TY - JOUR
T1 - Altered avalanche dynamics in a developmental NMDAR hypofunction model of cognitive impairment
AU - Seshadri, Saurav
AU - Klaus, Andreas
AU - Winkowski, Daniel E.
AU - Kanold, Patrick O.
AU - Plenz, Dietmar
N1 - Funding Information:
We thank Kunal Goel for assistance with image processing. We also thank the NIDA Optogenetics and Transgenic Technology Core for providing the PV-Cre transgenic rat line, and the NIH Section on Instrumentation Core Facility for producing custom tools for head-fixed 2PI. This research was supported by the Intramural Research Program of the National Institute of Mental Health and BRAIN initiative grant 1U01NS090569-01. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih. gov).
Publisher Copyright:
© 2017 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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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U2 - 10.1038/s41398-017-0060-z
DO - 10.1038/s41398-017-0060-z
M3 - Article
C2 - 29317600
AN - SCOPUS:85040529612
SN - 2158-3188
VL - 8
JO - Translational psychiatry
JF - Translational psychiatry
IS - 1
M1 - 60
ER -