Calcium -permeable AMPA receptors as pathways for synaptic calcium influx in dorsal horn neurons

Abstract

Glutamate receptors of the AMPA family have an established role in the central nervous system (CNS) as the main mediators of excitatory synaptic transmission. However, some AMPA receptors are also permeable to Ca ²⁺, a powerful modulator of synaptic and cellular function. In the spinal dorsal horn, a large fraction of the neurons express Ca²⁺-permeable AMPA receptors. The dorsal horn is a complex and plastic circuit, which has a pivotal role in relaying nociceptive information and in modulating this information under a variety of influences from both the environment and the brain. Ca²⁺ influx through Ca²⁺-permeable AMPA receptors in dorsal horn synapses may play a role in this modulation, which necessarily involves modulation of synaptic transmission. In order to propose such a role, however, some basic questions about the distribution and functionality of Ca²⁺-permeable AMPA receptors must first be answered.

In this thesis, the pattern of expression of Ca²⁺-permeable AMPA receptors amongst and within dorsal horn neurons has been explored. I have shown that Ca²⁺-permeable AMPA receptors are selectively expressed by subpopulations of both excitatory and inhibitory neurons, including some projection neurons; and that they are specifically excluded from at least two subpopulations of excitatory interneurons.

Moreover, I have demonstrated that Ca²⁺-permeable AMPA receptors in dorsal horn neurons are synaptic and mediate significant Ca ²⁺ fluxes when synaptically activated. Those synapses were shown to potentially include both intrinsic and primary afferent synapses onto dorsal horn neurons. Additionally, evidence is provided of selective targeting of Ca²⁺-permeable and Ca²⁺-impermeable AMPA receptors to distinct domains within the same neuron.

Finally, the distribution of Ca²⁺-permeable AMPA receptors and NMDA receptors within single synapses was compared. Ca²⁺-permeable AMPA receptors consistently co-localize with NMDA receptors within the same release site, and trigger synaptic [Ca²⁺] increases under conditions where NMDA receptors contribute little or not at all, due to their distinct voltage-dependencies. The possible implications of these data for synaptic modulation in the dorsal horn are discussed.