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

Abstract

Fragile X syndrome (FXS) patients do not make the fragile X mental retardation protein (FMRP). 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 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.

Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome

“…Similar to findings in Fmr1 KO mouse cortex [34], we found a shift toward reduced influence of alpha frequency oscillations on gamma power and synchronization in FXS compared to controls. Cortical networks in healthy controls generally utilize alpha oscillations to control and inhibit local network excitation [45]; in FXS, these networks may rely more consistently on slower theta waves or even delta waves (see Additional file 1) to modulate gamma frequency, given the lack of deficit in theta-gamma coupling.…”

“…Theta and alpha band modulation of gamma activity were of particular interest, as previous studies have suggested theta and alpha abnormalities in FXS patients [32, 33] and KO rodent models [34]. Frequency bands of interest were chosen as follows based on standard low-frequency and gamma band cut-offs: theta, 4–7 Hz; alpha, 8–12 Hz; gamma, 30–80 Hz.…”

Active place avoidance is no more stressful than unreinforced exploration of a familiar environment

“…Place avoidance tasks are rapidly learned and sensitive to hippocampus dysfunction (Cimadevilla et al, 2000;Cimadevilla et al, 2001b). The experience of mild foot shock in a particular location induces place avoidance memories that require persistent hippocampal LTP and causes changes in hippocampal synaptic network function that persist for at least a month (Cimadevilla et al, 2001b;Pastalkova et al, 2006;Burghardt et al, 2012;Kheirbek et al, 2013;Park et al, 2015;Pavlowsky et al, 2016;Radwan et al, 2016). Because stress is known to modify synaptic plasticity and memory-related biochemical signaling (Korz and Frey, 2003;Ahmed et al, 2006), it is of substantial importance to determine to what extent place avoidance training is stressful.…”

Hippocampal spike-time correlations and place-field overlaps during open field foraging

“…One possible explanation for this could be that although the coordination of spikes between place cells are lowered in the knockout mice to a level that the phase-distance relationship is lost, there is still a significant enough level of theta modulation of the neurons that some structure in the distribution of phases remains. In any case, further work should address whether this phase code, relevant at behavioural timescales, is needed for long-term memory formation of independent representations of spatially informed tasks, since knock-out mice present deficiencies when required to perform discrimination tasks of past events with a spatial component, as opposed to performing as well as wild-type mice at learning and retaining unchanging spatial information (Radwan et al, 2016;Kooy et al, 1996;Krueger et al, 2011).…”