Abstract
Purpose :
Retinocollicular projections represent the first part of the extrageniculate visual pathway. Its lesion could lead to navigation, orientation and visual attention deficits. We focused on defining processes and mechanisms underlying the early stage of hypoxic injury of the neurotransmission in the originaly-developed in vitro model of the retinocollicular pathway.
Methods :
The in vitro model was a coculture of dissociated rat retinal cells and superficial superior colliculus (SSC) neurons. Using the paired patch-clamp technique, we recorded pharmacologically isolated NMDA−, AMPA− and GABAA−mediated postsynaptic currents in SSC neurons by generation action potentials in presynaptic retinal ganglion cells. The local application of hypoxic solutions on pairs of neurons was used to mimic short-term hypoxic states.
Results :
The hypoxia induces long-term depression (LTD) of GABAA neurotransmission (34 ± 9%, P < 0.001, n = 23), temporary suppression of AMPA (32 ± 7%, P < 0.01, n = 22) and long-term potentiation (LTP) of NMDA transmission (170 ± 11%, P < 0.01, n = 26). Also, oxygen deprivation leads to a reduction of voltage-dependent magnesium blockade of evoked NMDA response. All NMDA currents were analyzed in terms of their kinetic characteristics. This analysis revealed that hypoxia-induced LTP and reduction were accompanied by a rapid and irreversible decrease of the decay time of the NMDA currents (from 37.2 ± 5.4 ms to 18.5 ± 7.2 ms, respectively).
Conclusions :
The hypoxia-induced LTP of NMDA transmission mediates an increase of calcium ions influx and leads to apoptotic cell death. There are several protective mechanisms to prevent that. The first one belongs to the GABAergic retinocollicular projections. Their physiological role is in the regulation of the activation of NMDA transmission. The next one is the voltage-dependent magnesium blockade of NMDA receptors. Hypoxia impairs both protective mechanisms and enhances the pathological effect of LTP of NMDA transmission. Moreover, data strongly suggest that irreversible increase in NR2A-to-NR2B subunit ratio underlies the hypoxia-induced pathological LTP of retinocollicular NMDA neurotransmission. The results obtained reflect the electrophysiological basis and may serve to reveal new approaches for pharmacological and therapeutic interventions for a hypoxia-involved pathological lesion of the retinocollicular pathway.
This is a 2021 ARVO Annual Meeting abstract.