Impaired cognitive discrimination and discoordination of coupled theta–gamma oscillations in Fmr1 knockout mice

• Published in: Neurobiology of disease Vol. 88; pp. 125 - 138
• Main Authors: Radwan, Basma, Dvorak, Dino, Fenton, André A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2016; Elsevier
• Subjects: Analysis of Variance; Animals; Avoidance Learning - physiology; Azides; Cognition Disorders - etiology; Cognition Disorders - pathology; Cross-frequency coupling; Discrimination (Psychology) - physiology; Disease Models, Animal; Fragile X; Fragile X Mental Retardation Protein - genetics; Fragile X Mental Retardation Protein - metabolism; Fragile X Syndrome - complications; Fragile X Syndrome - genetics; Gamma Rhythm - genetics; Hippocampus - physiopathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Neural coordination; Neurology; Octreotide - analogs & derivatives; Phase–amplitude coupling; Spatial cognition; Spectrum Analysis; Theta Rhythm - genetics; Theta–gamma comodulation; Time Factors; Cross-frequency coupling; Phase–amplitude coupling; Neural coordination; Spatial cognition; Theta–gamma comodulation; Fragile X
• ISSN: 0969-9961; 1095-953X; 1095-953X
• DOI: 10.1016/j.nbd.2016.01.003

Fragile X syndrome (FXS) patients do not make the fragile X mental retardation protein (FMRP). The absence of FMRP causes dysregulated translation, abnormal synaptic plasticity and the most common form of inherited intellectual disability. But FMRP loss has minimal effects on memory itself, making it difficult to understand why the absence of FMRP impairs memory discrimination and increases risk of autistic symptoms in patients, such as exaggerated responses to environmental changes. While Fmr1 knockout (KO) and wild-type (WT) mice perform cognitive discrimination tasks, we find abnormal patterns of coupling between theta and gamma oscillations in perisomatic and dendritic hippocampal CA1 local field potentials of the KO. Perisomatic CA1 theta–gamma phase–amplitude coupling (PAC) decreases with familiarity in both the WT and KO, but activating an invisible shock zone, subsequently changing its location, or turning it off, changes the pattern of oscillatory events in the LFPs recorded along the somato-dendritic axis of CA1. The cognition-dependent changes of this pattern of neural activity are relatively constrained in WT mice compared to KO mice, which exhibit abnormally weak changes during the cognitive challenge caused by changing the location of the shock zone and exaggerated patterns of change when the shock zone is turned off. Such pathophysiology might explain how dysregulated translation leads to intellectual disability in FXS. These findings demonstrate major functional abnormalities after the loss of FMRP in the dynamics of neural oscillations and that these impairments would be difficult to detect by steady-state measurements with the subject at rest or in steady conditions. •Related cognitive and electrophysiological impairments in Fmr1 null mice•Inability of Fmr1 null mice to judiciously discriminate between related memories•Abnormal hippocampal theta–gamma phase amplitude coupling in Fmr1 null mice•Frequency-specific LFP discoordination of CA1 inputs and output in Fmr1 null mice•Hippocampus input- and cognitive task-specific pathophysiology in Fmr1 null mice