The long-term objective of this proposal is to understand how multiple neurotransmitter-receptor systems encode visual information within the retinal network. The premise is that specialized postsynaptic receptors are able to convey unique components of a presynaptic signal. Therefore, the utilization of multiple receptors for the same neurotransmitter permits a multiplexing of information and this attribute contributes to the complex process of information decomposition that takes place in the vertebrate retina. The model system for this proposal is the GABA system in the retinal inner plexiform layer. This layer is the site for synaptic integration of excitatory and inhibitory signals that culminates in the message that ganglion cells send to the brain. Most of the inhibitory input comes from amacrine cells, many of which are GABAergic. The last few years have witnessed the discovery of new GABA receptors which were first identified in retina. But the identification of these receptors has not been matched with an understanding of their function in retinal information processing.
The aims of this proposal are to clarify the pharmacology, physiology, and pathways of these diverse GABA receptors. Specifically, this includes a re-examination of the role of the GABA/A receptor, and a characterization of two types of GABA/B receptor and the GABA/C receptor. A working hypothesis is that GABA/A receptors are specialized for powerful but phasic inhibition of transient ON and OFF excitation and a weaker but more tonic inhibition of sustained ON and OFF excitation. The GABA/C receptor suppresses the ON pathway and may be involved in the transition between rod and cone vision. While the baclofen sensitive GABA/B receptor suppresses tonic ON or OFF responses, the CACA sensitive GABA/B receptor may suppress OFF responses. Current clamp and voltage clamp experiments will be employed to test this model and other properties of GABA physiology. Molecular modeling will be used to characterize agonist specificity for each GABA receptor subtype. GABA inhibition is a prominent and often critical feature in the healthy functioning of the nervous system. Consequently, drugs that modulate GABAergic function have long been implicated in a number of pathologies, including seizures, spasticity, and anxiety. An expanded understanding of GABA receptor diversity and its physiological implications will permit a more refined treatment of related nervous system dysfunction.
|Garaycochea, Jay; Slaughter, Malcolm M (2016) GABAB receptors enhance excitatory responses in isolated rat retinal ganglion cells. J Physiol 594:5543-54|
|Wu, Fuguo; Kaczynski, Tadeusz J; Sethuramanujam, Santhosh et al. (2015) Two transcription factors, Pou4f2 and Isl1, are sufficient to specify the retinal ganglion cell fate. Proc Natl Acad Sci U S A 112:E1559-68|
|Sethuramanujam, Santhosh; Slaughter, Malcolm M (2014) Disinhibitory recruitment of NMDA receptor pathways in retina. J Neurophysiol 112:193-203|
|Li, Ping; Slaughter, Malcolm M (2012) Gating effects on picrotin block of glycine receptors. Neuroreport 23:1017-20|
|Song, Yunbo; Slaughter, Malcolm M (2010) GABA(B) receptor feedback regulation of bipolar cell transmitter release. J Physiol 588:4937-49|
|Duan, Lei; Yang, Jaeyoung; Slaughter, Malcolm M (2009) Caffeine inhibition of ionotropic glycine receptors. J Physiol 587:4063-75|
|Frolov, R V; Slaughter, M M; Singh, S (2008) Effects of celecoxib on ionic currents and spontaneous firing in rat retinal neurons. Neuroscience 154:1525-32|
|Shen, W; Slaughter, M M (2001) Multireceptor GABAergic regulation of synaptic communication in amphibian retina. J Physiol 530:55-67|
|Tian, N; Slaughter, M M (1994) Pharmacology of the GABAB receptor in amphibian retina. Brain Res 660:267-74|
|Tian, N; Slaughter, M M (1994) Pharmacological similarity between the retinal APB receptor and the family of metabotropic glutamate receptors. J Neurophysiol 71:2258-68|
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