Ketamine Restores Thalamic-Prefrontal Cortex Functional Connectivity in a Mouse Model of Neurodevelopmental Disorder-Associated 2p16.3 Deletion.
Rebecca B Hughes, Jayde Whittingham-Dowd, Rachel E Simmons, Steven J Clapcote, Susan J Broughton, Neil Dawson
Cerebral Cortex April 14, 2020 DOI: 10.1093/cercor/bhz244 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study (preclinical mouse model) Peer reviewed |
|---|---|
| Population | Nrxn1α heterozygous mice (Nrxn1α+/-) |
| Interventions | Ketamine Dextro-amphetamine |
| Dose | subanesthetic ketamine (dose not specified) |
| Topics | Esketamine Ketamine |
| Keywords | Nmda receptor Autism Functional brain imaging Graph theory Schizophrenia |
| Key points | Heterozygous Nrxn1α deletion in mice alters cerebral metabolism in thalamic, mesolimbic, and cortical regions and reduces functional brain network efficiency through lost thalamic and prefrontal hub connectivity. Subanesthetic ketamine normalizes thalamic hypermetabolism and partially normalizes thalamic disconnectivity, while dextro-amphetamine responses are unchanged. The authors suggest the thalamic dysfunction may be NMDA receptor-dependent. |
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cited by 3
- Case report: Adult with bipolar disorder and autism treated with ketamine assisted psychotherapy. Frontiers in Psychiatry 2024
- Psychedelics and the thalamocortical system: A scoping review Pharmacology, Biochemistry, and Behavior July 9, 2026
- Ketamine Self-Medication in a Patient with Autism Spectrum Disorder and Comorbid Therapy-Resistant Depression Psychiatry and Clinical Psychopharmacology September 1, 2022
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