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Contribution of NMDA receptors to dorsolateral prefrontal cortical networks in primates.

ABSTRACT: Cognitive disorders such as schizophrenia and Alzheimer's disease are associated with dysfunction of the highly evolved dorsolateral prefrontal cortex (dlPFC), and with changes in glutamatergic N-methyl-D-aspartate receptors (NMDARs). Recent research on the primate dlPFC discovered that the pyramidal cell circuits that generate the persistent firing underlying spatial working memory communicate through synapses on spines containing NMDARs with NR2B subunits (GluN2B) in the post-synaptic density. This contrasts with synapses in the hippocampus and primary visual cortex, where GluN2B receptors are both synaptic and extrasynaptic. Blockade of GluN2B in the dlPFC markedly reduces the persistent firing of the Delay cells needed for neuronal representations of visual space. Cholinergic stimulation of nicotinic α7 receptors within the glutamate synapse is necessary for NMDAR actions. In contrast, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors have only subtle effects on the persistent firing of Delay cells, but contribute substantially to the firing of Cue and Response cells. Systemic administration of the NMDAR antagonist ketamine reduces the persistent firing of Delay cells, but increases the firing of some Response cells. The reduction in persistent firing produced by ketamine may explain why this drug can mimic or worsen the cognitive symptoms of schizophrenia. Similar actions in the medial PFC circuits representing the emotional aspects of pain may contribute to the rapid analgesic and anti-depressant actions of ketamine.

SUBMITTER: Wang M

PROVIDER: S-EPMC4734117 | biostudies-other | 2015 Apr

REPOSITORIES: biostudies-other

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Project description:Alcohol is associated with nearly half of all violent crimes committed in the United States; yet, a potential neural basis for this type of pathological aggression remains elusive. Alcohol may act on N-methyl-d-aspartate receptors (NMDARs) within cortical circuits to impede processing and to promote aggression. Here, male mice were characterized as alcohol-heightened (AHAs) or alcohol non-heightened aggressors (ANAs) during resident-intruder confrontations after self-administering 1.0 g/kg alcohol (6% w/v) or water. Alcohol produced a pathological-like pattern of aggression in AHAs; these mice shifted their bites to more vulnerable locations on the body of a submissive animal, including the anterior back and ventrum after consuming alcohol. In addition, through immunoblotting, we found that AHAs overexpressed the NMDAR GluN2D subunit in the prefrontal cortex (PFC) as compared to ANAs while the two phenotypes expressed similar levels of GluN1, GluN2A and GluN2B. After identifying several behavioral and molecular characteristics that distinguish AHAs from ANAs, we tested additional mice for their aggression following preferential antagonism of GluN2D-containing NMDARs. In these experiments, groups of AHAs and ANAs self-administered 1.0 g/kg alcohol (6% w/v) or water before receiving intraperitoneal (i.p.) doses of ketamine or memantine, or infusions of memantine directly into the prelimbic (PLmPFC) or infralimbic medial PFC (ILmPFC). Moderate doses of IP ketamine, IP memantine, or intra-PLmPFC memantine increased aggression in AHAs, but only in the absence of alcohol. Prior alcohol intake blocked the pro-aggressive effects of ketamine or memantine. In contrast, only memantine, administered systemically or intra-PLmPFC, interacted with prior alcohol intake to escalate aggression in ANAs. Intra-ILmPFC memantine had no effect on aggression in either AHAs or ANAs. In sum, this work illustrates a potential role of GluN2D-containing NMDARs in the PLmPFC in alcohol-heightened aggression. GluN2D-containing NMDARs are highly expressed on cortical parvalbumin-containing interneurons, suggesting that, in a subset of individuals, alcohol may functionally alter signal integration within cortical microcircuits to dysregulate threat reactivity and promote aggression. This work suggests that targeting GluN2D-NMDARs may be of use in reducing the impact of alcohol-related violence in the human population.

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Contribution of NMDA receptors to dorsolateral prefrontal cortical networks in primates.

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