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Abstract

O:09 Animal Models for Schizophrenia, Why do we Bother?

D. Eyles

Queensland Centre for Mental Health Research, School of Biomedical Sciences, The University of Queensland, Brisbane, Qld 4072, Australia Email: Eyles@uq.edu.au

Aims The speaker will review the literature in a way that conveys to the clinical audience why we non-clinicians i.e. neuroscientists/animal behaviouralists/pharmacologists model the most human of all diseases in non-humans.

Methods The presenter will attempt to portray the most useful features of existing models i.e. how they relate to what we know about disease eitiology (construct validity); how accurately they reproduce the symptoms of the human disease (face validity) and ultimately how do they respond to therapeutic intervention (predictive validity).

Results Briefly the presenter will

List the contribution made to the field by the speakers at this symposia.

List what has been achieved internationally in this field.

Discuss what do we have left to do?

Conclusions Schizophrenia is multifactorial (multiple genes interact with multiple environments to create multiple phenotypes). Therefore any single animal model could never hope to explain so much variability. Animals, in particular the most commonly studied, rodents, most likely also do not experience schizophrenia. Despite this we have learned much about the fundamental processes that operate in how the brain develops, what genes affect the development and function of this organ; and what interventions spatially and temporally affect the way the animal brain works. The leap of faith that we as a research community (basic and clinical) make is that this research in animal brains can translate to processes governing these events in patients.

O:10 Modeling cognitive deficits in schizophrenia using rodents

T.H.J. Burne^1,2

¹ QCMHR, The Park Centre for Mental Health, Wacol QLD 4076, Australia. ² Neurobiology Program, Institute for Cell and Molecular Therapies, Griffith University, Brisbane, QLD 4111

Background Cognitive deficits in schizophrenia are seen across seven separate domains including working memory, attention/vigilance, verbal learning and memory, visual learning and memory, speed of processing, reasoning and problem solving, and social cognition. A number of behavioural tests are used in rodents to model the symptoms of schizophrenia, including prepulse inhibition of the acoustic startle response (PPI), latent inhibition, tests of attention and associative learning, as well open field behaviour and maze learning. This presentation will provide an overview of the cognitive tests used in rodents and describe the extent to which different behavioural tests are incorporated in rodent models of schizophrenia.

Methods A literature search of research articles published between 1990–2005 incorporating rodent models of schizophrenia was performed. A pubmed search using schizophrenia and behaviour; and either mouse (178) or rat (525) was used. The studies were categorized according to the types of behavioural tests used. The behaviour tests were grouped into the following categories; motor activity, sensorimotor gating, and cognition. Tests of cognition were subdivided into working memory, attention (including latent inhibition), learning, executive function, problem solving and social interaction.

Results Most rodent models of schizophrenia used two behavioural tests; motor activity (46%) and PPI (21%). Behavioural tests of cognition were underrepresented in the literature; learning (19%), attention (13%), social interaction (7%), working memory (5%), executive function (0.4%) and problem solving (0%). There were relatively few cases of thorough behavioural phenotyping of animals.

Conclusions Behavioural paradigms modeling cognitive deficits seen in schizophrenia are underrepresented in animal models of schizophrenia. This is in part due to the challenge of modeling a complex disorder such as schizophrenia in a rodent. Although automated tests such as motor activity and PPI are amenable to pharmacological studies, a more holistic approach to modeling cognitive deficits in rodents is needed to best understand this multifactorial disease.

O:11 Prepulse Inhibition of the Startle Reflex in Patients Treated With Atypical Neuroleptics

M.T. Martin-Iverson∗^1,3, K. Reid-Milligan³, J. Lee²

¹ Centre for Clinical Research in Neuropsychiatry, ² Graylands Hospital, & ³ School of Medicine & Pharmacology, University of Western Australia

Aims/Background To determine whether there are deficits in prepulse inhibition of the startle reflex (PPI) in patients with schizophrenia treated with atypical neuroleptics and if any such deficits are influenced by attention.

Methods A methodology based on dose-response analysis was used. Instead of a range of drug doses, a range of startling stimulus intensities were used (70–115 dB as sound pressure level), and the resulting response curve of the electromyographic signal from the orbicularis oculi muscle under the right eye was fitted to a sigmoid function with nonlinear regression. The abilities of a prepulse (10 dB above 70 dB white noise auditory background) to reduce the Rmax (the response magnitude maximum derived from the fitted curve) was evaluated, Each person (30 community controls and 20 patients suffering from schizophrenia and treated with atypical neuroleptics) was tested on the same day under two attentional conditions (“Attend” or “Ignore” the prepulse and startling stimuli) with the order counterbalanced.

Results Community controls exhibited clear inhibition of Rmax after a prepulse 100 ms prior to the startling stimuli under both attention conditions. Patients exhibited PPI of Rmax in the ignore condition, but not in the attend condition.

