Knockout and Mutant Rats

Müller, Maria; Olivier, Jocelien; Homberg, Judith R.

doi:10.1007/978-1-60761-474-6_2

Cited by 5 publications

(7 citation statements)

References 71 publications

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“…Normal rodents placed in a narrow tank of water from which there is no escape will exhibit vigorous swimming and struggling activity for the duration of the test (typically 6–12 minutes) and only rarely adopt a characteristic immobile posture (floating). In contrast, animals treated with either pharmacological agents (such as hormones or via depletion of the amino acid tryptophan necessary to make serotonin [99, 100]), environmental manipulations (unpredictable chronic stress, social isolation [101–103]), or genetic alterations (Flinders strain, SERT knockouts [104, 105]) thought to be important in the etiology of depression more rapidly become immobile and maintain this immobility for a significantly great proportion of time than control subjects [106]. This is thought to represent “behavioral despair” or helplessness.…”

Section: Introductionmentioning

confidence: 99%

The MRL/lpr Mouse Strain as a Model for Neuropsychiatric Systemic Lupus Erythematosus

Gulinello

Putterman

2011

Journal of Biomedicine and Biotechnology

115

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To date, CNS disease and neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) have been understudied compared to end-organ failure and peripheral pathology. In this review, we focus on a specific mouse model of lupus and the ways in which this model reflects some of the most common manifestations and potential mechanisms of human NP-SLE. The mouse MRL lymphoproliferation strain (a.k.a. MRL/lpr) spontaneously develops the hallmark serological markers and peripheral pathologies typifying lupus in addition to displaying the cognitive and affective dysfunction characteristic of NP-SLE, which may be among the earliest symptoms of lupus. We suggest that although NP-SLE may share common mechanisms with peripheral organ pathology in lupus, especially in the latter stages of the disease, the immunologically privileged nature of the CNS indicates that early manifestations of particularly mood disorders maybe derived from some unique mechanisms. These include altered cytokine profiles that can activate astrocytes, microglia, and alter neuronal function before dysregulation of the blood-brain barrier and development of clinical autoantibody titres.

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Section: Introductionmentioning

confidence: 99%

The MRL/lpr Mouse Strain as a Model for Neuropsychiatric Systemic Lupus Erythematosus

Gulinello

Putterman

2011

Journal of Biomedicine and Biotechnology

115

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“…Homberg, Schiepers, Schoffelmeer, Cuppen, and Vanderschuren (2007) showed that juvenile SERT -/rats had significant reductions in play behaviour and exhibited aberrant play behaviours patterns when compared with their wild type controls. The reduced social behaviours exhibited by SERT -/rats was replicated by Muller, Olivier, and Homberg (2010). The findings in rats are similar to the reductions in social initiation behaviours that were identified in SERT knockout mice (Kalueff, Fox, Gallagher, & Murphy, 2007).…”

Section: Serotonin Transporter Knockout Modelsupporting

confidence: 78%

“…Previous studies have used the SERT -/genotype to demonstrate the ASD-like deficits of these animals with studies showing significant reductions in play behaviour, and abnormal play behaviour patterns (Homberg et al, 2007;Muller et al, 2010). However, the full genetic deletion of the SERT is not a direct model of the genetic variants found in ASD populations (refer to chapter one section 1.6).…”

Section: Contribution Of Reduced Sert Function To the Asd Animal Modelmentioning

confidence: 99%

When Genetic and Environmental Factors Meet in Modelling Autism

Pettie¹

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<p>Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder, characterised by deficits in verbal and non-verbal communication, social interaction and repetitive behaviours (APA, 2013). The aetiology of ASD is mostly unknown, with continued research identifying a multitude of genetic and non-genetic factors. However, it is the interaction between environmental factors and the genetic background of an individual which leads to the development of ASD. There is an urgent need for improved animal models of ASD to further our understanding of the aetiology and particularly its pathophysiology, as this will aid in the development of much needed pharmaceutical treatments to alleviate the impact of adverse symptoms for individuals with ASD. Current animal models of ASD examine the genetic (e.g. serotonin transporter knock out rats) or the environmental (e.g. prenatal exposure to Valproate) contributions to the disorder, and very rarely a combination of the two. This thesis aimed to improve the Valproate (VPA) induced ASD animal model with a genetic × environmental interaction approach, as well as optimising chronic administration of the VPA to pregnant rats. To this aim, a non-invasive method of delivering VPA was used, which allowed genetically normal rats to voluntarily consume VPA throughout pregnancy. The prenatal exposure to VPA led to ASD-like behaviours in the offspring (communication delays, increased social behaviour, and social aversion). Next, rats with a genetic deficit in SERT (SERT+/-) exposed to VPA throughout gestation, with an optimised administration method using gelatine pellets, which allowed for voluntary non-invasive consumption, and a more accurate administration of increased VPA doses. Overall, the chronic prenatal exposure to VPA in SERT+/- rats led to a mild ASD-like phenotype, with rats exhibiting communication delays, abnormal play behaviour, disrupted social preference, and to some extent increased anxiety-like behaviour. The brains of the adult offspring were examined for neuronal changes in the GABA interneurons in brain regions associated with social behaviour (amygdala and hippocampus). However, no significant effects of prenatal VPA exposure, genotype, or sex were found. Thus, the variations GABAergic system is unlikely to underlie the earlier identified behavioural alterations. Ultimately, this thesis has furthered the VPA induced ASD animal model with a genetic × environmental interaction approach, as well as optimising the chronic administration method for pregnant rats.</p>

