Impaired cognitive discrimination and discoordination of coupled theta–gamma oscillations in Fmr1 knockout mice
Introduction
Cognitive discriminations require distinguishing between similar but distinct experiences. Since multiple experiences are always serial, at least one must be represented in memory. Such discriminations require the coordinated temporal binding and segregation of neural representations in the ongoing electrical activity within and between networks of neurons (Phillips and Singer, 1997, Johnson and Redish, 2007, Lisman and Buzsaki, 2008, Buzsaki, 2010, Kelemen and Fenton, 2010, Kelemen and Fenton, 2013).
Cognitive discriminations are impaired in Fragile X Syndrome (FXS) patients (Bailey et al., 1998, Holsen et al., 2008, Hooper et al., 2008, Ornstein et al., 2008), which may result in both impaired learning and exaggerated responding to small alterations of the environment. FXS is caused by silencing of the FMR1 gene (Pieretti et al., 1991, Colak et al., 2014) and the consequent failure to make the fragile X mental retardation protein (FMRP) that participates in RNA metabolism (Jin et al., 2004, Park et al., 2008, Kao et al., 2010, Melko and Bardoni, 2010). Despite detailed molecular knowledge of the role of FMRP and the consequences of its absence, the systems-level knowledge is inadequate and how dysregulated translation results in cognitive dysfunction is unknown.
Loss of FMRP in mouse models is associated with alterations in synaptic development and function (Comery et al., 1997, Braun and Segal, 2000, Bassell and Warren, 2008). Cognitive discrimination deficits are prominent in Fmr1 knockout (KO) rodents that do not make FMRP, although learning and memory per se are relatively normal (Bakker et al., 1994, D'Hooge et al., 1997, Zhao et al., 2005, Brennan et al., 2006, Bhattacharya et al., 2012, Till et al., 2015). Indeed, loss of FMRP did not alter activity-dependent synaptic plasticity in cultured neurons (Segal et al., 2003) but is associated with enhanced mGluR-stimulated hippocampal long-term depression (LTD) (Huber et al., 2002). While altered hippocampal long-term potentiation (LTP) is not typical in Fmr1 KO mice (Godfraind et al., 1996), when it is observed the deficit is in LTP stability (Lauterborn et al., 2007). Reduced or abolished LTP is observed in neocortex and amygdala (Larson et al., 2005, Zhao et al., 2005, Shang et al., 2009, Chen et al., 2014). However, the functional changes that link dysregulated translation to impaired cognition are unknown, and a theory is lacking.
In spatially layered structures like hippocampus (Fig. 1A, B), oscillations in the local field potential (LFP) arise from locally synchronous activation of synaptic currents. When filtered for the major oscillatory bands such as theta (5–12 Hz) and gamma (30–100 Hz; Fig. 1C), these local events appear synchronized across layers but upon closer inspection there are also significant deviations from global synchrony that are localized in both time and space (Fig. 1D). These local oscillatory variations reflect significant local variations in synaptic activity and representational information, as demonstrated by decoding the current position of a freely-moving rat from local variations of theta oscillations (Agarwal et al., 2014). As illustrated in Fig. 1, while unitary theta and gamma oscillations can synchronize across layers of hippocampus (Fig. 1B), the coupling of theta and gamma oscillations is variably synchronized between layers because the nesting of local gamma oscillations within the concurrent theta oscillation can change abruptly and these changes can synchronize across specific hippocampal layers. The example LFPs from across dorsal hippocampus that are shown in Fig. 1D are all from within the same recording session. The two leftmost examples illustrate, respectively, independent and synchronized organization of gamma oscillations by theta phase between stratum pyramidale (sp) and adjacent stratum radiatum (sr). The two rightmost examples illustrate, respectively, independent and synchronized theta–gamma phase–amplitude organization between the molecular layer (DGm) and the suprapyramidal cell layer (DGs) of the dentate gyrus. The desynchronization and synchronization of such higher-order oscillatory phenomena and their potential to reflect cognition-dependent neural computations by synaptic activity (Colgin et al., 2009, Buzsaki, 2010) leads us to hypothesize that dysregulated translation in FXS is linked to impaired cognition by discoordinated oscillations of neuronal activity. This discoordination hypothesis reflects the fact that unitary processes can be intact, while their interactions are abnormal (Phillips and Silverstein, 2003, Lee et al., 2012, Lee et al., 2014, O'Reilly et al., 2014, Fenton, 2015). The discoordination hypothesis predicts relatively intact unitary neural oscillations such as theta due to rhythmic