Prenatal Disruption of Neocortical Development Alters Prefrontal Cortical Neuron Responses to Dopamine in Adult Rats

Abstract

A growing body of evidence suggests that structural changes in the cortex may disrupt dopaminergic transmission in circuits involving the prefrontal cortex (PFC) and may contribute to the etiology of schizophrenia. In this study, we utilize a rodent model of neonatal disruption of cortical development using prenatal administration of the mitotoxin methylazoxymethanol acetate (MAM). Using intracellular recordings in vivo, we compare the physiology of prefrontal cortical neurons and their responses to topical administration of dopamine (DA) in intact animals and adult rats treated prenatally with MAM. Topical administration of DA hyperpolarized the membrane potential (MP) and decreased the firing rate of neurons recorded in deep layers of the PFC in intact animals. Furthermore, electrical stimulation of the VTA evoked fast onset epsps or long-lasting depolarizations in PFC neurons. In comparison, PFC neurons recorded in MAM-treated animals had significantly faster baseline firing rates. Moreover, topical administration of DA did not affect the MP or firing rate of the neurons in MAM-treated animals. However, MAM-treated animals exhibited an increase in the percentage of neurons responding with long-lasting depolarizations to stimulation of the VTA. The results of this study indicate that PFC neurons in the MAM-treated rats are not responsive to DA administered superficially, while at the same time exhibit greater responsiveness to VTA stimulation. These results are consistent with a rewiring of the corticolimbic system in response to neurodevelopmental insults.

Gestational Methylazoxymethanol Acetate Treatment Impairs Select Cognitive Functions: Parallels to Schizophrenia

“…Lesions of the prefrontal cortex have been shown to selectively increase perseveration to a previously learned dimension in non-human primates (Dias et al, 1996) and humans (Elliott et al, 1995;Owen et al, 1993). Given the likelihood that MAM disrupts prefrontal cortex function (Flagstad et al, 2004;Lavin et al, 2005) it would be expected that MAM-treated animals would likewise show increases in perseveration, and that this might serve as the basis for the deficit observed in the present study. In addition to an impairment in EDS learning, MAM-treated animals were impaired when required to make a simple reversal of a previously acquired discrimination (for two out of three reversals).…”

“…MAM treatment could have impaired performance on the set-shifting task by altering functioning in one or all of these brain areas. The prefrontal cortex would seem a likely candidate since several previous reports have shown that MAM treatment at gestation day 17 disrupts prefrontal morphology and function (Flagstad et al, 2005;Lavin et al, 2005;Moore et al, 2006). It is unclear as to whether difficulties in shifting attentional set are due to a failure to ignore a previously reinforced dimension or to attend to a previously irrelevant dimension.…”

“…Neonatal methylazoxymethanol acetate (MAM) treatment induces brain abnormalities that may be similar to the types of changes seen in schizophrenia, including abnormalities in hippocampal (Chen and Hillman, 1986;Ferguson and Holson, 1997;Flagstad et al, 2004;Gourevitch et al, 2004;Shimizu et al, 1991;Virgili et al, 1997) and cortical (Lavin et al, 2005;Talamini et al, 1999) function and morphology. These changes are accompanied by changes in mesolimbic dopamine function, as indicated by an increased sensitivity to the behavioral and neurochemical effects of amphetamine (Ferguson and Holson, 1997;Flagstad et al, 2004).…”

Contribution of nonprimate animal models in understanding the etiology of schizophrenia

“…For example, although it has been shown that MAM-exposed offspring display dopaminergic dysregulation and cortical impairments consistent with the neurodevelopmental hypothesis of schizophrenia, the administration of an antimitotic compound could also disrupt functioning in many other organs. 217 Despite these shortcomings, such models complement the literature on schizophrenia in humans by providing a more direct assessment of the effects of abnormal neuronal development and cell migration on the development of schizophrenia in a manner that could not be carried out with human participants.…”

Cellular and Circuit Models of Increased Resting State Network Gamma Activity in Schizophrenia

“…As an alternative to genetic approaches, schizophrenia has also been modeled developmentally by administration of a mitotoxin methylazoxymethanol (MAM) on gestational day 17 (GD17) to rats. This model is thought to recapitulate a disruption of developmental process and leads to schizophrenia-like phenotypes in rodent offspring, which include altered neuronal processing (Lavin et al, 2005;Goto and Grace, 2006;Lodge and Grace, 2007). The MAM gestational model of schizophrenia also shows an increase in baseline gamma activity in the prefrontal cortex in awake animals (Kocsis et al, 2013).…”