Gisela Grecksch

Two sensitive periods for the amnesic effect of anisomycin

Impairment of retention of a brightness discrimination in rats was obtained when anisomycin (80 microgram bilaterally into both hippocampi) was injected 10 min before and 80 min after training or 240 and 360 min after training. No amnesia was observed when anisomycin was injected 45 and 165 min post training. The two separate sensitive periods for the amnesic effect of the inhibitor obviously correspond to the two phases of increased protein synthesis during the consolidation of the same learning procedure. The results support the previous findings of the two independent and qualitatively different macromolecular processes. They also argue for the inhibition of protein synthesis as an important mechanism in the amnesic effect of anisomycin.

Social behaviour in rats lesioned with ibotenic acid in the hippocampus: quantitative and qualitative analysis

Abstract  Rationale: Neonatal ibotenic acid lesion of the ventral hippocampus was proposed as a relevant animal model of schizophrenia reflecting positive as well as negative symptoms of this disease. Before and after reaching maturity, specific alterations in the animals’ social behaviour were found. Objective: In this study, social behaviour of ventral hippocampal lesioned rats was analysed. For comparison, rats lesioned either in the ventral hippocampus or the dorsal hippocampus at the age of 8 weeks were tested. Methods: Rats on day 7 of age were lesioned with ibotenic acid in the ventral hippocampus and social behaviour was tested at the age of 13 weeks. For comparison, adult 8-week-old rats were lesioned either in the ventral or the dorsal hippocampus. Their social behaviour was tested at the age of 18 weeks. Results: It was found that neonatal lesion resulted in significantly decreased time spent in social interaction and an enhanced level of aggressive behaviour. This shift is not due to anxiety because we could not find differences between control rats and lesioned rats in the elevated plus-maze. Lesion in the ventral and dorsal hippocampus, respectively, in 8-week-old rats did not affect social behaviour. Conclusions: The results of our study indicate that ibotenic acid-induced hippocampal damage per se is not related to the shift in social behaviour. We favour the hypothesis that these changes are due to lesion-induced impairments in neurodevelopmental processes at an early stage of ontogenesis.

Transient prenatal vitamin D deficiency is associated with subtle alterations in learning and memory functions in adult rats

Based on clues from epidemiology, low prenatal vitamin D has been proposed as a candidate risk factor for schizophrenia. Recent animal experiments have demonstrated that transient prenatal vitamin D deficiency is associated with persistent alterations in brain morphology and neurotrophin expression. In order to explore the utility of the vitamin D animal model of schizophrenia, we examined different types of learning and memory in adult rats exposed to transient prenatal vitamin D deficiency. Compared to control animals, the prenatally deplete animals had a significant impairment of latent inhibition, a feature often associated with schizophrenia. In addition, the deplete group was (a) significantly impaired on hole board habituation and (b) significantly better at maintaining previously learnt rules of brightness discrimination in a Y-chamber. In contrast, the prenatally deplete animals showed no impairment on the spatial learning task in the radial maze, nor on two-way active avoidance learning in the shuttle-box. The results indicate that transient prenatal vitamin D depletion in the rat is associated with subtle and discrete alterations in learning and memory. The behavioural phenotype associated with this animal model may provide insights into the neurobiological correlates of the cognitive impairments of schizophrenia.

Kindling and its consequences on learning in rats

To study the learning performance of pentylenetetrazol- and amygdala-kindled Wistar rats we used the following learning tests: short-term memory was tested in the response-to-change model, brightness discrimination was tested in a Y-chamber, and two-way active avoidance learning was tested in a shuttle-box. Short-term memory was not impaired by both kindling procedures. Considering two-way active avoidance learning the performance of pentylenetetrazol (PTZ)-kindled rats was significantly diminished. This effect persists over a period of 4 weeks. However, amygdala (AMY)-kindled rats acquired this task like the controls. In brightness discrimination reaction (BDR) the learning performance of PTZ-kindled animals was not influenced. Although the acquisition of BDR was nearly identical, the 24-h retention was remarkably diminished in AMY-kindled rats. It was hypothesized that the different kindling procedures interfere in different ways and extent with neuronal circuits resulting in different functional impairments.

Ketamine-induced changes in rat behaviour: a possible animal model of schizophrenia. Test of predictive validity

Previously, it was shown that subchronic application of the NMDA receptor antagonist ketamine (Ket) induces schizophrenia-related alterations, e.g. decreased non-aggressive behaviour in the social interaction test, which might be a useful animal model in the study of negative symptoms of this disease. In order to further evaluate the predictive validity of this model, the anxioloytic diazepam, the classic neuroleptic haloperidol and the atypical neuroleptics clozapine and risperidone were tested after acute and subchronic treatment. The experiments demonstrated that haloperidol did not normalise the behavioural effects of Ket. After acute administration, diazepam was ineffective in control animals but increased non-aggressive behaviour in Ket-treated animals. Similar effects were found in animals injected with either clozapine or risperidone. Twenty-four hours after discontinuation of subchronic treatment with both substances, there was an increase in the percentage of non-aggressive behaviour in the ketamine group and a decrease in the control animals. This decrease was explained in terms of withdrawal. Different effects in the control groups and the Ket groups were found when the test was performed 1 h after subchronic clozapine or risperidone treatment. The data suggest that atypical antipsychotic drugs (APD) effectively counteract Ket-induced alterations in social behaviour. Regarding false-positive effects by anxiolytic drugs without antipsychotic efficacy, this model may have some predictive validity for identifying anxiolytic effects of novel antipsychotic compounds.

