9 Neurotransmitter Stimulation for Retinal Prosthesis: The Artificial Synapse Chip |
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Table 9.1 Major transmitters released by retinal cells |
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Cell type |
Transmitters |
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Photoreceptors |
Glutamate |
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Horizontal |
GABA |
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Bipolar cells |
Glutamate |
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Amacrine |
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AII |
GABA, glycine |
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A4 |
Glycine |
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A8 |
Glycine |
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A10 |
GABA |
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A17, A18, A20 |
GABA, serotonin |
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A18 |
GABA, dopamine |
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A22 |
GABA, substance P |
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Starburst |
GABA, acetylcholine |
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Retinal ganglion cells (RGC) |
Glutamate |
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9.2.1 Outer Plexiform Layer
In the OPL, glutamate release from photoreceptors directly modulates horizontal and bipolar cell responses. Horizontal cells exhibit AMPA type receptors, depolarize to glutamate release from PR, and reciprocally modulate photoreceptor responses through GABAergic neurotransmission. Horizontal cell transmission plays a major role in the surround inhibition, but not by GABAergic inhibition [36, 65, 104]. GABA released from horizontal cell has a depolarizing effect on photoreceptors via GABAA receptors [54, 55], and modulates the temporal properties of light responses [43, 110]. Bipolar cell responses are dependent on the glutamate receptor types they express: OFF-center bipolar (human: flat midget bipolar (FMB)) express ionotropic glutamate receptors (AMPA) and hyperpolarize to light (like photoreceptors); whereas rod and ON-center cone bipolar cells (invaginating midget bipolar [IMB]), depolarize in response to light, due to decreased activation of g-protein coupled metabotropic glutamate, mGluR6 receptors [70, 72, 94, 95], which invert the signal from photoreceptors. Therefore, glutamate in the OPL differentially activates ON and OFF pathways.
9.2.2 Inner Plexiform Layer
Transmitter and interneuronal signaling in the IPL is more complex, but a simplification of the major interactions can be used to examine possible pathways for artificially stimulating the retina.
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Table 9.2 Simplified transmitter/receptor basis of retinal interactions
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Presynaptic cells |
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Bipolar cells |
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Amacrine |
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Photoreceptors |
Horizontal |
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AII, A4, A8, A10, |
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Cone-ON |
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Cone-OFF |
Rod |
A17, A18, A20, A22, |
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starburst |
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Photoreceptors |
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GABA |
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Horizontal |
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AMPA |
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AmacrineBipolar cells |
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Cone-ON |
mGlur6 |
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Gap junctions |
Postsynapticcell receptors |
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AMPA, NMDA |
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ON |
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Cone-OFF |
AMPA |
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Rod |
mGlur6 |
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AII, A4, A8, A10, |
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AMPA? |
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Gap junctions; GABA; |
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A17, A18, A20, |
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glycine; mGluR; |
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A22, starburst |
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dopamine; other |
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receptors |
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RGCs |
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OFF |
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AMPA, NMDA |
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ON–OFF |
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AMPA, NMDA |
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AMPA, NMDA |
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Blank cells no known/normal synaptic contacts from cell type above to cell type at left |
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Finlayson .G.P and Iezzi .R
9 Neurotransmitter Stimulation for Retinal Prosthesis: The Artificial Synapse Chip |
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9.2.2.1 Bipolar Cell Excitation of Retinal Ganglion Cells
Glutamate is released from cone bipolar cell ribbon synapses in the IPL, where it directly activates retinal ganglion cells (RGCs), through AMPA, NMDA and kainate receptors [10, 12, 42, 58, 59, 109], and also excites amacrine cells [3]. Rod bipolar cells do not directly contact RGCs, but contact amacrine cells (review: [2, 93]). Amacrine (AII) cells contact cone bipolar cells and other AII cells through gap junctions. Therefore, depolarization of AII amacrine cells by ionotropic (AMPA and kainate) glutamate receptors leads to depolarization of cone bipolar cells and excitation of RGCs.
9.2.2.2 Amacrine Cell Modulation of Signal Processing
The many different types of amacrine cells in the IPL perform different functional roles, including lateral inhibition, and contributing to spatial tuning, direction selectivity and center surround receptive fields [13, 24, 88, 101]. For example, direction selectivity of RGCs involve GABA, likely originating in starburst amacrine cells [48]. Amacrine cells modulate bipolar, ganglion and other amacrine cells by releasing glycine, GABA, biogenic amines (5HT, dopamine and acetylcholine) and neuropeptides in the IPL. In addition to ionotropic glutamate excitation, a subset of amacrine cells are likely modulated by metabotropic (mGlur1, mGlur2/3, mGlur5) receptors [9, 39, 49].
9.2.2.3 Inhibitory Transmitters
Inhibitory transmitters differentially affect ON, OFF and rod pathways, based on cell type, preor post-synaptic action and current duration of GABAA, GABAC and glycine receptors [19–21, 68, 106]. GABAB receptor subunits R1a are found in the INL and RGC layer, while R1b is only found in the RGC layer [111, 112]. RGCs exhibit spontaneous and light evoked GABA and glycine responses [102], and are inhibited by GABA and glycine released by amacrine cells [24, 57]. In addition, OFF-bipolar cells are predominantly inhibited by glycine. Rod bipolar cells also receive glycinergic inputs but their major inhibitory response is through GABA acting on GABAC receptors, which have slow kinetics, while ON bipolar cells are inhibited through GABAA receptors.
9.2.2.4 Acetylcholine and Dopamine
Acetylcholine is also released from amacrine cells [40]. Both muscarinic [32, 33, 110] and nicotinic cholinergic receptors are found in retina (chick IPL and RGC layer [46]. Nicotinic alpha7 receptors are also localized on bipolar, amacrine and ganglion cells in rabbit retina [17]. Nicotinic receptors are also expressed by a