Hyperdopaminergia and NMDA Receptor Hypofunction Disrupt Neural Phase Signaling

Abstract

Neural phase signaling has gained attention as a putative coding mechanism through which the brain binds the activity of neurons across distributed brain areas to generate thoughts, percepts, and behaviors. Neural phase signaling has been shown to play a role in various cognitive processes, and it has been suggested that altered phase signaling may play a role in mediating the cognitive deficits observed across neuropsychiatric illness. Here, we investigated neural phase signaling in two mouse models of cognitive dysfunction: mice with genetically induced hyperdopaminergia [dopamine transporter knock-out (DAT-KO) mice] and mice with genetically induced NMDA receptor hypofunction [NMDA receptor subunit-1 knockdown (NR1-KD) mice]. Cognitive function in these mice was assessed using a radial-arm maze task, and local field potentials were recorded from dorsal hippocampus and prefrontal cortex as DAT-KO mice, NR1-KD mice, and their littermate controls engaged in behavioral exploration. Our results demonstrate that both DAT-KO and NR1-KD mice display deficits in spatial cognitive performance. Moreover, we show that persistent hyperdopaminergia alters interstructural phase signaling, whereas NMDA receptor hypofunction alters interstructural and intrastructural phase signaling. These results demonstrate that dopamine and NMDA receptor dependent glutamate signaling play a critical role in coordinating neural phase signaling, and encourage further studies to investigate the role that deficits in phase signaling play in mediating cognitive dysfunction.

Proteomic systems evaluation of the molecular validity of preclinical psychosis models compared to schizophrenia brain pathology

“…Ketamine doses induced hyperlocomotion, stereotypy, impaired information processing with abnormalities in cognitive function, and impaired social interaction, behavioural characterizations which has been described in previous acute ketamine models (Becker et al, 2003;Gastambide et al, 2013). NR1-knockdown mice displayed both hyperlocomotion and increased stereotypic behaviour in addition to impairments in cognition and escape behaviours as found previously (Dzirasa et al, 2009).…”

N-Aryl Piperazine Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators Possess Efficacy in Preclinical Models of NMDA Hypofunction and Cognitive Enhancement

“…Thus, we evaluated the ability of DPFE to reverse the behavioral deficits in NR1KD mice, a genetic model of NMDAR hypofunction (Ramsey, 2009), to avoid potential confounds observed with NMDAR antagonist challenge models. NR1KD mice display an approximately 90% decrease in functional NMDARs in limbic and forebrain regions and corresponding behavioral alterations, including hyperlocomotor activity and performance deficits in social interaction and cognition (Dzirasa et al, 2009;Halene et al, 2009;Ramsey, 2009;Moy et al, 2012), comparable to those induced with NMDAR antagonists. Treatment with DPFE reversed the hyperlocomotor activity observed in the NR1KD mice similar to the effects observed with clinically available antipsychotics (Mohn et al, 1999).…”

Oscillations and Neuronal Dynamics in Schizophrenia: The Search for Basic Symptoms and Translational Opportunities

“…In addition to inhibitory and excitatory neurotransmission, there is also evidence for the potential contribution of monoamines, such as DA, to the modulation of high-frequency oscillations [44][45][46] [47]. However, further research is required to systematically address this relationship.…”