Synaptic and non-synaptic AMPA receptors permeable to calcium.

For a long time, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors permeable to calcium have been considered to be either non-existent or as "atypical". There is now ample evidence that these receptors exist in numerous regions of the nervous system and in many neuronal as well as non-neuronal cell populations. This evidence has been accumulated by several methods, including electrophysiological recording, calcium imaging and cobalt-loading. Functional AMPA receptors permeable to calcium are already expressed at very early stages of embryonic development, well before the onset of synaptogenesis. They are probably involved in the paracrine signaling necessary for construction of the nervous system before becoming involved in synaptic transmission. In immature cells, cyclothiazide strongly increases the steady-state level of responses not only to AMPA, but also to kainate. Ingestion, during pregnancy, of food or drug substances that can cross the placental barrier and act upon the embryonic receptors may constitute a risk for normal development. In the adult nervous system, synaptic as well as non-synaptic (paracrine) AMPA receptors permeable to calcium are probably widely expressed in both glial and neuronal cells. They may also participate in controlling some aspects related to adult neurogenesis, in particular the migration of newly formed neurons.

AMPA receptor activation leads to neurite retraction in tangentially migrating neurons in the intermediate zone of the embryonic rat neocortex.

In rat (König et al. [1998] 28th Annual Meeting of the Society of Neuroscience, Los Angeles. 24:314.6) and mouse (Métin et al. [2000] J. Neurosci. 20:696-708), neurons migrating tangentially in the intermediate zone (IZ) of the neocortical anlage express functional AMPA receptors permeable to calcium. The role of these receptors is as yet unknown. We exposed organotypic cultures of rat telencephalon (embryonic day 15) to AMPA receptor agonists or antagonists, and analyzed the effects of these treatments on cells in the IZ labeled with antibodies against the isoforms a, b and c of microtubule associated protein 2 (MAP2) and the polysialylated neural cell adhesion molecule (PSA-NCAM). The presence of functional AMPA receptors permeable to calcium was checked by cobalt-loading. After exposure to AMPA alone for at least 6 hr, we observed a significant increase in the number of rounded, MAP2 positive cells in the IZ close to the migratory front. When AMPA was combined with cyclothiazide, the increase was already significant after 3 hr. These effects were dose-dependent and could be partially or totally blocked by DNQX or GYKI 53655 respectively, that suggests that they are mediated by AMPA receptors. Paracrine AMPA receptor activation might participate, together with other signals, in guiding the migratory stream, or provide stop signals for migrating cells.