Ketamine Restores Thalamic-Prefrontal Cortex Functional Connectivity in a Mouse Model of Neurodevelopmental Disorder-Associated 2p16.3 Deletion

Hughes, Rebecca and Whittingham-Dowd, Jayde and Simmons, Rachel and Clapcote, Stephen and Broughton, Susan and Dawson, Neil (2020) Ketamine Restores Thalamic-Prefrontal Cortex Functional Connectivity in a Mouse Model of Neurodevelopmental Disorder-Associated 2p16.3 Deletion. Cerebral Cortex (4). 2358–2371. ISSN 1047-3211

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Abstract

2p16.3 deletions, involving heterozygous NEUREXIN1 (NRXN1) deletion, dramatically increase the risk of developing neurodevelopmental disorders, including autism and schizophrenia. We have little understanding of how NRXN1 heterozygosity increases the risk of developing these disorders, particularly in terms of the impact on brain and neurotransmitter system function and brain network connectivity. Thus, here we characterize cerebral metabolism and functional brain network connectivity in Nrxn1α heterozygous mice (Nrxn1α+/− mice), and assess the impact of ketamine and dextro-amphetamine on cerebral metabolism in these animals. We show that heterozygous Nrxn1α deletion alters cerebral metabolism in neural systems implicated in autism and schizophrenia including the thalamus, mesolimbic system, and select cortical regions. Nrxn1α heterozygosity also reduces the efficiency of functional brain networks, through lost thalamic “rich club” and prefrontal cortex (PFC) hub connectivity and through reduced thalamic-PFC and thalamic “rich club” regional interconnectivity. Subanesthetic ketamine administration normalizes the thalamic hypermetabolism and partially normalizes thalamic disconnectivity present in Nrxn1α+/− mice, while cerebral metabolic responses to dextro-amphetamine are unaltered. The data provide new insight into the systems-level impact of heterozygous Nrxn1α deletion and how this increases the risk of developing neurodevelopmental disorders. The data also suggest that the thalamic dysfunction induced by heterozygous Nrxn1α deletion may be NMDA receptor-dependent.

Item Type:
Journal Article
Journal or Publication Title:
Cerebral Cortex
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/2700/2700
Subjects:
?? autismfunctional brain imaginggraph theorynmda receptorschizophreniageneral medicinecellular and molecular neurosciencecognitive neurosciencemedicine(all) ??
ID Code:
139509
Deposited By:
Deposited On:
09 Dec 2019 15:55
Refereed?:
Yes
Published?:
Published
Last Modified:
25 Sep 2024 00:51