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Transl Psychiatry. 2018 Jan 10;8(1):3. doi: 10.1038/s41398-017-0060-z.

Altered avalanche dynamics in a developmental NMDAR hypofunction model of cognitive impairment.

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Section on Critical Brain Dynamics, National Institute of Mental Health, Bethesda, MD, USA.
Department of Biology, Univ. of Maryland, College Park, MD, USA.
Section on Critical Brain Dynamics, National Institute of Mental Health, Bethesda, MD, USA.


Disturbed activity patterns in cortical networks contribute to the pathophysiology of schizophrenia (SZ). Several lines of evidence implicate NMDA receptor hypofunction in SZ, and blocking NMDA receptor signaling during early neurodevelopment produces cognitive deficits in rodent models that resemble those seen in schizophrenic patients. However, the altered network dynamics underlying these cognitive impairments largely remain to be characterized, especially at the cellular level. Here, we use in vivo two-photon calcium imaging to describe pathological dynamics, occurring in parallel with cognitive dysfunction, in a developmental NMDA receptor hypofunction model. We observed increased synchrony and specific alterations in spatiotemporal activity propagation, which could be causally linked to a previously unidentified persistent bursting phenotype. This phenotype was rescued by acute treatment with the NMDA receptor co-agonist D-serine or the GABAB receptor agonist baclofen, which similarly rescued working memory performance. It was not reproduced by optogenetic inhibition of fast-spiking interneurons. These results provide novel insight into network-level abnormalities mediating the cognitive impairment induced by NMDA receptor hypofunction.

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