Lateral Septal Circuits Govern Schizophrenia-Like Effects of Ketamine on Social Behavior
Ruixiang Wang, Zeru Peterson, Nagalakshmi Balasubramanian, Kanza M. Khan, Michael S. Chimenti, Daniel Thedens, Thomas Nickl-Jockschat, Catherine A. Marcinkiewcz
bioRxiv Preprint Server August 8, 2023 preprint DOI: 10.1101/2023.08.08.552372 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Translational animal model |
|---|---|
| Population | Mice |
| Intervention | ketamine |
| Dose | 30 mg/kg/day for 10 days |
| Duration | 10 days |
| Topics | Esketamine Ketamine |
| Keywords | Schizophrenia-like symptoms Psychiatric disorder Mental illness Neurobiology Brain circuits Lateral septum Brain region Neural circuits Brain function Impaired social behavior Social challenges Behavioral restoration Therapeutics New therapies Treatments Interventions Brain stimulation Targeted therapy |
| Citations | 1 |
| Key points | Chronic ketamine treatment in mice causes hypoactivation of the lateral septum, and chemogenetic activation of LS neurons rescues social deficits, while inhibition recapitulates them, implicating LS dysfunction in schizophrenia-like social impairments. |
Abstract
Schizophrenia is marked by poor social functioning that can have a severe impact on quality of life and independence, but the underlying neural circuity is not well understood. Here we used a translational model of subanesthetic ketamine in mice to delineate neural pathways in the brain linked to social deficits in schizophrenia. Mice treated with chronic ketamine (30 mg/kg/day for 10 days) exhibit profound social and sensorimotor deficits as previously reported. Using three- dimensional c-Fos immunolabeling and volume imaging (iDISCO), we show that ketamine treatment resulted in hypoactivation of the lateral septum (LS) in response to social stimuli. Chemogenetic activation of the LS rescued social deficits after ketamine treatment, while chemogenetic inhibition of previously active populations in the LS (i.e. social engram neurons) recapitulated social deficits in ketamine-naïve mice. We then examined the translatome of LS social engram neurons and found that ketamine treatment dysregulated genes implicated in neuronal excitability and apoptosis, which may contribute to LS hypoactivation. We also identified 38 differentially expressed genes (DEGs) in common with human schizophrenia, including those involved in mitochondrial function, apoptosis, and neuroinflammatory pathways. Chemogenetic activation of LS social engram neurons induced downstream activity in the ventral part of the basolateral amygdala, subparafascicular nucleus of the thalamus, intercalated amygdalar nucleus, olfactory areas, and dentate gyrus, and it also reduces connectivity of the LS with the piriform cortex and caudate-putamen. In sum, schizophrenia-like social deficits may emerge via changes in the intrinsic excitability of a discrete subpopulation of LS neurons that serve as a central hub to coordinate social behavior via downstream projections to reward, fear extinction, motor and sensory processing regions of the brain.
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
Cites 8
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- Reviewing the ketamine model for schizophrenia Journal of Psychopharmacology November 20, 2013
- Association of Ketamine With Psychiatric Symptoms and Implications for Its Therapeutic Use and for Understanding Schizophrenia JAMA Network Open May 1, 2020
- Ketamine-Induced Modulation of the Thalamo-Cortical Network in Healthy Volunteers As a Model for Schizophrenia The International Journal of Neuropsychopharmacology April 19, 2015
- Prevention and reversal of ketamine-induced schizophrenia related behavior by minocycline in mice: Possible involvement of antioxidant and nitrergic pathways Journal of Psychopharmacology September 17, 2013
and 3 more in the library