interneuron discharge (Buzsaki et al., 1983), and gamma oscillations due to GABAergic neurotransmission (Whittington et al., 1995, Csicsvari et al., 2003a, Whittington and Traub, 2003), but inappropriate interactions between neural oscillations such as the theta phase coupling of gamma oscillations illustrated in Fig. 1D (Bragin et al., 1995, Canolty et al., 2006, Tort et al., 2008), especially during cognitive discrimination challenges. According to this view, neural discoordination would alter computational processes and thus increase failures in cognitive discrimination and cognitive control that depend on the appropriate selection and suppression of neural representations of information (Fenton, 2008, Lisman and Buzsaki, 2008, Lee et al., 2012, Lee et al., 2014). Further, because the hypothesis predicts impaired interactions, this notion extends to spatial interactions, predicting that theta–gamma discoordination will be specific to particular recording sites such as the hippocampus CA1 stratum pyramidale (sp), stratum radiatum (sr), and stratum lacunosum moleculare (slm). The sr and slm sites receive distinct hippocampal CA3 and entorhinal cortical (EC) inputs, respectively (Fig. 1A). These inputs carry different kinds of spatial information that CA1 pyramidal cells must integrate and segregate, as appropriate for the specific cognitive requirements. CA3 principal cells are mainly place cells signaling location, whereas ECIII cells are grid cells, border and directional cells signaling conjunctions of distance, environmental borders, and direction information (O'Keefe and Burgess, 1996, Sargolini et al., 2006, Savelli et al., 2008, Zhang et al., 2013). Furthermore, it has been proposed that the CA3 → CA1 sr synapses are more associated with memory and expectations whereas the EC → CA1 slm synapses are associated with the current information that is to be encoded (Colgin et al., 2009, Fries, 2009, Bieri et al., 2014). According to this view, theta–gamma coupling of oscillations in the CA1 LFP will be necessary for the coordinated integration and segregation of neural activity and information when a subject is challenged to discriminate and selectively use memorized and current information. We tested these predictions by recording site-specific hippocampal LFPs and by estimating features of the theta–gamma phase amplitude coupling (Fig. 1E), as well as the phase synchrony of these oscillations between the input layers (Fig. 1F). These investigations were performed while WT and Fmr1 KO mice performed a rapidly learned, hippocampus- and LTP-dependent active place avoidance task with systematically varied demands for cognitive discrimination that are sufficient to persistently modify hippocampal neural network function (Cimadevilla et al., 2001, Pastalkova et al., 2006, Burghardt et al., 2012, Kheirbek et al., 2013, Park et al., 2015). Because we hypothesize these oscillatory phenomena reflect ongoing cognitive information processing, we did not assume that they are stationary across either the recording sites or the behavioral sessions, which varied in cognitive demand and experience.
Section snippets
Cognitive discrimination is impaired in Fmr1 KO mice
We began by establishing that cognitive discrimination is impaired in Fmr1 KO mice using the active place avoidance paradigm (Fig. 2A) because, with this paradigm it is feasible to assess cognition-related neural coordination (Kelemen and Fenton, 2010, Lee et al., 2012, Kelemen and Fenton, 2013) while varying cognitive demand and holding the behavioral and sensory conditions effectively constant. Fmr1 KO mice were more active during pretraining (genotype × time, where time is the 10-min interval:
Summary
We find that spatial learning (Fig. 2) and the power of oscillations in hippocampal LFPs appear essentially normal in Fmr1 KO and WT mice (Fig. S1) but that the KO mice express deficits in cognitive discrimination, abnormal coordination of site-specific hippocampal theta and gamma oscillations (Figs. 3, 4), and abnormal input-specific oscillation phase synchrony (Fig. 5), especially when they are challenged to discriminate between conflicting memories. This pattern of spared and impaired
Experimental procedures
All methods complied with the Public Health Service Policy on Humane Care and Use of Laboratory Animals and were approved by the New York University and State University of New York, Downstate Medical Center Institutional Animal Care and Use Committees.
Author contributions
DD and AAF created software and hardware for data collection, BR collected data, BR and DD analyzed data and created figures, AAF designed and supervised research and wrote the manuscript.
Competing interests
There are no competing interests.
Acknowledgments
This study is supported by the NIH grant R01MH099128.
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These authors made equal contributions to this work.