MK-801 Impairs Cognitive Coordination on a Rotating Arena (Carousel) and Contextual Specificity of Hippocampal Immediate-Early Gene Expression in a Rat Model of Psychosis

Abstract

Flexible behavior in dynamic, real-world environments requires more than static spatial learning and memory. Discordant and unstable cues must be organized in coherent subsets to give rise to meaningful spatial representations. We model this form of cognitive coordination on a rotating arena – Carousel where arena- and room-bound spatial cues are dissociated. Hippocampal neuronal ensemble activity can repeatedly switch between multiple representations of such an environment. Injection of tetrodotoxin into one hippocampus prevents cognitive coordination during avoidance of a stationary room-defined place on the Carousel and increases coactivity of previously unrelated neurons in the uninjected hippocampus. Place avoidance on the Carousel is impaired after systemic administration of non-competitive NMDAr blockers (MK-801) used to model schizophrenia in animals and people. We tested if this effect is due to cognitive disorganization or other effect of NMDAr antagonism such as hyperlocomotion, spatial memory impairment, or general learning deficit. We also examined if the same dose of MK-801 alters patterns of immediate-early gene (IEG) expression in the hippocampus. IEG expression is triggered in neuronal nuclei in a context-specific manner after behavioral exploration and it is used to map activity in neuronal populations. IEG expression is critical for maintenance of synaptic plasticity and memory consolidation. We show that the same dose of MK-801 that impairs spatial coordination of rats on the Carousel also eliminates contextual specificity of IEG expression in hippocampal CA1 ensembles. This effect is due to increased similarity between ensembles activated in different environments, consistent with the idea that it is caused by increased coactivity between neurons, which did not previously fire together. Our data support the proposition of the Hypersynchrony theory that cognitive disorganization in psychosis is due to increased coactivity between unrelated neurons.

Neural and neuronal discoordination in schizophrenia: From ensembles through networks to symptoms

“…Hamm and colleagues used viral transgenic expression of a fluorescent Ca 2+ indicator to compare population activity patterns in the rodent visual cortex after chronic ketamine and in a genetic mouse model (Df A+/− ) of schizophrenia susceptibility. In a striking, parallel to the effect of other NMDAR antagonists (MK‐801, PCP) on immediate‐early gene expression and on electrophysiological neuronal activity in anaesthetized as well as in awake rats, cortical ensemble activity patterns were less distinct and their (re‐)activation was less reliable in both the chronic ketamine and Df A+/− genetic model . In other words, different ensembles were less distinct and similar ensembles were less similar.…”

“…Bottom Schz : In an MK‐801 animal model of psychosis, the Es (A/A) is reduced (less reliable reactivation) and Es (A/B) is increased (loss of distinctiveness) so that Es (A/A) ≥ Es (A/B). Right: Bar graphs (adapted from Kubik et al) showing the Similarity Score of ensembles active during the 2 time periods. Group A/A explored the same environment twice, group A/B explored 2 different environments.…”

“…Error bars display SEM. Bar graphs adapted from Kubik et al For details see works by Guzowski, Vazdarjanova and Kubik…”

The role of rat posterior parietal cortex in coordinating spatial representations during place avoidance in dissociated reference frames on a continuously rotating arena (Carousel)

“…Thus, in principle, we can use two variants of this task: a room-based task in light with emphasis on visual cues and arena-based task in darkness where navigation is guided by, largely self-generated, local cues on the arena floor. Notably, both tasks require segregation of stimuli room-and arena-cues into coherent subsets [20].…”

Cognitive deficits in schizophrenia and other neuropsychiatric disorders: Convergence of preclinical and clinical evidence

“…Pei et al (2014) report divergent phenotypes of neuregulin-1-mutant mice, an animal model of schizophrenia, and the effect of valproate, a mood stabilizer, to improve cognition. Kubík et al (2014) employed a pharmacological animal model of acute psychosis using the NMDA receptor antagonist MK-801. They found a selective deficit in the co-ordination of multiple informational streams and contextual specificity of neuronal activity, measured by the expression of immediate-early genes.…”