Conclusion Patients with schizophrenia treated with atypical neuroleptics show normal or disrupted PPI depending on the attention condition.

O:12 The somatosensory system and schizophrenia

L.A. Chahl∗, P. Newson, V.J. Carr

Neuroscience Institute of Schizophrenia and Allied Disorders and School of Biomedical Sciences, University of Newcastle, NSW 2308

Background Schizophrenia is widely accepted to be a neurodevelopmental disorder. Neuronal activity is a powerful stimulus to neuronal development. The possibility that the somatosensory system might be abnormal in schizophrenia was raised by observations that subjects with schizophrenia have reduced pain sensitivity and reduced niacin skin flare responses [1, 2]. Pain and flare responses are mediated by small diameter primary afferent neurons that are sensitive to capsaicin.

Aim The aim of the project was to determine whether deficit in somatosensory input via capsaicin-sensitive primary afferent neurons causes changes in rat brain similar to those seen in the brain of subjects with schizophrenia.

Methods Wistar rats under ice anaesthesia were treated on neonatal day 2 with capsaicin 50 mg/kg s.c. or vehicle. A lethal dose of sodium pentobarbitone was given at either 5–7 weeks [3] or 11–12 weeks of age. Brains were removed, fixed in formalin and coronal sections, 50 μm, cut and Nissl stained.

Results Neonatal capsaicin treatment resulted in reduced brain weight, reduced hippocampal and cross-sectional area, reduced cortical thickness and increased neuronal density in both immature and mature rats. Thus neonatal capsaicin treatment produced morphological changes in rat brain similar to those found in schizophrenia.

Conclusions The neonatal capsaicin treated rat might be a useful animal model of schizophrenia.

Footnotes

O:13 Maternal deprivation and corticosterone administration in rats as a neurodevelopmental model of schizophrenia: effects on behaviour and dopamine receptor density

M. Van Den Buuse∗, K.H. Choy, Y. De Visser

Behavioural Neuroscience Laboratory, Mental Health Research Institute, Parkville, VIC 3052, Australia

Background and Aims The ‘two-hit’ hypothesis of schizophrenia proposes that the illness is caused by at least two disruptions during the lifespan. The first disruption occurs during an early developmental stage and increases vulnerability. The second stressful disruption occurs later in life and triggers the onset of overt symptoms. Our aim was to investigate this model in rats by combining maternal deprivation stress (24 hours, postnatal day 9) and ‘adolescent’ treatment with the stress hormone, corticosterone (8 to 10 weeks of age).

Methods Rats were tested for locomotor hyperactivity, a model of psychosis, and for prepulse inhibition (PPI), a model of sensorimotor gating, at 12 weeks of age. Dopamine D2 and D1 receptor densities were analysed with autoradiography.

Results Locomotor hyperactivity to amphetamine or phencyclidine treatment were not different between groups. In contrast, while apomorphine treatment disrupted PPI in rats after either maternal deprivation or corticosterone treatment, there was no effect in rats with the combined treatment. Dopamine D2 density tended to be increased in the nucleus accumbens of ‘two-hit’ rats, possibly representing an attempt to overcome the functional desensitisation seen in PPI. Dopamine D1 density was significantly increased in maternallydeprived rats, however this effect was less pronounced in ‘two-hit’ animals.

Conclusions These results suggest selective alterations in dopaminergic regulation of PPI by two disruptions along the neurodevelopmental axis. These behavioural results can not be explained by reduced dopamine receptor density, suggesting receptor signalling changes are responsible for the combined effect of the two ‘hits’.

O:14 Developmental Vitamin D Depletion alters adult rat behaviour and response to psychomimetic drugs: a relevant model for schizophrenia

J.P. Kesby∗, J. O'Loan, T.H. Burne, J.J. McGrath, D.W. Eyles

School of Biomedical Science, University of Queensland, QLD 4072, Australia

Aims Developmental vitamin D, (DVD), deficiency has been proposed as a risk factor for schizophrenia. The behavioural phenotype of adult rats subjected to transient low prenatal vitamin D includes noveltyinduced hyperlocomotion that appears to be sensitive to handling procedures and a sensitivity to MK-801 induced hyperlocomotion that can be prevented or ameliorated via dietary intervention or antipsychotic treatment. The aim of this presentation is to discuss the behavioural phenotype of the model and its strengths as a model for schizophrenia.

Methods Sprague-Dawley rats raised under conditions of maternal vitamin D deprivation were assessed in the open field. Rats were treated with both MK-801 and Haloperidol.

Results Handling procedures were shown to affect the subtle hyperlocomotion phenotype seen in this model.

