Developmental changes in the mRNA expression of neuropeptides and dopamine and glutamate receptors in neonates and adult rats after ventral hippocampal lesion
Introduction
Abnormal cortical neurodevelopment has been suggested to play a major role in the pathophysiology of schizophrenia. Neonatal excitotoxic lesions of the ventral hippocampus (VH) in rats result in the post-pubertal onset of abnormal dopamine (DA)-dependent behaviors such as exacerbated hyperlocomotion in a novel environment and enhanced stereotypy after apomorphine (for review see Lipska and Weinberger, 2002), enhanced sensitivity to the N-Methyl-d-Aspartate (NMDA) antagonist MK-801 (Al-Amin et al., 2000) and deficits in working memory (Lipska et al., 2002), sensorimotor gating (Grecksch et al., 1999) and social interaction (Becker et al., 1999) similar to those seen in schizophrenia. The postpubertal behavioral abnormalities are mostly secondary to alteration of the neurodevelopment of prefrontal cortex (PFC) (Wood et al., 2003) as lesions in the PFC can abolish these abnormalities (Flores et al., 2005, Lipska et al., 1998).
Preclinical, clinical, neuroimaging and post-mortem studies have supported the role of the dopamine system in the pathophysiology of schizophrenia (see recent reviews by Meisenzahl et al., 2007, Toda and Abi-Dargham, 2007). However the exact abnormalities of this system in the different brain regions involved in schizophrenia are still not very clear. Data from animal models and postmortem neurochemical studies have also implicated the NMDA receptors and the glutamate system in the neurobiology of schizophrenia (Coyle, 2006, Kristiansen et al., 2007, Morris et al., 2005, Mouri et al., 2007, Shim et al., 2008). Several clinical studies support the use of NMDA/glycine site agonists as potential new treatments for persistent negative symptoms of schizophrenia (Javitt, 2006). Furthermore, recent data have demonstrated the postpubertal emergence of disruption of the PFC dopamine–glutamate interaction in rats with neonatal ventral hippocampus lesion (Tseng et al., 2007).
The neuropeptides in the brain have also been shown to alter the function of the dopamine and glutamate systems and to play a major role in many neuropsychiatric disorders (see review by Holsboer, 2003). In patients with schizophrenia, postmortem measures showed that nigral pro-enkephalin (ENK)-derived peptide in D2 receptor-containing neurons was significantly elevated while substance P (SP) and dynorphin (DYN) which are expressed in D1 receptor-containing neurons were unchanged (Iadarola et al., 1991). Horger and Roth (1996) proposed that neuropeptides can uniquely modulate the mesoprefrontal DA neurons and contribute to their activation following exposure to mild stress. Both typical and atypical antipsychotics have been shown to activate the dynorphinergic gamma amino butyric acid (GABA) neurons in the nucleus accumbens (NAC) (Ma et al., 2003).
This study investigates the possibility that postpubertal emergence of behavioral and cognitive abnormalities seen in the neonatal VH lesion animal model might involve alteration of the neurodevelopment of dopamine, glutamate and neuropeptides functions in the striatum and cortical regions. We studied the effects of neonatal VH lesion in rats on the mRNA expression of DA D1 and D2, NMDA (subunits NR1 and NR2A) receptors I and IIA and neuropeptides (ENK, DYN and SP) at two stages of development (prepuberty and postpuberty) and compared the results to sham controls. The brain regions studied are the caudate putamen (CPu), NAC core and shell (NAC-c and NAC-s respectively), cingulum, frontal and parietal cortices (Fig. 1B). To assure that the findings are related to changes in neurodevelopment and not secondary to VH lesion per se we evaluated the effects of VH lesion in adult rats on the same parameters. To the extent that this animal model reproduces some aspects of schizophrenia, identifying molecular substrates of the disease process can provide better understanding of the pathophysiology of schizophrenia.
Section snippets
Subjects and surgery
In the experiments with neonatal VH-lesioned rats, female Sprague–Dawley rats were brought pregnant at 14 days of gestation and housed individually in breeding cages. Litters of four to six male pups were formed. Surgery was performed as previously described by Al-Amin et al. (2004) with minor modifications. Sprague–Dawley male pups (age 7 days and weight 12–16 g) were anesthetized by hypothermia (placed on wet ice for 10–20 min) and then placed on a stereotaxic instrument (Stoelting, Wood
Verification of lesion
Coronal sections (40 µm) through the hippocampus of lesioned rats were colored with cresyl violet in order to identify the extension of the lesion. As previously demonstrated (Al-Amin et al., 2004), the damage was restricted to the VH in the majority of rats. The damage as seen by cell loss, cavitations, and gliosis was evident in all the cytoarchitectural subdivisions (CA1–CA3) of the hippocampal formation. The dorsal hippocampus was spared and the lateral ventricles were enlarged (Fig. 1).
