Development of calcium‐permeable AMPA receptors and their correlation with NMDA receptors in fast‐spiking interneurons of rat prefrontal cortex

Abstract

Abnormal influx of Ca2+ is thought to contribute to the neuronal injury associated with a number of brain disorders, and Ca 2+ -permeable AMPA receptors (CP-AMPARs) play a critical role in the pathological process. Despite the apparent vulnerability of fast-spiking (FS) interneurons in neurological disorders, little is known about the CP-AMPARs expressed by functionally identified FS interneurons in the developing prefrontal cortex (PFC). We investigated the development of inwardly rectifying AMPA receptor-mediated currents and their correlation with NMDA receptor-mediated currents in FS interneurons in the rat PFC. We found that 78% of the FS interneurons expressed a low rectification index, presumably Ca 2+ -permeable AMPARs, with only 22% exhibiting AMPARs with a high rectification index, probably Ca 2+ impermeable (CI). FS interneurons with CP-AMPARs exhibited properties distinct from those expressing CI-AMPARs, although both displayed similar morphologies, passive membrane properties and AMPA currents at resting membrane potentials. The AMPA receptors also exhibited dramatic changes during cortical development with significantly more FS interneurons with CP-AMPARs and a clearly decreased rectification index during adolescence. In addition, FS interneurons with CP-AMPARs exhibited few or no NMDA currents, distinct frequency-dependent synaptic facilitation, and protracted maturation in short-term plasticity. These data suggest that CP-AMPARs in FS interneurons may play a critical role in neuronal integration and that their characteristic properties may make these cells particularly vulnerable to disruptive influences in the PFC, thus contributing to the onset of many psychiatric disorders.

Adolescent Onset of Cortical Disinhibition in Schizophrenia: Insights From Animal Models

“…Indeed, PFC interneurons exhibit NMDA receptors with higher proportion of NR2B subunits, 34 but they also express NR2C and 2D subunits, which yield NMDA receptors with a lower degree of Mg þþ blockade. 35 Although these reports of high-density NMDA receptors in PFC interneurons contrast with recent studies showing negligible NMDA currents in this cell population, 36,37 it is possible that either noncompeting NMDA antagonists affect a subpopulation of interneurons or the slice preparation loses a critical input that drives cortical interneurons and does not reflect well the in vivo condition. The consequence of NMDA antagonism on PFC circuits will likely be a reduced local inhibition and altered excitation-inhibition balance in the cortex that can result in a noisy pattern of activity in cortical ensembles.…”

The translationally relevant mouse model of the 15q13.3 microdeletion syndrome reveals deficits in neuronal spike firing matching clinical neurophysiological biomarkers seen in schizophrenia

“…Thus, after having established physiological response properties at the single cell level in the Df(h15q13)/+ mice that in many ways resemble previously reported results in patients with schizophrenia, we decided to evaluate whether a pharmacological manipulation aimed at normalizing the deficient fast‐spiking properties in Df(h15q13)/+ mice could help normalizing the aberrant responses in the two testing paradigms. In order for a neural network to sustain spiking with high temporal precision, FSIs are thought to be particularly important (Wang & Gao 2010). For this reason, RE1, a substance that speeds up the opening kinetics of the voltage‐dependent potassium channels Kv3.1, which are known to be highly expressed in FSIs, could potentially restore certain aspects of the deviating response patterns observed in Df(h15q13)/+ mice.…”

Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction

“…Experiments were conducted as previously described (75). For AMD3100 experiments, 6 hours after i.c.v.…”