Effect of sepsis on behavioral changes on the ketamine-induced animal model of schizophrenia

Comim, Clarissa M.; Silva, Napoleão C.; Patrício, J.J.S.; Palmas, Daphne; Mendonça, Bruna P.; Bittencourt, Mariana O.; Cassol-Jr, Omar J.; Barichello, Tatiana; Zugno, Alexandra I.; Quevedo, João; Dal‐Pizzol, Felipe

doi:10.1016/j.jneuroim.2015.02.012

Cited by 6 publications

(4 citation statements)

References 31 publications

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“…It is generally recognized that CNS inflammation plays a critical role in the development of long-lasting cognitive impairment following early life inflammation [ 35 , 36 ]. Proinflammatory cytokines, particularly IL-1β, play an important role in the CNS inflammation process after neonatal inflammation [ 16 , 17 ].…”

Section: Discussionmentioning

confidence: 99%

Severe inflammation in new-borns induces long-term cognitive impairment by activation of IL-1β/KCC2 signaling during early development

Zhang

Yang

et al. 2022

BMC Med

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Background Neonatal sepsis can induce long-term cognitive impairment in adolescence or adulthood, but the underlying molecular mechanism is not fully understood. The expression of K+-Cl– co-transporter 2 (KCC2) plays a pivotal role in the GABAergic shift from depolarizing to hyperpolarizing during early postnatal development. In this study, we aimed to determine whether neonatal severe inflammation-induced cognitive impairment was associated with the expression of KCC2 during early development. Methods Neonatal severe inflammation was established by intraperitoneal injection of high dose lipopolysaccharide (LPS, 1 mg kg–1) in postnatal day 3 (P3) rats. The Morris water maze task and fear conditioning test were used to investigate long-term cognitive functions. ELISA, RT-PCR and Western blotting were used to examine the expression levels of proinflammatory cytokines and KCC2. Perforated patch-clamping recordings were used to determine the GABAergic shift. Results Neonatal severe inflammation led to long-term cognitive impairment in rats. Meanwhile, sustained elevation of interleukin-1 beta (IL-1β) levels was found in the hippocampus until P30 after LPS injection. Elevated expression of KCC2 and hyperpolarized GABA reversal potential (EGABA) were observed in CA1 hippocampal pyramidal neurons from the P7-P10 and P14-P16 rats after LPS injection. Specific knockdown of IL-1β mRNA expression rescued the elevated expression of KCC2 and the hyperpolarized EGABA at P7-P10 and P14-P16. Accordingly, specific knockdown of IL-1β or KCC2 expression improved the cognitive impairment induced by neonatal severe inflammation. Conclusions Sustained elevation of IL-1β in the hippocampus may induce cognitive impairment by upregulation of KCC2 during early development.

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Section: Discussionmentioning

confidence: 99%

Severe inflammation in new-borns induces long-term cognitive impairment by activation of IL-1β/KCC2 signaling during early development

Zhang

Yang

et al. 2022

BMC Med

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“…These chronic alterations in in ammatory parameters caused by CLP can help elucidate the relationship between in ammation, behavior, and changes in neurotrophic levels. Notably, some studies have shown that the CLP model of sepsis can also induce a depressive-like behavior and predispose to schizophrenia-like behavior in rodents [5,24] .…”

Section: Discussionmentioning

confidence: 99%

Bimodal effect of ketamine on neurotrophic factors and inflammatory parameters in cecal ligation and puncture-induced sepsis model

Valvassori

Réus

Mastella

et al. 2022

Preprint

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Background: Studies have demonstrated an important impact of systemic inflammation in the central nervous system, which could be related to psychiatric disorders’ pathophysiology. Ketamine can have anti-inflammatory proprieties, but dose-dependently effects need to be studied. Objective: To evaluate the effect of different doses of ketamine on levels of neurotrophins and inflammatory cytokines in the brains of rats. Methods: Wistar rats were submitted to the cecal ligation and puncture (CLP) model of sepsis. Thirty days after the CLP procedure, the rats received an intraperitoneal injection (i.p.) of ketamine (5, 15, or 25 mg/kg) or saline, once a day for seven days. The rats were killed 30 minutes after the last i.p. injection. The frontal cortex, hippocampus, and striatum were dissected for analysis of IL-1𝛽, IL-6, IL-10, TNF-α, BDNF, NGF, NT-3, and GDNF levels. Results: CLP increased the levels of IL-1𝛽, IL-6, IL-10, and TNF-α levels in the frontal cortex and/or hippocampus of rats. Besides, BDNF levels were decreased by CLP in all structures analyzed. NGF and GDNF were decreased only in the hippocampus. Ketamine at 5 mg/kg reversed all alterations caused by CLP and per se increased the levels of BDNF and NGF in the frontal cortex and/or hippocampus. Ketamine at 15 mg/kg increased BDNF and NGF levels. In turn, Ketamine at 25mg/kg potentiates the inflammatory injury on the brain induced by CLP. Conclusion:We suggest that ketamine could work differently in a systemic inflammation environment, and caution needs to be taken depending on the inflammatory history of the patient.

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“…Although it has been showed that the interaction between susceptibility genes and environmental factors after birth induces more apparent phenotypes of schizophrenia, only a few studies have investigated the social behavior in double‐hit models . KET with maternal deprivation or with sepsis has resulted in increased latency to start social behavior in adult rats without significant differences for the number of contacts and the time spent in social engagement .…”

Section: Discussionmentioning

confidence: 99%

Impaired GAD1 expression in schizophrenia‐related WISKET rat model with sex‐dependent aggressive behavior and motivational deficit

Büki

Horváth

Benedek

et al. 2018

Genes Brain and Behavior

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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.

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Effect of sepsis on behavioral changes on the ketamine-induced animal model of schizophrenia

Cited by 6 publications

References 31 publications

Severe inflammation in new-borns induces long-term cognitive impairment by activation of IL-1β/KCC2 signaling during early development

Severe inflammation in new-borns induces long-term cognitive impairment by activation of IL-1β/KCC2 signaling during early development

Bimodal effect of ketamine on neurotrophic factors and inflammatory parameters in cecal ligation and puncture-induced sepsis model

Impaired GAD1 expression in schizophrenia‐related WISKET rat model with sex‐dependent aggressive behavior and motivational deficit

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