Abstract
Purpose: :
Activity-dependent activation of synaptic glutamate receptors at central synapses can induce a lasting change in number or composition of AMPA receptors (AMPARs). Extrasynaptic NMDA receptors (NMDARs) can be stimulated through an increase in presynaptic activity and have been shown to be involved in the induction of this and other forms of synaptic plasticity. Retinal ganglion cells (RGCs) signal through both AMPARs and NMDARs, however synaptic plasticity at this synapse has yet to be established. This study explores NMDAR induced AMPAR plasticity in RGCs.
Methods: :
Whole cell patch-clamp recordings were obtained from ganglion cells in whole mount mouse retinas. To measure the AMPAR-mediated light response, ganglion cells were stimulated with 10 ms flashes of full-field (500nm) light at a range of intensities. Spermine was included in the patch pipette to block Ca2+-permeable AMPARs at depolarizing membrane potentials.
Results: :
We found threshold responses are exclusively mediated by Ca2+-permeable AMPARs, and as the light intensity increases to rod pathway saturation, Ca2+-impermeable AMPARs are recruited. Bath application of NMDA induced a decrease in rectification and in the current attributable to Ca2+-impermeable AMPARs, specifically within the intermediate range of rod pathway light intensities. This plasticity occurs in ON cells but not OFF cells and in the ON response of ON-OFF cells, indicating that it is exclusive to the ON pathway. Depolarization of ON bipolar cells with an mGluR6 antagonist (CPPG) produced a similar change in subunit composition, indicating that this switch could be triggered by presynaptic activity. Moreover, increasing synaptic activity with a series of full-field light flashes at 1-10 Hz, brought about a comparable decrease in rectification to that of the pharmacological manipulations. Addition of an NMDA receptor antagonist (D-AP5) or an intracellular Ca2+-chelator (BAPTA) blocked this change, supporting a role for NMDA receptor activation and subsequent Ca2+ influx in this process.
Conclusions: :
These findings suggest that activation of extrasynaptic NMDARs possibly by glutamate spillover is an important mechanism that detects increases in synaptic activity and subsequently exerts a Ca2+-dependent regulation of AMPAR subtypes at the synapse. This plasticity could represent a mechanism for inner retinal adaptation in the ON pathway under scotopic conditions.
Keywords: ganglion cells • receptors • plasticity