Neonatal lesions of the rat ventral hippocampus result in hyperlocomotion and deficits in social behaviour in adulthood

Abstract

The neonatal ibotenic acid lesion of the ventral hippocampus in the rat is an animal model of several aspects of schizophrenia. This lesion produces a number of behavioural abnormalities, such as hyperlocomotion and deficits in prepulse inhibition of startle, that present themselves relatively late in development, i.e. after puberty. Some of these abnormalities, which are thought to model the positive symptoms of schizophrenia, can be normalized by chronic treatment with neuroleptics. In the present study, we examined the effects of the neonatal hippocampal lesion on social behaviour. Social withdrawal and isolation are key components of the negative symptoms of schizophrenia that have not been previously addressed in this model. Rats were lesioned on postnatal day 7 (PD7) and tested for social interaction on PD35 and PD65. They were then treated with clozapine (1.9 and 7.4 micromol/kg or 0.63 and 2.5 mg/kg) for 21 days and retested. The results show that although, as previously reported, spontaneous hyperlocomotion emerged in the lesioned rats only after puberty (PD65), social interaction deficits and behaviors that may reflect anxiety were present at both PD35 and PD65. Clozapine normalized locomotion, but did not ameliorate putative anxiety or social interaction deficits in the neonatally lesioned rats. Our results indicate that the neonatal hippocampal lesion in the rat models some aspects of both positive and negative symptoms of schizophrenia. The effects of clozapine appear inconsistent with its putative benefit for negative symptoms.

BDNF in schizophrenia, depression and corresponding animal models

“…[63][64][65][66] For example, neonatal damage of the ventral hippocampus or amygdala, [67][68][69] administration of amphetamine 70 inducing disruption (and probably blocking) of latent inhibition, or phencyclidine 71 inducing changes in the startle response provided productive animal models with construct, face, and predictive validity for schizophrenia. It has been shown 72,73 that interference with neurogenesis in the mediotemporal allocortex of rat embryos, during the earliest stages of cortical proliferation, results not only in a thickness reduction of the adult entorhinal cortex and hippocampus 55,73 but also in other morphological characteristics resembling those observed in patients with schizophrenia.…”

Excitotoxic Lesions of the Rat Medial Prefrontal Cortex Effects on Abnormal Behaviors Associated with Neonatal Hippocampal Damage

“…19 , NO . 6 behaviors that implicate dysfunction of the PFC (Chambers et al 1996;Sams-Dodd et al 1997), possibly because neonatal damage of the ventral hippocampus disrupts neuronal development of the PFC, with which the hippocampus is closely interconnected (Swanson 1981;Ferino et al 1987;Jay et al 1989;Laroche et al 1990;Jay et al 1992;Carr and Sesack 1996). Because PFC dysfunction has been shown in rodents (Adler 1961;Lynch et al 1969;Iversen 1971;Pycock et al 1980;Kolb 1984;Reibaud et al 1984;Louilot et al 1989;Jaskiw et al 1991;Vezina et al 1991;Deutch 1992;Jaskiw and Weinberger 1992;King and Finlay 1995;Taber et al 1995;Karreman and Moghaddam 1996) and in primates (Kolachana et al 1995;Roberts et al 1994) to affect subcortical dopamine activity, the effect of the VH lesion on dopamine function might be indirectly mediated by an alteration at the level of the mPFC.…”

“…19, NO. 6 Excitotoxic Lesions of the Medial Prefrontal Cortex 461 Al-Amin et al 1997, Sams-Dodd et al 1997. We speculated that neonatal deafferentation of the mPFC by the excitotoxic hippocampal lesion might alter the response of mPFC neurons to various stimuli and result in anomalous regulation of projections to subcortical sites, thus contributing to aberrant hyperdopaminergic behaviors.…”

Effect of Dopamine D3 Antagonists on PPI in DBA/2J Mice or PPI Deficit Induced by Neonatal Ventral Hippocampal Lesions in Rats

“…Indeed, NVH-lesioned rats showed behavioral deficits resembling several aspects of schizophrenia. For instance, NVH-lesioned rats showed hyperactivity, PPI deficits, disruption of social interaction, and cognitive deficits (Becker and Grecksch, 2000;Becker et al, 1999;Lipska et al, 2002Lipska et al, , 1995Sams-Dodd et al, 1997), resembling positive, negative, and cognitive symptoms of schizophrenia, respectively. The onset of the schizophrenic symptoms typically appears in early adulthood, and the NVH lesion-induced behavioral abnormality in rats also appeared only after puberty (Lipska et al, 1993(Lipska et al, , 1995.…”