Alterations in Medial Prefrontal Cortical Activity and Plasticity in Rats with Disruption of Cortical Development

doi:10.1016/j.biopsych.2006.05.046

Biological Psychiatry

Volume 60, Issue 11, 1 December 2006, Pages 1259-1267

https://doi.org/10.1016/j.biopsych.2006.05.046 Get rights and content

Background

Psychiatric disorders such as schizophrenia are believed to emerge from an interaction of several factors. Thus, a genetic predisposition can lead to developmental compromises that may leave the system more susceptible to deficits induced by subsequent environmental variables such as stress.

Methods

The impact of neurodevelopmental interruption induced by exposure of rats prenatally to a compound methylazoxymethanol acetate (MAM) that disrupts neuronal proliferation was investigated using in vivo electrophysiologic recordings from the prefrontal cortex of adult rats.

Results

Prenatal exposure to MAM resulted in alterations in the medial prefrontal cortex indicative of a compromise in information processing. Specifically, we observed a disruption in activity patterns consistent with deficits in neuronal synchronization and abnormal augmentation of synaptic plasticity that was more severely disrupted by stress exposure than in normal animals. Furthermore, these deficits could be reversed by manipulating the mesocortical dopamine system.

Conclusions

These results suggest that disruption of early cortical development causes impairments in medial prefrontal cortical function at adulthood that are more vulnerable to disruptive influences, despite the presence of only subtle structural alterations in the brain.

Section snippets

Animal

All experiments were conducted in accordance with the USPHS Guide for the Care and Use of Laboratory Animals and were approved by the University of Pittsburgh Institutional Animal Care and Use Committee.

Pregnant Fisher 344 rats were obtained at GD 14 (Hilltop; Scottdale, Pennsylvania) and housed individually in a room with a normal 12-hour light–dark cycle with food and water available ad libitum. On GD17, either MAM (22 mg/kg dissolved in 1.0 mL of saline; purchased from Midwest Research

Alterations in Local Field Potential

In vivo local field potential recordings were obtained from the mPFC of MAM- and SAL-treated animals. Slow field potential oscillations of approximately 1 Hz were observed in SAL-treated animals, similar to that reported in the cortex of normal anesthetized animals (Figure 1A;Steriade et al 1993). In contrast, slow field potential oscillations were absent in MAM-treated animals (Figure 1A). Power spectral analysis (Forward Fast Fourier Transformation using Hamming window method and +1[science]

Discussion

Prenatal MAM treatment was found to alter the activity and plasticity of mPFC neurons of adult rats along several dimensions. Thus, we have shown a virtual absence of the characteristic slow (∼1-Hz) and fast (∼40-Hz) field potential oscillations in the mPFC of MAM-treated animals. Because these oscillations are believed to be critical for information processing in this region (Engel et al 2001, Engel and Singer 2001, Kaiser and Lutzenberger 2003), this disruption of network synchrony is likely

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These results are consistent with imaging studies that reported hyperactive hippocampus in SCZ patients (Bolkan et al., 2016; Heckers and Konradi, 2015; Modinos et al., 2015; Schobel et al., 2013). Moreover, increased firing in response to VTA stimulation and abnormalities in synchrony have also been observed within the PFC of E17 MAM-exposed rats (Goto and Grace, 2006). E17 MAM-exposed rats modelling certain neuropathological, neurochemical and behavioural abnormalities reported in SCZ patients have been well established and accepted.
Gestational and perinatal disruption of neural development increases the risk of developing schizophrenia (SCZ) later in life. Embryonic day 17 (E17) methylazoxymethanol (MAM) treatment leads to histological, physiological and behavioural abnormalities in post-puberty rats that model the neuropathological and cognitive deficits reported in SCZ patients. However, the validity of E17 MAM-exposed mice to model SCZ has not been explored. Here we treated E17 C57BL/6 mouse dams with various dosages of MAM. We found that this mouse strain was more vulnerable to MAM treatment than rats and there were gender differences in behavioural abnormalities, histological changes and prefrontal cortical gene expression profiles in MAM (7.5 mg/kg)-exposed mice. Both male and female MAM-exposed mice had deficits in prepulse inhibition. Female MAM-exposed mice exhibited mildly increased spontaneous locomotion activity and social recognition deficits, while male mice were normal. Consistently, only female MAM-exposed mice exhibited reduced brain weight, decreased size of prefrontal cortex (PFC) and enlarged lateral ventricles. Transcriptome analysis of the PFC revealed that there were more differentially expressed genes in female MAM-exposed mice than those in male mice. Moreover, expression of Pvalb, Arc and genes in their association networks were downregulated in the PFC of female MAM-exposed mice. These results indicate that E17 MAM-exposure in C57BL/6 mice leads to behavioural changes that model certain deficits reported in SCZ patients. MAM-exposed female mice may be used to study gene expression changes, inhibitory neural circuit dysfunction and glutamatergic synaptic plasticity deficits with a possible relation to those in the brains of SCZ patients.
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Original articleAlterations in Medial Prefrontal Cortical Activity and Plasticity in Rats with Disruption of Cortical Development