Disruption of Latent Inhibition in Rats with Postnatal Hippocampal Lesions

Disruption of latent inhibition has been proposed as a possible model of cognitive abnormalities that underlie positive symptoms of a schizophrenia. We tested neonatal hippocampal lesioned rats in a latent inhibition paradigm. Lesions of the ventral hippocampus were induced by bilateral injections of ibotenic acid in 7 days old rats. The behavior of lesioned rats was tested postpubertally. We found a hyperresponsiveness to dopaminergic stimulation by apomorphine in locomotion tests. Latent inhibition was tested using the acquisition of a conditioned reaction in a two-way shuttle box. Sham operated control animals showed after preexposure of the to-be-conditioned stimulus (combined tone and light stimulus) a low acquisition. Ibotenic acid lesioned animals learned the conditioned reaction with and without preexposure in the same way, indicating disturbed latent inhibition. These results demonstrate disturbances in early postnatal hippocampal lesioned rats comparable with those seen in schizophrenic patients, thus further validating this procedure as a useful animal model of some aspects of schizophrenia.

Cell Proliferation is Influenced by Bulbectomy and Normalized by Imipramine Treatment in a Region-Specific Manner

Growing evidence indicates that alterations of neuroplasticity may contribute to the pathophysiology of depression. In contrast, various antidepressants increase adult hippocampal neurogenesis and block the effects of stress. These findings result in the ‘neurogenesis hypothesis of depression’. The present study seeks to determine out whether cell proliferation is altered in the hippocampus, subventricular zone (SVZ), and basolateral amygdala of adult rats exposed to bilateral olfactory bulbectomy, another established model of depression and, if so, how imipramine effects bulbectomy-induced changes of cell genesis. Bulbectomy results in a significant reduction of cell proliferation in the hippocampus and SVZ, an effect that is normalized by subchronic doses of imipramine. Moreover, an increase in cell genesis in the basolateral amygdala, which is not affected by imipramine, is demonstrated. TUNEL staining indicates an enhanced apoptosis after bulbectomy in the SVZ that cannot be reduced by imipramine. Cell death rates in the hippocampus and amygdala are not affected by bulbectomy. The opposing effects of bulbectomy and imipramine treatment in the hippocampus and amygdala demonstrate that these structures of the limbic system, both integrated in emotional processing, react quite differently with regard to neuroplasticity. Further to this, we discuss a possible link between the pathogenesis of depression and changed neuronal plasticity in the SVZ.

Convulsions induced by submaximal dose of pentylenetetrazol in mice are antagonized by the benzodiazepine antagonist Ro 15-1788

The effects of benzodiazepine antagonist Ro 15-1788, alone or with diazepam, were studied in mice on convulsions induced by pentylenetetrazol (PTZ). We found that Ro 15-1788 (1 mg/kg) was able to antagonize the anticonvulsive effects of diazepam (1 mg/kg), but also had, with submaximal doses of PTZ (65 mg/kg), its own anticonvulsive action. At very low doses (0.1 mg/kg), it even potentiated the anticonvulsive effects of diazepam (0.05 mg/kg). This dual action provides evidence for partial agonist properties of the antagonist Ro 15-1788.

Increased neurogenesis in a rat ketamine model of schizophrenia

BACKGROUND Growing evidence implicates abnormal neurodevelopment in schizophrenia, which manifests itself, for example, in reduced volume and cellular disarray of the hippocampus. This prompted us to investigate if there are indications of an altered neurodevelopment in this brain region. While neuron birth is largely completed by the end of gestation, granule neurons of the dentate gyrus are generated throughout life, thus offering an opportunity to investigate neurogenesis postnatally. METHODS We investigated whether repeated application of subanesthetic doses of the noncompetitive N-methyl-D-aspartate receptor antagonist ketamine, which has been shown to mimic model aspects of schizophrenia in animals, affects the hippocampal neurogenesis detected by bromodeoxyuridine incorporation. Cells were identified by immunocytochemistry. RESULTS Subanesthetic doses of ketamine applied subchronically enhance neurogenesis in the hippocampal subgranular zone. CONCLUSIONS In our animal model of schizophrenia, ketamine may evoke its stimulating effect on neurogenesis via a block of the N-methyl-D-aspartate receptor directly by reducing the c-Fos/c-Jun expression, resulting in a depression of the AP1 transcription factor complex and/or by a reduced nitric oxide production or an enhanced serotonergic activity. The newly formed neurons are not able to overcome the schizophrenia-related loss of parvalbumin expressing neurons and the behavioral abnormalities indicating that their functional integration is crucial.

Alterations of the dopaminergic and glutamatergic neurotransmission in adult rats with postnatal ibotenic acid hippocampal lesion

Abstract In 6-week and 8-week-old rats (pre- and postpubertally) with neonatal excitotoxic lesions of the ventral hippocampus with ibotenic acid (IBO), we have studied apomorphine-induced motor activity and glutamate and dopamine D1 and D2 binding sites in the hippocampus, striatum, nc. accumbens and frontal cortex as well as K+-stimulated (3H)-D-aspartate release from hippocampal and frontal cortical slices. Specific glutamate binding was enhanced in the frontal cortex of 8-week-old IBO-treated animals, whereas that in other brain regions remained unchanged. Both D1 and D2 binding sites were downregulated in the striatum without changes in other brain structures. In 6-week-old rats, neither the glutamate nor the dopamine binding sites were altered. The amino acid release from hippocampal and frontal cortical slices of adult IBO treated rats was significantly decreased in comparison to controls, whereas in 6-week-old rats, no significant alterations were detectable. The additionally monitored motor activity was enhanced only in adult IBO-lesioned rats after apomorphine pretreatment. The present data are in agreement with the hypothesis of hyperactive dopamine and hypoactive glutamate systems in schizophrenia and are discussed in the light of schizophrenia-like behavioral changes in rats after postnatal hippocampal IBO lesion.