Conclusions Combined these results suggest that decreased levels of vitamin D throughout development can alter the development of specific neurotransmitter systems involved in locomotion. The sensitivity seen to the psychomimetic compound, MK-801, is reminiscent of that seen within schizophrenia patients and the ability of the well known antipsychotic haloperidol to ameliorate this behaviour suggest dopamine is involved. To further investigate this theory studies of the response to amphetamine are currently being conducted.

O:15 Brain development disruption from PCP causes behavioural deficits in the forced swim test in later life

T.M. Du Bois∗, C. Deng, Y.Y. Tan, X-F. Huang

Neuroscience Institute for Schizophrenia and Allied Disorders (NISAD); Neurobiology Research Centre for Metabolic and Psychiatric Disorders, School of Health Sciences, University of Wollongong, Northfields Avenue Wollongong, NSW 2522 Australia

Aims/Background Interruption to brain development at an early stage can alter chemically coded neural networks and can affect behaviour in later life. Phencyclidine (PCP) disrupts brain development through its antagonism of NMDA receptors, which leads to neuronal damage and causes behavioural alterations in rodents that mimics aspects of schizophrenia psychosis. The aim of this study was to compare behaviour in rats treated with PCP before or after brain maturation.

Methods PCP (10 mg/kg) or saline was administered in three intermittent doses to 7 day old female rat pups (Group 1; n = 13) and 10 week old adult female rats (Group 2; n = 14). All rats underwent forced swim and elevated plus maze tests 10 weeks after their last PCP injection. Group 2 rats also performed these tests a week after their last PCP injection.

Results Group 1 rats displayed 31% increased climbing time and 29% decreased swimming time compared to controls in the forced swim test (p < 0.05), while immobility times did not differ. Although Group 2 rats showed similar trends in the test one week after PCP injections, statistical significance was not reached. These trends were absent in the test 10 weeks after injections. There was no effect of treatment on any scores in the elevated plus maze test in either group.

Conclusions This study has shown that early insult to the brain from NMDA receptor antagonist treatment results in behavioural deficits in later life which may be due to a hyperdopaminergic response to the stress challenge. These results support the idea that schizophrenia is a disorder of neurodevelopment, involving hyperfunction of the dopamine system.

O:16 Genetic animal models for neuregulin 1 – valuable tools for schizophrenia research?

T. Karl∗^1,2, L. Duffy^1,2, A. Boucher^1,3, J. Arnold^1,3, P. Schofield^1,2,4,5

¹ Neuroscience Institute of Schizophrenia and Allied Disorders (NISAD), Sydney NSW 2010, Australia. ² Neuroscience Research Program, Garvan Institute of Medical Research, Sydney NSW 2010, Australia. ³ Department of Pharmacology, University of Sydney, Sydney NSW 2006, Australia. ⁴ Prince of Wales Medical Research Institute, Sydney NSW 2031, Australia. ⁵ University of New South Wales, Sydney, NSW 2052, Australia

Background Neuregulin 1 (NRG1) is one of the most promising susceptibility genes for schizophrenia and is known to influence neurodevelopmental processes in the CNS potentially related to schizophrenia. The neurodevelopmental theory of schizophrenia suggests that interactions between genetic and environmental factors are responsible for biochemical alterations leading to schizophrenia.

Methods To investigate these interactions, we applied a comprehensive behavioural phenotyping strategy for the domains motor activity, exploration, and anxiety in two animal models for Nrg1 deficiency. We also examined the effect of the external factors age, housing condition, and treatment with the main psychoactive constituent of cannabis, delta-9 tetrahydrocannabinol (THC) on the performance of heterozygous transmembrane (TM) and EGF-like domain (EGF) Nrg1 knockout (ko) mice.

Results We discovered an age-dependent exploration- and locomotion-related hyperactive phenotype in TM Nrg1 mutant mice, whereas the EGF ko model was not affected by age. Environmental enrichment had a significant impact on TM Nrg1 ko mice and caused a taskdependent advanced onset of hyperactivity. Anxiety levels appear to be reduced in both, TM and EGF Nrg1 mutant mice, although anxiolysis – intensified by enriched housing – was more obvious in TM Nrg1 hypomorphic mice. THC had a significant impact on this animal model for schizophrenia as well.

Conclusions Heterozygous Nrg1 knockout mice are important to investigate the interaction between genetic and environmental factors of schizophrenia. Interactions are consistent with the pathophysiology of schizophrenia and the neurodevelopmental theory. Furthermore, our findings reinforce the importance of carefully controlling experimental designs for external factors and of using comprehensive, integrative phenotyping strategies.

References

1. Blumensohn

R. E.

. J. Nerv. Mental Dis. 2002; 190: 481–483.

2. Messamore

. Schizophrenia Res. 2003; 62: 251–258.

3. Newson

. Br. J. Pharmacol. 2005; 146: 408–418.

Symposium: Animal Models in Schizophrenia