NMDA receptors underlie stress-induced dynamic changes in prefrontal cortical networks: plasticity and function.

Abstract

The prefrontal cortex (PFC) is a region in the frontal lobe of the cerebral cortex necessary for the proper execution of cognitive behaviors such as attention, memory, and the ordering of actions to accomplish a task. In rodents, lesions of the medial prefrontal cortex (mPFC) impact visiospatial working-memory (vsWM) functions. Neurons in the cerebral cortex are typically silent in alert animals but can become persistently active when brain networks engage them to participate in computations necessary to accomplish a task. During vsWM tasks, neurons in mPFC become persistently active for the delay period of a WM task. The persistent activation of neurons in mPFC by local networks during the delay period of a working memory task in vivo has been suggested to represent a basic neural substrate for maintenance of an internal representation. Stress can alter the performance of animals attempting working memory tasks, and its effects are dynamic over the span of days following a single exposure. Immediately following stress, vsWM is negatively affected and performance on a vsWM task is hindered, while four to twenty-four hours following exposure to stress, vsWM is enhanced. It has been hypothesized that plasticity in local mPFC glutamatergic networks in vivo, driven by stress-response mediators, alters AMPA- and NMDA-mediated neurotransmission as a function of the number of stress exposures and that this plasticity affects persistent, network-driven activity. A previous study has shown that both AMPA- and NMDA-mediated neurotransmission are upregulated twenty-four hours after exposure to mild FS stress (Yuen et al., 2009). The following doctoral thesis supports this conclusion and extends this work to quantify the effects of multiple stress exposures, over several days, on mPFC plasticity and describes a correlation between enhanced glutamatergic synaptic drive and changes in persistent activity. In animals exposed to multiple days of ten-minute, forced-swim stress, NMDA-mediated glutamatergic neurotransmission was upregulated relative to unstressed, naïve animals while AMPA-mediated neurotransmission and intrinsic cellular phenomena remained unaffected. Close examination of isolated NMDA currents from neurons in three-day stressed mice revealed a decrease in the decay rate of these currents relative to naive animals. This augmentation of NMDA-ergic tone yields greater charge entry that could potentially increase the impact of synaptic drive on neuronal activity as well as enhance synaptic integration. The upregulation of NMDA-mediated neurotransmission in three-day stressed animals was found to occur via the upregulation of the NR2B subunits at synaptic NMDA receptors. Together, a decrease in NMDA current decay rate via inclusion of NR2B subunits and the lack of evidence for stress-induced AMPA current modulation resulted in an increase in NMDA-to-AMPA ratio (NAR) at synaptic mPFC networks. These observed changes in glutamatergic neurotransmission, after a single or multiple exposures to forced swim, are paralleled by changes in persistent activity. Individual PA events were recorded from naïve, one-day and three-day stressed mice. PA events recorded from both stressed groups were increased in duration relative to naïve animals. These data support the conclusion that stress regulates glutamatergic neurotransmission in the mPFC, affecting the ability of neurons to remain persistently active.