Междисциплинарный семинар Руководитель семинара — К.В. Анохин





Март 23, 2011

Jan M. van Ree

Rudolf Magnus Institute of Neuroscience,
Department of Pharmacology and Anatomy,
University Medical Center Utrecht,
Universiteitsweg 100, 3584 CG Utrecht.

Schizophrenia is a psychiatric disorder affecting different aspects of perception, behaviour and cognition.The symptoms of schizophrenia can be classified into general categories of positive, negative and cognitive symptoms. There is evidence for a genetic component in the etiology of schizophrenia. For instance, a higher genetic liability was found in siblings and children of schizophrenic probands, and a higher concordance for monozygotic twins was found as compared to dizygotic twins.
Modeling a human psychiatric disorder like schizophrenia in animals meets difficulties since the psychopathology of schizophrenia is still unknown. Moreover, behavioural symptoms involving human communication and language are difficult to simulate in animals and therapeutical strategies of schizophrenia are hardly available. Nonetheless, the need for fundamental research has provided animal models for schizophrenia. In general, these models can be divided in three categories, i.e. models that investigate behaviours in animals that are disturbed in schizophrenic patients (e.g. prepulse inhibition of the acoustic startle response and latent inhibition), pharmacological models, and experimentally induced brain pathology e.g. brain lesion models.
One of the pharmacological models to study mechanisms possibly involved in some of the symptoms of schizophrenia is to study the effects of psychostimulant drugs in animals. Psychomimetic drugs most frequently used for this purpose are LSD, amphetamine and phencyclidine (PCP). The psychotic effects of these drugs in healthy humans can be compared to the positive symptoms in schizophrenia, and PCP also induces negative symptoms. In rats, amphetamine and PCP induce hyperactivity, stereotypy and inactivity (amphetamine) or ataxia (PCP) and impaired social behaviour (PCP). Comparison to clinical studies suggested that hyperactivity and stereotyped behaviour following amphetamine and PCP were produced by an hyperdopaminergic state and accordingly, in theory, this state closely aligned certain aspect of the positive symptoms, whereas PCP-induced social impairments correspond to aspects of negative symptoms.
Animal models for schizophrenia using the concept of brain lesions can be divided in lesions made in adulthood or early in life. Non-human primates, hippocamptomized in adulthood, exhibited attentional deficits, recognition memory deficits, hyperactivity and stereotyped behaviour. They were proposed to provide an adequate model for several symptoms seen in schizophrenia. Additionally, a model of cognitive dysfunction in schizophrenia was reported with prefrontal cortex lesions in adult non-human primates and rats. Finally, rats with 6-OHDA lesions within the nucleus accumbens exhibited impaired prepulse inhibition and were suggested to represent an animal model for schizophrenia as well.
In 1987, a neurodevelopmental model of schizophrenia was described [3]. It was hypothesized that early damage, instead of an ongoing neuropathological process, underlies the schizophrenic disorder. The proposed early damage was derived from postmortem findings of cytoarchitectural abnormalities in brain structures of schizophrenic patients, without signs of reactive gliosis, dying neurons, inclusion bodies or inflammation. The authors of these postmortem studies interpreted these abnormalities as presumably genetic ‘lesions'. The delayed onset of schizophrenia in early adulthood was suggested to be due to an interaction between a static developmental deficit and the normal program of central nervous system maturation that takes place in early adulthood. Hence, the neurodevelopmental theory implicates the primary event to take place in utero or around birth, while typical symptoms arise two decades later, perhaps only after functional maturation or completion of other, associated, systems or processes (e.g. myelination or synaptic pruning). Structures suggested to be target of neurodevelopmental deficits early in life, based on the cytoarchitectural deficits or functional features, are temporal lobe structures, the limbic system, and the prefrontal, temporal, cingulate, or entorhinal cortex. Animal models for the neurodevelopmental hypothesis of schizophrenia are based on brain damage induced early in life [e.g. 1,2].
Recently, we described a neurodevelopmental animal model for schizophrenia based on brain damage induced during a critical period early in life [4,5]. In this model the effect of an early neonatal (PD 7) amygdala lesion was compared to the effects of a lesion later in life (PD 21). The early loss of amygdala input in projection areas may interfere with the normal development of these structures. If the amygdala input is removed later in life, the development of the projection areas is in a further stage and may, thus, have not such severe effects. The early amygdala lesions were made by bilateral injection of ibotenic acid, which produces selective lesions of the neurons without destruction of the passing fibers. Animals lesioned in the basolateral amygdala on PD7 displayed behavioural changes on a number of behavioural paradigms investigated. In summary, locomotor stereotypy, diminished habituation, decreased social behaviour, decreased prepulse inhibition of the acoustic startle response, and altered behavioural response to stressful stimuli and to pharmacological challenges (phencyclidine and apomorphine) were observed. In contrast, animals lesioned on PD21 did not show any of the significant changes as seen after lesioning the amygdala on PD 7, except for a disruption of social behaviours. According to the model of neurodevelopmental disorders, the deficits observed in animals lesioned on PD7 are mediated by (dysfunctional) structures connected to the damaged area. Indeed, the cerebral glucose utilization, a measure of cerebral functional activity, in animals that received amygdala damage on PD7 was decreased in the amygdala itself and in other brain regions, i.e. the cingulate cortex, olfactory tubercle, anterior caudatus putamen, diagonal band of Broca, lateral septum, rostral hippocampus and thalamus.
To gain insight into the connecting brain structures from and to the basolateral amygdala early in life, retrogade and anterograde tracers were injected into the basolateral amygdala. The innervation from the basolateral amygdala to the nucleus accumbens and the mediodorsal thalamic nucleus appeared to be already mature at PD7, while the innervation to the prefrontal cortex became mature after PD11. The innervation to the basolateral amygdala from the substantion innominata and thalamic regions were already at the mature level, while the innervation from the prefrontal cortex became mature after PD9-11. Thus, lesions of the basolateral amygdala on PD7 may interfere with the normal development of the prefrontal cortex, which in turn may be the neuroanatomical basis of the observed behavioural deficits.
Besides the neurodevelopmental hypothesis of schizophrenia, the dopamine hypothesis takes a prominent place. The dopamine hypothesis states that hyperactivity of specific dopamine systems is related to psychotic symptoms seen in schizophrenia. We, therefore, were interested in the brain dopamine systems in our putative neurodevelopmental animal model for schizophrenia. Using in vitro dopamine receptor autoradiography it was found that both the dopamine D-1 and the D2-like receptors in the brain were reduced following a lesion of the basolateral amygdala on PD 7, but not following a similar lesion on PD 21. The D2-like receptors were mostly effected. Additional experiments showed that the D3-receptor was not changed after an amygdala lesion on D7, suggesting that especially the D2-receptor is disturbed. Interestingly, the decreases in D1- and D2-like receptors were present in target areas of the mesolimbic (nucleus accumbens, olfactory tubercle), but not in the nigrostriatal (caudate putamen) dopamine system. These data seem to be in accordance with the observed increased dopamine turnover in the nucleus accumbens but not in the caudate putamen. In addition, noradrenergic neurotransmission was reduced in both the mesolimbic and nigrostriatal projections. Following the neonatal lesions. In contrast to the dopamine receptors, cannabinoid receptor binding was increased in the caudate putamen, but not in the nucleus accumbens and olfactory tubercle, and neurotensin binding was slightly changed in the hippocampal complex and in dopaminergic cell regions.
The results may serve to link the neurodevelopmental and dopamine hypotheses of schizophrenia and contribute to the validation of a neonatal amygdala lesion as a model for schizophrenia.

