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

Abstract

Abnormalities in functional connectivity between brain areas have been postulated as an important pathophysiological mechanism underlying schizophrenia 1,2 . In particular, macroscopic measurements of brain activity in patients suggest that functional connectivity between the frontal and temporal lobes may be altered 3,4 . 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 5 , 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 6 . 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 rats7. 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.Correspondence and requests for materials should be addressed to J. A. Gordon (jg343@columbia.edu) or J. A. Gogos (jag90@columbia.edu). Supplementary Information is linked to the online version of the paper at www.nature.com/nature. Author Contributions T.S., M.K., J. A. Gogos and J. A. Gordon designed the experiments. T.S. carried out the behavioural and electrophysiology experiments. K.L.S. engineered and supplied the mutant and control mice and contributed to the experimental design. T.S. and J. A. Gordon analysed the data. T.S., M.K., J. A. Gogos and J. A. Gordon interpreted the results and wrote the paper.Author Information Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests. NIH Public Access Author ManuscriptNature. Author manuscript; available in PMC 2010 October 1. Despite decades of research, the neural circuit abnormalities underlying schizophreni...

Hippocampal–Dorsolateral Prefrontal Coupling as a Species-Conserved Cognitive Mechanism: A Human Translational Imaging Study

“…Research in rodents has shown increasing evidence that HC-PFC coupling is required for spatial WM performance (Gordon, 2011;Jones and Wilson, 2005;Sigurdsson et al, 2010). Findings in humans, however, draw a different picture: several studies have shown that HC-DLPFC coupling seems to decrease with increasing WM load (Axmacher et al, 2008;Esslinger et al, 2009).…”

“…In the rodent literature, evidence has accumulated that HC-PFC coupling is related to spatial WM performance (Gordon, 2011;Jones and Wilson, 2005;Sigurdsson et al, 2010). Owing to the ceiling effect in our paradigm (with respect to performance in the test phase; Supplementary Materials and Methods), a direct correlation of connectivity and RAM performance was not possible.…”

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“…Sigurdson et al [47] (Figure 1) measured the synchronization between the hippocampus and the prefrontal cortex during working memory (WM) in Df(16)A +/-mice which provide a genetic model for the microdeletion on human chromosome 22 (22q11.2). The 22q11.2 microdeletion is one of the largest known genetic risk factors for schizophrenia [48].…”

Activation of 5-HT6 Receptors Modulates Sleep–Wake Activity and Hippocampal Theta Oscillation

“…For example, theta modulation of gamma activity in the prefrontal cortex is prominent during select cognitive tasks 12 and coherent theta rhythm links hippocampus with the amygdala during processing of emotional information. 13,14 Hippocampal theta activity has also been demonstrated in humans in similar conditions, for example, during spatial memory tasks as well as during REM sleep.…”