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R. E. Marc, B. W. Jones, P. Pandit, J. R. Anderson, T. M. Raleigh; Excitatory Drive Patterns of TH1 Dopaminergic Polyaxonal Cells in Rabbit Retina. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2432.
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The circuitry driving light-responses of TH1 dopaminergic polyaxonal cells (TH1 AxCs) in the retina is uncertain, and data support both (i) direct cone bipolar cell excitation and (ii) GABAergic disinhibition as key mechanisms. Our first goal was to assess the strength of ionotropic glutamate receptor (iGluR) mediated excitatory drive in TH1 AxCs in comparison with amacrine (ACs) and ganglion cell (GCs). Our second goal was to determine the likely primary fast neurotransmitter of TH1 AxCs.
Adult rabbits were euthanized via intraperitoneal urethane, the eyes enucleated and retinas incubated in vitro for excitation mapping with 1-amino-4-guanidobutane (AGB). Isolated retinas were incubated 10 min at 35 deg C in carboxygenated Ames medium + 5 mM AGB with and without iGluR agonists (AMPA 25 µM, KA 50 µM, NMDA 1 mM), followed by conventional fixation in buffered aldehydes, embedding in exopy resins and serial sectioning at 200 nm (Marc RE 1999 JCN 407:47-64). Retinal neurons were classified by computational molecular phenotyping (CMP, Marc and Jones 2002 J Neurosci22:413-427. ) using an array of small molecule signatures (asparate, glutamate, glycine, glutamine, glutathione, GABA, taurine) with the addition of tyrosine hydroxylase (TH) detection using Millipore AB152 IgGs.
Mammalian TH1 AxCs have a distinctive glutamatergic signature that places them in a classic GC rather than the AC superclass with which they have often been associated. Functionally, TH1 AxCs demonstrate quantitatively weak AMPA and KA drive, suggesting that they either express low densities of iGluRs or have dominant control by edited GluR2 subunits, leading to low unitary conductance channels. In contrast, TH1 AxCs demonstrate stong NMDA-mediated drive. This places them in a unique functional space along with classic sluggish-sustained GCs.
Cone bipolar cell inputs to TH1 AxCs act through a unique pairing of weak AMPA receptor / strong NMDA receptor drive. Whether this drive is strong enough in vivo to activate photophase dopamine release is unclear. However, based on recent evidence that TH1 AxCs may directly drive melanopsin-expressing GCs (ipGCs), the glutamatergic signature of TH1 AxCs supports a direct BC → TH1 AxC → ipGC pathway. However this poses a new conundrum. Either the BC of sublayer 1 is actually an ON BC or, in spite of the presence of direct BC drive, the TH1 AxC is dominated by disinhibition on an OFF BC → GABAergic AC → TH1 AxC → ipGC chain. In either case, the TH1 AxC → ipGC step suggests that TH1 AxCs are excitatory GC-like neurons as well as neuromodulatory cells.
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