Discussion
The main findings in our experiments showed that neonates and adult rats had similar decreases in D1 mRNA expression after 8 weeks in both sham and lesion groups. D2 mRNA expression was differentially affected by this lesion where in adults it was increased in CPu at 8 weeks post lesion but in neonates it decreased significantly at age 65 days in the lesion group (Fig. 3A). In regards to NMDA receptors, the expression of NR1 mRNA tends to decrease with age in both adults and neonates. However,
Conclusions
The study demonstrates clearly that the neurodevelopmental alterations of dopamine, NMDA and neuropeptides in the neonatal VH lesion animal model of schizophrenia occur mainly at postpuberty. This similarity with the reported postpubertal onset of abnormal behaviors in the same animal model and in schizophrenia provides further opportunities to understand the neurobiology of schizophrenia.
Role of the funding source
The sponsors had no role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Contributors
Hassen Al-Amin, Mohamed Jaber, Nayef Saadé and Samir Atweh designed the study and obtained the funding. Hassen Al-Amin and Nayef Saade did the animal surgery. Rana El-Rawas, Mohamed Jaber and Nathalie Thiriet designed and finished the ISH experiments. Hassen Al-Amin finished the statistical analysis. All authors contributed to and approved the final manuscript.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
This research was supported by grants from the Franco-Lebanese CEDRE project (2007–2008), CNRS-France (PICS: 2005–2006) and LNCSR-Lebanon. R El Rawas is a recipient of a CNRS PhD fellowship (BDI-PED, 2005–2008).
References (50)
- et al.
Delayed onset of enhanced MK-801-induced motor hyperactivity after neonatal lesions of the rat ventral hippocampus
Biol. Psychiatry.
(2001) - et al.
Effects of chronic dizocilpine on acute pain and on mRNA expression of neuropeptides and the dopamine and glutamate receptors
Brain Res.
(2003) - et al.
Neonatal ventral hippocampus lesion leads to reductions in nerve growth factor inducible-B mRNA in the prefrontal cortex and increased amphetamine response in the nucleus accumbens and dorsal striatum
Neuroscience
(2003) - et al.
A hypothermic miniaturized stereotaxic instrument for surgery in newborn rats
J. Neurosci. Meth.
(1993) - et al.
Disruption of latent inhibition in rats with postnatal hippocampal lesions
Neuropsychopharmacology
(1999) - et al.
Neurobiology of dopamine in schizophrenia
Int. Rev. Neurobiol.
(2007) - et al.
Phenotypic characterization of neuroleptic-sensitive neurons in the forebrain: contrasting targets of haloperidol and clozapine
Neuropsychopharmacology
(1998) - et al.
Enkephalin, dynorphin and substance P in postmortem substantia nigra from normals and schizophrenic patients
Life Sci.
(1991) - et al.
Dopamine receptors and brain function
Neuropharmacology
(1996) - et al.
NMDA receptors and schizophrenia
Curr. Opin. Pharmacol.
(2007)
Excitotoxic lesions of the rat medial prefrontal cortex. Effects on abnormal behaviors associated with neonatal hippocampal damage
Neuropsychopharmacology
Neonatal damage of the ventral hippocampus impairs working memory in the rat
Neuropsychopharmacology
Dynorphinergic GABA neurons are a target of both typical and atypical antipsychotic drugs in the nucleus accumbens shell, central amygdaloid nucleus and thalamic central medial nucleus
Neuroscience
PCP: from pharmacology to modelling schizophrenia
Curr. Opin. Pharmacol.
Phencyclidine animal models of schizophrenia: approaches from abnormality of glutamatergic neurotransmission and neurodevelopment
Neurochem. Int.
The vulnerability of striatal projection neurons and interneurons to excitotoxicity is differentially regulated by dopamine during development
Int. J. Dev. Neurosci.