1. Bachevalier, J. (1994) Medial temporal lobe structures and autism, a review of clinical and experimental findings. Neuropsychologia 32, 627-648.
2. R.Joober et al. Genetic of schizophrenia: from animal models to clinical studies. J.Psychiatry Neurosci. 2003; 27 (5): 336-47. download pdf
3. Lipska, B.K., Jaskiw, G.E., Weinberger, D.R., 1993, Postpuberal emergence of hyperresponsiveness to stress and to amphetamine after neonatal hippocampal damage, a potential animal model for schizophrenia. Neuropsychopharmacol. 122, 35-43.
4. Weinberger, R.R. (1987) Implications of normal brain development for the pathogenesis of schizophrenia. Arch. Gen. Psychiatry 44: 660-669.
5. Wolterink G., Daenen, E.W.P.M., Dubbeldam, S., Gerrits, M.A.F.M., Van Rijn, R., Kruse, C.G., Van der Heijden, J., Van Ree, J.M. (2001) Early amygdala damage in the rat as model for neurodevelopmental psychopathological. Eur. Neuropsychopharmacol. 11, 51-59.
6. Daenen E.W.P.M., Wolterink G., Gerrits M.A.F.M., Van Ree J.M. (2002) Amygdala or ventral hippocampal lesions at two early stages of life differentially affect open filed behaviour later in life: an animal model of neurodevelopmental psychopathological disorders. Behavioral Brain Research 131: 67-78

<<На главную