Enhancement of parvalbumin interneuron-mediated neurotransmission in the retrosplenial cortex of adolescent mice following third trimester-equivalent ethanol exposure

Abstract

Prenatal ethanol exposure causes a variety of cognitive deficits that have a persistent impact on quality of life, some of which may be explained by ethanol-induced alterations in interneuron function. Studies from several laboratories, including our own, have demonstrated that a single binge-like ethanol exposure during the equivalent to the third trimester of human pregnancy leads to acute apoptosis and long-term loss of interneurons in the rodent retrosplenial cortex (RSC). The RSC is interconnected with the hippocampus, thalamus, and other neocortical regions and plays distinct roles in visuospatial processing and storage, as well as retrieval of hippocampal-dependent episodic memories. Here we used slice electrophysiology to characterize the acute effects of ethanol on GABAergic neurotransmission in the RSC of neonatal mice, as well as the long-term effects of neonatal ethanol exposure on parvalbumin-interneuron mediated neurotransmission in adolescent mice. Mice were exposed to ethanol using vapor inhalation chambers. In postnatal day (P) 7 mouse pups, ethanol unexpectedly failed to potentiate GABAA receptor-mediated synaptic transmission. Binge-like ethanol exposure of P7 mice expressing channel rhodopsin in parvalbumin-positive interneurons enhanced the peak amplitudes, asynchronous activity and total charge, while decreasing the rise-times of optically-evoked GABAA receptor-mediated inhibitory postsynaptic currents in adolescent animals. These effects could partially explain the learning and memory deficits that have been documented in adolescent and young adult mice exposed to ethanol during the third trimester-equivalent developmental period.

FriendlyClearMap: An optimized toolkit for mouse brain mapping and analysis

“…We also found some early maturation levels in the retrosplenial cortex, where early ethanol exposure at P7 has been reported to affect PV + neurotransmission in adulthood 55 However, in addition we found that the orbitofrontal cortex did show a relatively high density at P14 as well, compared to e.g. visual cortex, which is an interesting deviation both temporally as well as spatially PV + neurons are typically thought to mature first in the sensory areas, then in a general rostral-to-caudal gradient.…”

FriendlyClearMap: an optimized toolkit for mouse brain mapping and analysis

“…We also found some early maturation levels in the retrosplenial cortex, where early ethanol exposure at P7 has been reported to affect PV + neurotransmission in adulthood [ 55 ]. However, in addition, we found that the orbitofrontal cortex did show a relatively high density at P14 as well, compared to the visual cortex, for example, which is an interesting deviation both temporally as well as spatially.…”

The positive allosteric modulator of NMDA receptors, GNE‐9278, blocks the ethanol‐induced decrease of excitability in developing retrosplenial cortex neurons from mice

“…Indeed, Hackos et al 13 showed that some GNE PAMs differentially affect NMDA receptors in pyramidal cells vs. interneurons. Finally, the mechanism of the pro‐apoptotic effects of ethanol on developing neurons also involves inhibition of AMPA receptors 10 and possibly, potentiation of GABA A receptors 19 (but see 20 ). Therefore, complete protection against these effects of ethanol would require modulation of other targets; PAMs that have been shown to potentiate both NMDA and AMPA receptors (GNE‐3419) could be particularly useful in this respect 13 …”