Dopamine and the action of opiates: a reevaluation of the dopamine hypothesis of schizophrenia. With special consideration of the role of endogenous opioids in the pathogenesis of schizophrenia
Biol. Psychiatry
The role of extrastriatal dopamine D2 receptors in schizophrenia
Biol. Psychiatry
Increased tachykinin NK(1) receptor immunoreactivity in the prefrontal cortex in schizophrenia
Biol. Psychiatry
Post-pubertal disruption of medial prefrontal cortical dopamine–glutamate interactions in a developmental animal model of schizophrenia
Biol. Psychiatry
Enhancement of postsynaptic sensitivity to dopaminergic agonists induced by neonatal hippocampal lesions
Neuropsychopharmacology
Age-related changes in the contents of neuropeptides in the rat brain and pituitary
Neurobiol. Aging
Selective alterations in ionotropic glutamate receptors in the anterior cingulate cortex in schizophrenia
Neuropsychopharmacology
Exaggerated MK-801-induced motor hyperactivity in rats with the neonatal lesion of the ventral hippocampus
Behav. Pharmacol.
Effects of ventral hippocampal lesion on thermal and mechanical nociception in neonates and adult rats
Eur. J. Neurosci.
Cited by (14)
Coupling of gene expression in medial prefrontal cortex and nucleus accumbens after neonatal ventral hippocampal lesions accompanies deficits in sensorimotor gating and auditory processing in rats
2013, NeuropharmacologyCitation Excerpt :Evidence exists for abnormal function in medial prefrontal cortex (mPFC) and ventral forebrain dopamine systems after NVHLs, and for abnormalities in gene expression in frontal and temporal cortex and striatum (e.g. El-Rawas et al., 2009; Flores et al., 2005; Marquis et al., 2006, 2008; Mitchell et al., 2005; Wong et al., 2005; Yabuki et al., 2013). These findings have come from both “agnostic” large microarray analyses (Wong et al., 2005) and from more focused, hypothesis-driven studies in which genes were selected based on specific biological models of schizophrenia (El-Rawas et al., 2009; Mitchell et al., 2005). Interestingly, the largest empirical survey of gene transcription profiles using over 5000 rat and 25,000 human cDNA's identified no significant effects of NVHLs on the expression of numerous genes that have been associated with schizophrenia risk via genomic analyses in humans (Wong et al., 2005), including catechol-O-methyltransferase (COMT) and neuregulin-1 (NRG1).
Differential role of NR2A and NR2B subunits in N-methyl-D-aspartate receptor antagonist-induced aberrant cortical gamma oscillations
2012, Biological PsychiatryCitation Excerpt :Accumulating evidence indicates that both chronic and acute damage due to NMDA-R antagonists may depend on the same type of the receptor containing the NR2A subunit. NR2A receptors were implicated in delayed behavioral deficits in several chronic animal models, such as in rats reared in isolation (30) or subjected to neonatal treatment with phencyclidine (14) or ventral hippocampal lesion (31), and now the results of this study show their preferential involvement in acute aberrant gamma activation after NMDA-R blockade as well. It should be noted that pharmacologic manipulation of a very complex receptor is not without limitations because of the imperfect selectivity of the available compounds.
Intact neurobehavioral development and dramatic impairments of procedural-like memory following neonatal ventral hippocampal lesion in rats
2012, NeuroscienceCitation Excerpt :Although there are no studies to date showing a striatal dysfunction in NVHL, related or not with procedural memory deficits, there are a few studies suggesting that NVHL-induced striatal dysfunctions might rely on glutamatergic and/or cholinergic alterations. El-Rawas et al. (2009) reported increased striatal NR1 mRNA expression, considered concurrent to the hypofunction of NMDA receptors. Laplante et al. (2005) showed an increase of M1 and M2 muscarinic receptor binding in the striatum, which would compensate for sensitized striatal dopaminergic activity.
Cortical disinhibition in the neonatal ventral hippocampal lesion model of schizophrenia: New vistas on possible therapeutic approaches
2012, Pharmacology and TherapeuticsCitation Excerpt :When a younger cohort was included, the deficits were observed in adult, not juvenile NVHL rats (Al-Amin et al., 2001; Goto & O'Donnell, 2002). Also, a similar lesion performed in adult rats did not yield the same array of anomalies (El-Rawas et al., 2009). Therefore, this model seems to imply two distinct and critical developmental periods: an early one, when the lesion is made and likely affecting the establishment of synaptic architecture, and a late one during adolescence in which these circuits would normally mature.
- 1
Tel.: +961 1 350000x5650; fax: +961 1 749209.