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Ruth Heidelberger, M.D., Ph.D.

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Mechanisms Of Neurotransmitter Release

Ruth Heidelberger, Ph.D., M.D. - Assistant ProfessorCommunication between neurons via chemical synaptic transmission is a fundamental and highly-conserved feature of nervous system function.  In my laboratory, we seek to understand the mechanisms of chemical neurotransmission at the level of synaptic vesicle dynamics in specialized glutamatergic synapses of the vertebrate retina known as ribbon-style synapses.  There are several reasons for our interest in these neurons.  First, the synaptic endings of retinal neurons that express ribbon-style synapses, photoreceptors and bipolar cells, are unusually large and accessible to biophysical examination.  Thus, they allow us to perform detailed analyses of the mechanisms of exocytosis and endocytosis that cannot be readily performed at many other central synapses.  Secondly, photoreceptors and bipolar cells comprise the major throughput pathway for visual information within the vertebrate retina.  Therefore to more fully appreciate how visual information is processed as it traverses the retina, it is important to understand the factors that regulate transmitter release and synaptic vesicle dynamics at these key synapses.  Thirdly, there are subtle molecular differences between retinal ribbon synapses and conventional synapses.  These differences can be exploited to study the function of a select synaptic protein in a retinal ribbon synapse of an otherwise healthy animal with intact conventional synapses.  To achieve our goals, biophysical approaches, such as time-resolved membrane capacitance measurements, are used in combination with computational and molecular approaches. 

B: The calcium dependence of the rate of synaptic vesicle fusion can be determined from experiments similar to that shown in A.
SV2B regulates Ca2+ signaling and exocytosis in rod bipolar cells. (A) Confocal fluorescence image of an isolated mouse rod bipolar cell double-labeled for the synaptic ribbon marker CtBP2 (green) and Protein Kinase C-α (red). Scale bar = 10 μm. (B) The depolarization-evoked rise in intraterminal Ca2+ (ΔCa2+) was greater in synaptic terminals of rod bipolar cells isolated from SV2B-/- mice (KO) than from WT. (C) Despite a greater stimulus-evoked rise in Ca2+, the amount of exocytosis evoked by the first pulse of the stimulus train, measured as the change in membrane capacitance (ΔCm), was significantly smaller in SV2B-/- terminals than in WT. (D) In contrast to the rapid synaptic depression of WT neurons, facilitation preceded depression in SV2B-/- rod bipolar cells, and the rate of depression was slower. (E) The apparent Ca2+ sensitivity of exocytosis was decreased in SV2B-/- rod bipolar cells compared to WT, as evidenced by the rightward shift in the relationship between the cumulative ΔCm and the cumulative ΔCa2+. Dotted line shows the relationship predicted for WT cells from previous studies. (Adapted from Wan et al., Neuron, 66:884-895, 2010.)

Do photoreceptors utilize a novel calcium sensor?  Our previous data suggest that the calcium sensor for release in the rod is highly atypical in that no more than three calcium binding sites need to be occupied in order for release to occur, rather than the expected five.  However, an intriguing alternate possibility is that the rod might use a conventional neuronal calcium sensor, but that release occurs from partially-bound states of the sensor, rather than being restricted to the fully-bound state, as is commonly assumed.  An attractive feature of this hypothesis is that the relationship between release and calcium will be shallow at low calcium values and grow steeper with increasing calcium. We are exploring this and other models using a combination of physiological and computational approaches.

Several kinetically discrete components of exocytosis have been characterized at ribbon synapses. We are interested in how these components relate to discrete vesicle pools, their mobilization, location, and the regulation of their recruitment. To provide this information, we are using a combination of physiological, pharmacological, and molecular approaches.  In particular, we are interested in learning the contributions of these different components to phasic release, sustained release and light adaptation.

To better study molecular mechanisms of presynaptic function, we have recently developed the mouse rod bipolar cell as a model system. We are now using this preparation to ascertain the roles of specific synaptic proteins in release using a combination of biophysical, molecular and genetic approaches.


Selected Reading

Thoreson WB, Rabl K, Townes-Anderson E, Heidelberger R.  (2004).  A highly Ca2+-sensitive pool of vesicles contributes to linearity at the rod photoreceptor ribbon synapse.  Neuron 42(4):595-605. 

Burr GS, Mitchell CK, Keflemariam YJ, Heidelberger R and O'Brien J.  Calcium-dependent binding of calmodulin to neuronal gap junction proteins.  Biochemical and Biophysical Research Communications, 335:1191-1198, 2005.

Sherry DM, and Heidelberger R.   Distribution of proteins associated with synaptic vesicle endocytosis in the mouse and goldfish retina.  Journal of Comparative Neurology, 484(4):440-457, 2005.

Zhou ZY, Wan QF, Thakur P and Heidelberger R.  (2006).  Capacitance measurements in the mouse rod bipolar cell identify a pool of releasable synaptic vesicles. Journal of Neurophysiology, 96(5):2539-2548.

Innocenti, B and Heidelberger, R.  (2008).  Mechanisms contributing to tonic release at the cone photoreceptor ribbon synapse.  Journal of Neurophysiology, 99(1):25-36.

Wan, QF, Vila, A, Zhou ZY, Heidelberger R.  (2008).  Synaptic vesicle dynamics in mouse rod bipolar cells.  Visual Neuroscience, 25(4):523-533.

Curtis L*, Datta P*, Liu X, Bogdanova N, Heidelberger R and Janz R.  (2010)
Syntaxin 3B is essential for the exocytosis of synaptic vesicles in ribbon synapses of the retina. Neuroscience 166(3):832-841.  *co-first authors

Duncan G, Rabl K, Gemp I, Heidelberger R, and Thoreson WB.  (2010)  Quantitative modeling of synaptic release at the photoreceptor synapse.  Biophysical Journal 98(10):2102-2110.

Wan QF,  Zhou ZY,  Thakur P,  Vila A, Sherry D, Janz R, and Heidelberger R (2010).  SV2B regulates intracellular Ca2+ and synaptic vesicle dynamics.  Neuron, 66:884-895.

Wan QF and Heidelberger R.  Synaptic release at mammalian bipolar cell terminals.  (2011).  Visual Neuroscience, 28(1):109-119.

Wan QF,  Nixon E, Heidelberger R.  (2012).  Regulation of presynaptic calcium in a mammalian synaptic terminal.  Journal of Neurophysiology, 108(11):3059-3067. 

Liu X, Heidelberger R, and Janz R.  Phosphorylation of syntaxin 3B by CaMKII regulates the formation of a t-SNARE complex(2014).  Molecular and Cellular Neuroscience, 60:553-562.


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