office: 2018 TLSB
research interests: Neurodegenerative Disorders; Spinal Cord Injury
Dr. Tobin's laboratory uses molecular and cellular techniques to study the function, regulation, and degeneration of GABA-producing neurons in the brain and spinal cord. This work addresses both mechanistic questions and issues of drug development for Huntington's disease, Parkinson's disease, epilepsy, and spinal cord injury. In collaboration with Dr. Bruce Dunn in the School of Engineering and Applied Science, Dr. Tobin's laboratory is also developing biosensors suitable for the detection of neurotransmitter release in real time with high spatial resolution. One project focuses on the two forms of the GABA-synthesizing enzyme, glutamic acid decarboxylase (GAD). The central hypothesis of this work is that the two GADs catalyze the synthesis of distinct pools of GABA, one vesicular and the other cytosolic. According to this model, membrane-associated GAD65 produces vesicular GABA, and cytosolic GAD67 produces cytosolic GABA. While vesicular GABA, released by exocytosis, is likely to be particularly important in point-to-point signaling in synapses, cytosolic GABA, released via plasma-membrane transporters, may serve a longer-range role, inhibiting neuronal activity in limited regions of the nervous system. A novel aspect of this project is the development of biosensors for glutamate and GABA. Another project examines cellular pathogenic mechanisms in Huntington's disease. The unifying hypothesis of this work is that an expanded polyglutamine tract encoded by the disease-causing allele irreversibly blocks proteasome activity, leading a failure of normal protein turnover and in cell dysfunction and death. A third project examines the plasticity of GABA-producing neurons during recovery from spinal cord injury. Different kinds of rehabilitative training,standing, stepping, and specific motor tasks, have distinctive effects on the pattern of GABA production in the spinal neurons.
N.J.K. Tillarakaratne, R.D. De Leon, T.X. Hoang, R.R. Roy, V.R. Edgerton, and A.J. Tobin,, "Use-dependent modulation of inhibitory capacity in the feline lumbar spinal cord", Journal of Neuroscience, 22 : 3130-3143 (2002) .
N.J.K. Tillakaratne, M. Mouria, N.B. Ziv, R.R. Roy, V.R. Edgerton, A.J. Tobin, "Increased expression of glutamate decarboxylase (GAD67) in feline lumbar spinal cord after complete thoracic spinal cord transection", Journal of Neuroscience Research, 60 : 219-230 (2000) .
K. Thompson, V. Antharam, S. Behrstock, E. Bongarzone, A. Campagnoni, and A.J. Tobin, "Conditionally immortalized cell lines, engineered to produce and release GABA, modulate the development of behavioral seizures", Experimental Neurology, 161 : 481-489 (2000) .
A.J. Tobin, E. Signer, "Huntington's disease: the challenge for cell biologists", Trends in Cell Biology, 10 : 531-536 (2000) .
C. Pinal, and A.J. Tobin, "Uniqueness and redundancy in GABA production", Perspectives on Developmental Neurobiology, 5 : 109-118 (1998) .