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

Saurav Seshadri,Andreas Klaus,Dietmar Plenz,Patrick O Kanold,Daniel E Winkowski

doi:10.1038/s41398-017-0060-z

Abstract

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.

Highlights

Network-level disturbances are thought to be a core pathological entity in schizophrenia (SZ)[1,2]
While this study advances our understanding of the altered network dynamics caused by N-methyl D-aspartate receptor (NMDAR) antagonism, our work is distinguished by several factors: first, we use a neurodevelopment-specific intervention, which may more accurately reproduce the etiology of cognitive impairment observed in SZ20; second, we use pharmacological rescue and behavioral validation to establish a link between dynamic phenotypes and cognitive impairment; and third, our analysis provides distinct, complementary insights by focusing on temporal propagation of neuronal activity rather than synchronous co-activation of neuronal ensembles
Key neuroanatomical deficits are seen in the medial prefrontal cortex as well as M110, suggesting that M1, which is accessible by minimally invasive 2-photon imaging (2PI), may show similar dynamic deficits to areas subserving working memory[49]

Summary

Introduction

Network-level disturbances are thought to be a core pathological entity in schizophrenia (SZ)[1,2]. These disturbances are brought about by a combination of genetic and environmental risk factors, which act early in neurodevelopment to disrupt the trajectory of network formation. One of the most extensively studied of these risk factors is N-methyl D-aspartate receptor (NMDAR) hypofunction, due to the psychotomimetic effects of NMDAR antagonists[3], consistent association of mutations in NMDAR signaling-related genes with SZ4, and successful reproduction of key SZ-associated phenotypes in NMDAR loss-of-function rodent models[5,6,7] Both SZ patients[8,9] and developmental NMDAR hypofunction model animals[10] show reduced immunoreactivity for the fast-spiking interneuron marker parvalbumin (PV). The precise nature of the network dysfunction mediating this effect remains unknown

Methods

Results

Conclusion