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Gating of information flow within the limbic system and the pathophysiology of schizophrenia

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Abstract

Although first thought of as a dopaminergic disorder, there is little direct evidence to support a primary pathology in the dopamine system as the etiological factor in schizophrenia. In contrast, evidence is amassing in support of a cortical disturbance in this disorder; one consequence of which is a disruption in the cortical regulation of subcortical dopamine systems. Our studies show that the hippocampus plays a major role in this interaction, in that, along with the dopamine system, it provides a gating influence over information flow from the prefrontal cortex at the level of the nucleus accumbens. Moreover, chemically-induced disruption of the development of the hippocampus and entorhinal cortex were found to lead to pathophysiological changes in these interactions in the limbic system of adult rats. Therefore, schizophrenia is proposed to be a developmentally-related disorder, in which disruption of the hippocampal influence over the limbic system during ontogeny results in a pathological alteration of corticoaccumbens interactions in the adult organism.

Section snippets

Introduction — the dopamine hypothesis of schizophrenia

For years, investigators have examined the human brain in a search for the etiology of schizophrenia using pharmacological and anatomical approaches. Nonetheless, only recently have these studies begun to yield information of relevance to advancing our understanding of this complex disorder. One of the initial models of schizophrenia that has been fruitful in this quest relates to the involvement of the neurotransmitter dopamine (DA). This model, which has become known as the DA hypothesis of

Evidence for cortical involvement in the pathophysiology of schizophrenia

Several studies have suggested that, instead of being a neurochemical disturbance within the DA system, schizophrenia may instead represent a dysfunction in cortical systems using the neurotransmitter glutamate. This was founded on initial studies suggesting that the schizophrenia patient exhibited a tonic decrease in activity within the prefrontal cortex 9, 20, 39, 72, 73, particularly in those patients with prominent deficit syndrome [116]. This condition was termed hypofrontality. However,

Relevance of the nucleus accumbens to schizophrenia

Among the limbic structures that have been investigated, the nucleus accumbens continues to attract the interest of researchers studying the neurobiological bases of schizophrenia for several reasons. With respect to neuroanatomy, the nucleus accumbens receives glutamatergic afferent input from each of the cortical regions that have been associated with schizophrenia, including the paleocortex (amygdala), archicortex (hippocampus) and neocortex (PFC) 7, 25, 40, 77, 84, 108, in addition to a

The cellular basis for hippocampal-PFC-DA interactions

As a way of integrating the above observations, current models into the pathophysiology of schizophrenia suggest that this disorder is not due to a primary pathology within the dopaminergic system. Instead, an emerging concept is that the DA system may be relatively normal, but is subjected to a dysregulation as a consequence of the abnormal control by cortical glutamatergic afferents, e.g., 21, 46. We have examined the mechanisms that may contribute to this type of pathological cortical

Potential role for DA in modulating synaptic interactions in the nucleus accumbens — the tonic/phasic model of DA system regulation

As reviewed above, evidence indicates that there are sufficient levels of DA in the extracellular fluid to produce a tonic inhibition of PFC afferent input to accumbens neurons [86]as well as to facilitate D1 modulation of dye coupling in the core of the accumbens [85]. In contrast, stimulation of D1 receptors in the accumbens appears to require higher levels of DA agonists 85, 89, 102. Indeed, this type of information formed the bases for the development of a hypothesis of schizophrenia based

Synaptic plasticity and the impact of neonatal hippocampal lesions on limbic system function in the adult

The evidence reviewed thus far indicates that lesions of the ventral hippocampus in neonatal but not adult rats leads to changes in DA regulation of limbic system-mediated behaviors in adult animals. However, the nature of this alteration has not been investigated at the cellular level. Therefore, we used another type of developmental disruption to mimic the pathophysiology of schizophrenia. As described above, studies by Lipska and Weinberger 75, 124demonstrated the importance of developmental

Acknowledgements

I would like to thank Dr. Holly Moore and Dr. Tony West for preparing figures for this manuscript, and for their helpful suggestions. This work was supported by USPHS MH01055, MH57440, and MH45156. Dr. Grace is a Wodecroft Fellow/NARSAD Distinguished Investigator.

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