Nothing Is Written in Stone

Abstract

a s c p “N othing is written in stone,” the late Seymour Levine once said about the amazing plasticity of the developing brain in adaptation to an ever-changing environment (1). These adaptations, in response to environmental input, may cause lasting changes in the function of the evolutionary older brain circuitry, underlying emotion and cognition. As a result, adverse experiences in early life are thought to enhance disease vulnerability. However, recent evidence suggests that early adversity does not inevitably lead to a negative outcome (2). Rather, depending on genes and environmental context, early experience may program the brain for life to come. In this issue, Bagot et al. (3) describe the crucial role of the N-methyl-D-aspartate (NMDA) receptor in this programming effect. Bagot et al. recorded synaptic transmission in the dentate gyrus of adult rats that were raised by mothers spending either extremely high or low amounts of time licking and grooming (LG) their offspring during the first postnatal week (High vs. Low LG mothers, respectively). Earlier studies, particularly from the group of Michael Meaney, have shown that offspring from High compared with Low LG mothers show more complex hippocampal cells, more efficient long-term potentiation (LTP), better spatial learning, and more efficient release patterns of corticosterone after stress (2,4). Crossfostering could reverse some of these effects, emphasizing the relevance of early life environment rather than genetic background in the development of these phenotypes. Using this model, the present study shows that the ratio between NMDA and alphaamino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor–mediated currents in dentate granule cells is enhanced in Low compared with High LG offspring. Field potential recordings indicate that this is caused by enhanced transmission via NMDA receptors, whereas AMPA receptor function seems unchanged. In agreement, protein levels of NMDA receptor subunits are higher in Low than High LG offspring. In other words, an adverse early postnatal environment appears to upregulate NMDA transmission in the dentate gyrus over the long term. This finding comes as a bit of a surprise, because earlier studies have shown that NMDA receptor expression is decreased and LTP impaired in the adult offspring from Low compared with High LG mothers (5). The incongruity in NMDA receptor expression drives home the message that the proof of the pudding is in the recording: the only way to determine the functionality of receptors is by doing the actual electrophysiologic recordings. The second point—reduced LTP in light of enhanced NMDA receptor function—is experimentally addressed by the authors. They argue that the location of the NMDA receptors, that is, intraversus extrasynaptic, is important and moreover that steady overstimulation of NMDA receptors may impair the ability to induce LTP. They confirm this view by showing that partial blockade of NMDA receptors in Low LG off-