Impaired hippocampal–prefrontal synchrony in a genetic mouse model of schizophrenia

By Torfi Sigurdsson, K. Stark, M. Karayiorgou, J. Gogos, J. Gordon. Nature, 2010

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Abnormalities in functional connectivity between brain areas have been postulated as an important pathophysiological mechanism underlying schizophrenia. In particular, macroscopic measurements of brain activity in patients suggest that functional connectivity between the frontal and temporal lobes may be altered. However, it remains unclear whether such dysconnectivity relates to the aetiology of the illness, and how it is manifested in the activity of neural circuits. Because schizophrenia has a strong genetic component, animal models of genetic risk factors are likely to aid our understanding of the pathogenesis and pathophysiology of the disease. Here we study Df(16)A+/– mice, which model a microdeletion on human chromosome 22 (22q11.2) that constitutes one of the largest known genetic risk factors for schizophrenia. To examine functional connectivity in these mice, we measured the synchronization of neural activity between the hippocampus and the prefrontal cortex during the performance of a task requiring working memory, which is one of the cognitive functions disrupted in the disease. In wild-type mice, hippocampal–prefrontal synchrony increased during working memory performance, consistent with previous reports in rats. Df(16)A+/– mice, which are impaired in the acquisition of the task, showed drastically reduced synchrony, measured both by phase-locking of prefrontal cells to hippocampal theta oscillations and by coherence of prefrontal and hippocampal local field potentials. Furthermore, the magnitude of hippocampal–prefrontal coherence at the onset of training could be used to predict the time it took the Df(16)A+/– mice to learn the task and increased more slowly during task acquisition. These data suggest how the deficits in functional connectivity observed in patients with schizophrenia may be realized at the single-neuron level. Our findings further suggest that impaired long-range synchrony of neural activity is one consequence of the 22q11.2 deletion and may be a fundamental component of the pathophysiology underlying schizophrenia.

Subfields: Cellular and Molecular Neuroscience, Cognitive Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a84f6e4d0e78366b4b7ecd2fc102356c223cfb0d

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Citations in the corpus

Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy (2012, background): “This in turn reflects a failure of PFC neurons to phase-lock with hippocampal θ-oscillations as a result of aberrant firing of GABAergic interneurons — a deficit seen in psychotic state”
Gamma-band synchronization in the neocortex: novel analysis methods and their application to sensory and motivational systems (2013, background): “, Singer, W., & Nikolic, D. (2011). Synchrony makes neurons fire in sequence, and stimulus properties determine who is ahead.”
Frontal Midline Theta Oscillations during Working Memory Maintenance and Episodic Encoding and Retrieval (2013, background): “Phase-locking of PFC spiking to hippocampal theta is behaviorally related to spatial memory performance (Jones and Wilson, 2005b; Kim et al., 2011; Sigurdsson et al., 2010) and it is most prominent after learning has occurred (Kim et al., 2011).”
Attentional Stimulus Selection through Selective Synchronization between Monkey Visual Areas (2012, neutral): “Interareal gamma-band coherence has been shown through intracranial recordings in several previous publications (Engel et al., 1991a, 1991b; von Stein et al., 2000; Fell et al., 2001; Buschman and Miller, 2007; Womelsdorf et al., 2007; Gregoriou et al., 2009; Colgin et al., 2009; Popescu et al., 200”
Aberrant Frontal and Temporal Complex Network Structure in Schizophrenia: A Graph Theoretical Analysis (2010, background): “…by functional MRI studies that report on increased and more isolated activity of the frontal cortex during cognitive tasks (Kircher et al., 2002; Sommer et al., 2003; Weiss et al., 2006) and aberrant connectivity during rest (Meda et al., 2009; Mannell et al., 2010; Sigurdsson et al., 2010).”
Automated long-term recording and analysis of neural activity in behaving animals (2016, background): “…recording lifetimes, we found that 87.0% of motor cortical (n=897) and 77.5% of striatal units (n=554) satisfied our conservative criteria (Quirk et al., 2009; Schmitzer-Torbert et al., 2005; Sigurdsson et al., 2010) (Isolation distance >= 25, L-ratio <= 0.3 and fraction of ISIs below 1 ms <= 1%).”
Directional prefrontal-thalamic information flow is selectively required during spatial working memory retrieval (2022, background): “The phase-locking of mPFC neuronal firing to hippocampal theta oscillations and theta-phase coherence between mPFC and hippocampus were enhanced during correct choices (Sigurdsson et al., 2010; Hallock et al., 2016).”