Impaired GAD1 expression in schizophrenia-related WISKET rat model with sex-dependent aggressive behavior and motivational deficit.
A Büki, G Horvath, G Benedek, E Ducza, G Kekesi
Genes, brain, and behavior August 29, 2018 DOI: 10.1111/gbb.12507 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study Peer reviewed |
|---|---|
| Population | Selectively bred Wistar rats (WISKET line) and naive Wistar rats, both male and female |
| Interventions | Isolation rearing Ketamine |
| Measures | holeboard (HB)-like test |
| Topics | Ketamine |
| Keywords | Hippocampus Prefrontal cortex Animals Rats, wistar Disease models, animal Glutamate decarboxylase Aggression Social isolation Motivation Schizophrenia Sex factors Female Behavior Selective breeding Gad1 Isolation rearing Two-hit rat model |
| Key findings | Male WISKET rats displayed impaired social activity, increased aggression, stress-related behavior, active social withdrawal, motivation deficit, and decreased exploration compared with Wistar rats and female WISKET rats. These behavioral alterations were accompanied by sex-dependent changes in GAD67 mRNA and protein expression in the prefrontal cortex and hippocampus. The authors propose that WISKET animals are valuable for preclinical drug discovery targeting negative symptoms with potential antipsychotic efficacy. |
Abstract
After peri-adolescence isolation rearing (IS) and subchronic ketamine (KET) treatment, adult, selectively bred Wistar rats (named WISKET) mimic abnormal behaviors reminiscent of human schizophrenia, including reduced prepulse-inhibition of startle reflex, disturbances in cognition, locomotor activity and thermoregulation, decreased pain sensitivity and electrophysiological alterations. To further validate our WISKET rat line, regarding its translational utility in schizophrenia research, we examined their social behavior and introduced a short and simple holeboard (HB)-like test to investigate their motivational deficit that predicts the cognitive disturbance. Sex-dependent alterations in schizophrenia may yield important insights into its etiology; thus, male and female WISKET rats were also investigated and compared with their naive Wistar counterparts. Considering the contribution of the hippocampal and cortical GABAergic inhibitory circuitry in these behavioral alterations, molecular-biology studies were also performed regarding the GAD1 gene products. Impaired social activity with increased aggression, stress-related behavior, active social withdrawal, motivation deficit and decreased exploration were observed, especially in male WISKET rats, compared with Wistar ones and their corresponding females. These alterations were accompanied by sex-dependent alterations regarding GAD67 mRNA and protein expression in the prefrontal cortex and hippocampus. In conclusion, the WISKET animals are valuable tools for animal-based preclinical drug discovery studies for predictive screening of novel compounds improving negative symptoms with potential antipsychotic efficacy.
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 2
- Down-Regulation of Hippocampal Genes Regulating Dopaminergic, GABAergic, and Glutamatergic Function Following Combined Neonatal Phencyclidine and Post-Weaning Social Isolation of Rats as a Neurodevelopmental Model for Schizophrenia. The International Journal of Neuropsychopharmacology November 2016
- Neonatal phencyclidine administration and post-weaning social isolation as a dual-hit model of 'schizophrenia-like' behaviour in the rat. Psychopharmacology June 2014