Background

Methods

Results

Conclusions

Section snippets

Animal

Alterations in Local Field Potential

Discussion

Neurosci Biobehav Rev

Physiol Behav

Trends Cogn Sci

Biol Psychiatry

Chem Biol Interact

Neuroscience

Brain Res Brain Res Rev

Curr Opin Neurobiol

Trends Pharmacol Sci

Neuropsychopharmacology

Biol Psychiatry

Neuroscience

Biol Psychiatry

Brain Res

Prog Neurobiol

Effects of (-)-sulpiride on dopamine release in striatum of developing rats: Degree of depolarization influences responsiveness

J Neurochem

Treatment with methylazoxymethanol at different gestational days: Physical, reflex development and spontaneous activity in the offspring

Neurotoxicology

Neonatal medial prefrontal cortex lesion enhances the sensitivity of the mesoaccumbal dopamine system

Eur J Neurosci

Measuring spike coding in the rat supraoptic nucleus

J Physiol

Dopamine gates LTP induction in lateral amygdala by suppressing feedforward inhibition

Nat Neurosci

Long-term synaptic depression in the striatum: Physiological and pharmacological characterization

J Neurosci

Hippocampal heterotopia lack functional Kv4.2 potassium channels in the methylazoxymethanol model of cortical malformations and epilepsy

J Neurosci

Developmental models of brain dysfunctions induced by targeted cellular ablations with methylazoxymethanol

Physiol Rev

Neuronal migration disorders: Heterotopic neocortical neurons in CA1 provide a bridge between the hippocampus and the neocortex

Proc Natl Acad Sci U S A

Comparison of the effects of neonatal and adult medial prefrontal cortex lesions on food hoarding and spatial delayed alternation

Behav Brain Res

The regional prefrontal syndromes: A theoretical and clinical overview

J Neuropsychiatry Clin Neurosci

Dynamic predictions: Oscillations and synchrony in top-down processing

Nat Rev Neurosci

Methylazoxymethanol acetate-induced apoptosis in the external granule cell layer of the developing cerebellum of the rat is associated with strong c-Jun expression and formation of high molecular weight c-Jun complexes

J Neuropathol Exp Neurol

Disruption of neurogenesis on gestational day 17 in the rat causes behavioral changes relevant to positive and negative schizophrenia symptoms and alters amphetamine-induced dopamine release in nucleus accumbens

Neuropsychopharmacology

Enhanced amphetamine sensitivity and increased expression of dopamine D2 receptors in postpubertal rats after neonatal excitotoxic lesions of the medial prefrontal cortex

J Neurosci

Stress, synaptic plasticity, and psychopathology

Rev Neurosci

Dopamine D1/D5 receptor activation modulates a persistent sodium current in rat prefrontal cortical neurons in vitro

J Neurophysiol

Original article
Alterations in Medial Prefrontal Cortical Activity and Plasticity in Rats with Disruption of Cortical Development