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


Abnormalities in functional connectivity between brain areas have been postulated as an important pathophysiological mechanism underlying schizophrenia1,2. In particular, macroscopic measurements of brain activity in patients suggest that functional connectivity between the frontal and temporal lobes may be altered3,4. 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 component5, 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 schizophrenia6. 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.

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Figure 1: Hippocampal–prefrontal synchrony during a spatial working memory task in mice.
Figure 2: Reduced hippocampal–prefrontal synchrony in Df(16)A +/– mice.
Figure 3: Reduced hippocampal–prefrontal synchrony correlates with behavioural performance in Df(16)A +/– mice.
Figure 4: Selectivity of hippocampal–prefrontal synchrony deficits in Df(16)A +/– mice.


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We would like to thank M. Topiwala, A. Adhikari and Y. Sun for technical assistance. We also thank A. Adhikari, L. Drew and A. Arguello for comments on the manuscript. This work was supported by the Simons Foundation (J. A. Gogos), US National Institute of Mental Health grants MH67068 (M.K. and J. A. Gogos) and MH081968 (J. A. Gordon), and the Lieber Center for Schizophrenia Research and Treatment.

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.

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Correspondence to Joseph A. Gogos or Joshua A. Gordon.

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Sigurdsson, T., Stark, K., Karayiorgou, M. et al. Impaired hippocampal–prefrontal synchrony in a genetic mouse model of schizophrenia. Nature 464, 763–767 (2010).

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