Lesion Models

While the topic of much debate, there is some evidence that schizophrenia may have a neurodegenerative or neurodevelopmental basis.48 For example, increases in the size of the ventricles, decrease in cortical and hippocampal volume, and selective decrease in subpopulations of GABAergic interneurons all suggest that neuronal loss may play a role in this disorder. Based on the lack of gross neurodevelopmental abnormalities that would occur from disruption of early stage neurogenesis, it has been proposed that the primary pathological changes that underlie schizophrenia may occur during the pre- or perinatal period. Based on this, a number of rodent models have been developed in which a lesion is produced during the pre-, peri-, or postnatal period. These include modeling of perinatal hypoxia and anoxia to mimic obstetric complications, and the aspiration, electrolytic, or excitotoxic lesioning of the prefrontal cortex or hippocampus. Hippocampal lesions in particular have been the focus of attention due to hippocampal projections to the nucleus accumbens and the ability of these projections to modulate the impact of prefrontal cortical inputs.

Interestingly, several neonatal lesion models exhibit a delayed onset of symptoms. The development of symptoms by the lesioned rodents in adolescence has been suggested to mirror the clinical presentation of symptoms in schizophrenic humans. For example, rats given a postnatal excitotoxic lesion of the ventral hippocampus are indistinguishable from nonlesioned littermates of postnatal day 35. However, by postnatal day 56, the animals begin to exhibit an increased sensitivity to amphetamine, a reduced sensitivity to haloperidol 26, disrupted latent inhibition, and deficits in PPI that respond to atypical antipsychotics.49 While these models appear to have some face validity, and the response to atypical antipsychotics suggests potential predictive validity, the extent and nature of the lesions are unlike anything observed in schizophrenic brains. Therefore, these models have questionable construct validity.

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