This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The major glial cells in the retina, M?ller cells, span the whole retinal thickness from photoreceptors to ganglion cells. M?ller cells contact and even delimit all neuronal compartments and can release neuroactive substances to directly regulate neurons. One likely candidate to regulate retinal neuronal activity is the endogenous polyamine spermine (SPM). The polyamines spermine and spermidine (SPM/SPD) are predominantly located in M?ller cells in the retina, but modulate many neuronal receptors and channels found on retinal neurons including AMPA, kainate, NMDA receptor channels and Kir channels. Our preliminary data demonstrate release of SPM/SPD from this glia to neuronal network under glial specific treatments. Our working hypothesis is that endogenous SPM acts as a signaling molecule between glial and neuronal cells in the retina: (i) SPM is accumulated and released from M?ller (glial) cells, potentially through unapposed hemi-gap junctions (hemichannels) and (ii) acts simultaneously on several types of neuronal receptors and channels to modulate retinal neuronal networks. Using electrophysiological and immunocytochemical techniques, we propose to test this hypothesis by the following specific aims:
Specific aim 1 ?To determine if M?ller glial cells express the biosynthetic enzymes necessary for polyamine synthesis under physiological and pathophysiological conditions.
Specific aim 2 ?To examine SPM flux potentially through connexin hemichannels or P2X7 receptors in retinal M?ller (glial) cells.
Specific aim 3 ?To determine the effect of spermine on glutamate receptors in isolated retinal neurons and in a retinal whole-mount preparation. The results of these studies will provide insight into spermine-dependent retinal activity and may ultimately result in interventions for glaucoma, retinas ischemia, glutamate excitotoxicity and subsequent neuronal death.
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