillet, N., Bailey, S., Avenarius, M., Steffy, B., Federe, G., Lagler, E., Banan, R., Hice, R., Grabowski, L., Keithley, E.M., Ryan, A.F, Housey, G.D, Wiltshire, T., Smith, R.J, Tarantino, L.M. and Müller, U. (2007) A forward genetics screen in mice identifies recessive deafness traits and reveals that pejvakin is essential for outer hair cell function. Journal of Neuroscience 27, 2163-2175.

• Vlajkovic, S.M., Wang, C.J.H., Soeller, C., Zimmermann, H., Thorne, P.R., Housley, G.D. (2007). Activation-dependent trafficking of NTPDase2 in Chinese hamster ovary cells. International Journal of Biochemistry & Cell Biology 39, 810-817.

• Vlajkovic, S.M., Abi, S.; Wang, C.; Housley, G.D.; Thorne, P.R. (2007) Differential distribution of adenosine receptors in the rat cochlea. Cell and Tissue Research 328, 461-471.

• Lorier, A.R. Huxtable, A.G., Robinson, D.M, Lipski, J., Housley, G.D. Funk, G.D. (2007) P2Y1 receptor modulation of the preBötzinger inspiratory rhythm generating network in vitro. Journal of Neuroscience 27(5):993-1005.

• Raybould, N.P., Jagger, D.J., Kanjhan, R., Greenwood, D., Laslo, P., Hoya, N., Soeller, C., Cannell, M.B., Housley, G.D. (2007) TRPC-like conductance mediates restoration of intracellular Ca2+ in cochlear outer hair cells. Journal of Physiology. (London) 579:101-113.

• Khan, A.F., Thorne, P.R., Muñoz, D.J.B., Wang, C.J.H., Housley, G.D. and Vlajkovic, S.M. (2007) Nucleoside transporter expression and adenosine uptake in the rat cochlea. NeuroReport 18 (3): 235-239.

Review Articles

• Housley, G.D., Marcotti, W., Navaratnam, D., Yamoah, E. (2006) Hair cells – beyond the transducer. Journal of Membrane Biology 209(2-3):89-118.

• Thorne, P.R., Munoz, D.J.B., Nikolic, P., Mander, L., Jagger, D., Greenwood, D., Vlajkovic, S. and Housley, G.D. (2002) Potential role of purinergic signalling in cochlear pathology. Audiology & Neuro-Otology 7, 180-184 .

• Housley, G.D. (2001) Nucleoside and Nucleotide Transmission in Sensory Systems. In: M.P. Abbracchio and M. Williams, Eds, Purinergic and Pyrimidinergic Signalling. Handbook of Experimental Pharmacology, 151/I Springer-Verlag, Berlin, Chapter 12 , pp. 339-369.

• Housley, G.D., Jagger, D.J, Greenwood, D., Raybould, N.P., Salih, S.G., Järlebark, L.E., Vlajkovic, S.M., Kanjhan, R., Nikolic, P., Munoz, D.J.M, and Thorne, P.R. (2002) Purinergic regulation of sound transduction and auditory neurotransmission. Audiology & Neuro-Otology 7, 55-61.

• Housley, G.D. (2000) Physiological effects of extracellular nucleotides in the inner ear. Clinical and Experimental Pharmacology and Physiology 27, 575-580.

• Housley, G.D. and Thorne, P.R. (2000) Purinergic signalling: An experimental perspective. J. Auton. Nerv. Syst. 81. 139-145.

• Housley, G.D. (1998) Extracellular nucleotide signaling in the inner ear. Molecular Neurobiology 16, 21- 48.

• Housley, G.D. and Ryan, A.F. (1997) Cholinergic and Purinergic Neurohumoral Signalling in the Inner Ear: A Molecular Physiological Analysis. Audiology and Neuro-Otology 2, 92-110.

• Thorne, P.R. and Housley, G.D. (1996) “Purinergic signalling in sensory systems” Seminars in the Neurosciences 8(4), 233-246.