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“…Consistent with Muller et al (2010), the DAD1 -/rats' free feeding weights (M = 341 grams) were 15-20% less than the DAD1 +/-(M = 408 grams) and DAD1 +/+ (M = 398 grams) control rats. Rats were bred and housed at Victoria University of Wellington's animal facility.…”

Section: Subjectssupporting

confidence: 64%

“…Down-regulated D1 receptor function in DAD1 -/rats is further supported by the finding that cocaine-induced locomotor activity was strongly reduced in these animals (unpublished data, reported in Muller, Olivier, & Homberg, 2010). Not only does the DAD1 -/rats model circumvent the issue posed by a lack of pharmacological agents specific for D1 vs. D5…”

Section: Cognitive Changes Associated With Acute Mdma Exposure: Proactive Interference (Perseveration) and Da D1-like Receptorsmentioning

confidence: 66%

Behavioural and Neurochemical Effects of Acute (±) 3,4 methylenedioxymethamphetamine (MDMA) in the Dopamine D1 Receptor Mutant Rat

Squire¹

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<p>Rationale: (±) 3,4-methylenedioxymethamphetamine (MDMA; ‘ecstasy’) is a recreationally abused psychostimulant that leads to detrimental effects on memory performance. MDMA’s acute effects on memory are often attributed to a working memory impairment resulting from compromised serotonin systems. However, recent evidence from non-human animal experimental studies suggests that acute MDMA may impair memory performance through an MDMA-induced increase in dopamine (DA) release, leading to overstimulation of DA D1 receptors. The overstimulation of D1 receptors during acute MDMA exposure is thought to indirectly impair memory by increasing a subject’s susceptibility to proactive interference, leading to a perseverative pattern of responding during memory tasks. Objective: This project investigates the hypothesis that acute MDMA impairs memory performance via overstimulation of D1 receptors. The acute actions of MDMA will be assessed using DA D1 mutant (DAD1-/-) rats which possess a selective down-regulation in functional DA D1 receptors. On the basis that acute MDMA impairs memory function via overstimulation of D1 receptors it is predicted that, compared to control rats, DAD1-/- rats will be protected from the acute memory deficits caused by MDMA. Due to the novelty of the DAD1-/- rat model, prior to the assessment of the acute effects of MDMA on memory performance in these rats, behavioural and neurochemical characterisations will be conducted. Methods: Firstly, a behavioural characterisation was conducted to explore the tendencies of DAD1-/- rats, compared to controls, in a drug free state. Behaviours relevant for motivation and reward, movement, and memory were the focus of the behavioural investigation due to evidence suggesting a role for D1-like receptors in these functions. Secondly, a neurochemical assessment of DAD1-/- and controls rats in response to MDMA (3 mg/kg) was assayed using c-fos expression, a marker for neuronal activity, in several brain regions with known DA innervation. Thirdly, to assess the acute effects of MDMA on memory performance, DAD1-/- and control rats were trained on a spatial working memory T-maze task, delayed non-matching to position (DNMTP), over 25 sessions. Once trained, rats were administered either MDMA (1.5, 2.25 and 3 mg/kg) or saline fifteen minutes prior to testing on DNMTP, with all subjects experiencing all drug doses three time each. In addition, to further investigate the hypothesis that overstimulation of D1 receptors impairs memory performance, the effects of a D1 receptor agonist, SKF 81297 (0.5, 1, 1.5, 3, 4.5 mg/kg) on DNMTP performance were also assessed. Results: The behavioural characterisation revealed that DAD1-/- rats are capable of performing many behaviours relevant for reward processing, movement and memory function. However, DAD1-/- rats were impaired with regard to some reward-related behaviours, such as the acquitision of lever pressing for sugar pellets. The assessment of c-fos expression demonstrated that DAD1-/- rats express less c-fos in the medial prefrontal cortex, striatum and nucleus accumbens compared to control rats following MDMA administration. Lastly, the effects of acute MDMA administration on memory performance were tested. During the third block of MDMA administration, control rats demonstrated decreased accuracy on the DMNTP task at both the 2.25 and 3 mg/kg doses. The decrease in accuracy during MDMA exposure in control rats was driven by an increase in perseverative errors. On the contrary, DAD1-/- rats were not impaired on the DNMTP task following acute MDMA at any of the doses tested. Administration of SKF 81297 did not lead to any systematic changes in performance, but at the 3 mg/kg dose DAD1-/- rats displayed increased accuracy compared to control rats. Conclusions: DAD1-/- rats were protected from an MDMA-induced decrease in accuracy on the DNMTP task compared to control rats. This finding challenges the assumption that MDMA’s acute effects on memory performance are wholly due to serononergic mechanisms. Specifically, the current study provides evidence for the hypothesis that acute MDMA exposure impairs memory performance in rats.</p>

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Knockout and Mutant Rats

Cited by 5 publications

References 71 publications

The MRL/lpr Mouse Strain as a Model for Neuropsychiatric Systemic Lupus Erythematosus

The MRL/lpr Mouse Strain as a Model for Neuropsychiatric Systemic Lupus Erythematosus

When Genetic and Environmental Factors Meet in Modelling Autism

Behavioural and Neurochemical Effects of Acute (±) 3,4 methylenedioxymethamphetamine (MDMA) in the Dopamine D1 Receptor Mutant Rat

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