Neonatal Ventral Hippocampal Lesion Research Articles

Neonatal exposure to phenobarbital potentiates schizophrenia-like behavioral outcomes in the rat

Previous work has indicated an association between seizures early in life and increased risk of psychiatric disorders, including schizophrenia. However, because early-life seizures are commonly treated with antiepileptic drugs (AEDs) such as phenobarbital, the possibility that drug treatment may affect later-life psychiatric outcomes needs to be evaluated. We therefore tested the hypothesis that phenobarbital exposure in the neonatal rat increases the risk of schizophrenia-like behavioral abnormalities in adulthood. Thus, in this study, we examined the effects of a single acute neonatal exposure to phenobarbital on adult behavioral outcomes in the rat neonatal ventral hippocampal (nVH) lesion model of schizophrenia. We compared these outcomes to those in rats a) without nVH lesions and b) with nVH lesions, without phenobarbital. The tasks used for behavioral evaluation were: amphetamine-induced locomotion, prepulse inhibition, elevated plus-maze, and novel object recognition task. We found that neonatal phenobarbital treatment (in the absence of nVH lesions) was sufficient to disrupt sensorimotor gating (as tested by prepulse inhibition) in adulthood to an extent equivalent to nVH lesions. Additionally, neonatal phenobarbital exposure enhanced the locomotor response to amphetamine in adult animals with and without nVH lesions. Our findings suggest that neonatal exposure to phenobarbital can predispose to schizophrenia-like behavioral abnormalities. Our findings underscore the importance of examining AED exposure early in life as a potential risk factor for later-life neuropsychiatric abnormalities in clinical populations.

Intact neurobehavioral development and dramatic impairments of procedural-like memory following neonatal ventral hippocampal lesion in rats

Neonatal ventral hippocampal lesions (NVHL) in rats are considered a potent developmental model of schizophrenia. After NVHL, rats appear normal during their preadolescent time, whereas in early adulthood, they develop behavioral deficits paralleling symptomatic aspects of schizophrenia, including hyperactivity, hypersensitivity to amphetamine (AMPH), prepulse and latent inhibition deficits, reduced social interactions, and spatial working and reference memory alterations. Surprisingly, the question of the consequences of NVHL on postnatal neurobehavioral development has not been addressed. This is of particular importance, as a defective neurobehavioral development could contribute to impairments seen in adult rats. Therefore, at several time points of the early postsurgical life of NVHL rats, we assessed behaviors accounting for neurobehavioral development, including negative geotaxis and grip strength (PD11), locomotor coordination (PD21), and open-field (PD25). At adulthood, the rats were tested for anxiety levels, locomotor activity, as well as spatial reference memory performance. Using a novel task, we also investigated the consequences of the lesions on procedural-like memory, which had never been tested following NVHL. Our results point to preserved neurobehavioral development. They also confirm the already documented locomotor hyperactivity, spatial reference memory impairment, and hyperresponsiveness to AMPH. Finally, our rseults show for the first time that NVHL disabled the development of behavioral routines, suggesting dramatic procedural memory deficits. The presence of procedural memory deficits in adult rats subjected to NHVL suggests that the lesions lead to a wider range of cognitive deficits than previously shown. Interestingly, procedural or implicit memory impairments have also been reported in schizophrenic patients.

Clozapine administration reverses behavioral, neuronal, and nitric oxide disturbances in the neonatal ventral hippocampus rat

Clozapine is widely used in the treatment of schizophrenia; however its complete mechanism of action is not fully established. The neonatal ventral hippocampal lesion (nVHL) has emerged as a model of schizophrenia-related behavior. Our group has previously shown hyperresponsiveness to novel environment, neuronal atrophy in prefrontal cortex (PFC) and nucleus accumbens (NAcc) neurons as well as abnormal levels of nitric oxide (NO) in the PFC of the nVHL rat. In the present study, we aimed to investigate the role of repeated clozapine administration (2 mg/kg/day for 21 days) in a novel environment, neuronal rearrangement in PFC, NAcc and basolateral amygdala (BLA) as well as NO levels in this model. Clozapine administration reversed the hyperlocomotion observed in a novel environment in the nVHL rat with no effect on locomotion in sham animals. Quantitative morphological analysis demonstrated a retracted neuronal arborization and decreased spinogenesis in the NAcc, PFC and BLA in nVHL rat. Interestingly, clozapine administration also rescued neuronal atrophy in these brain regions. The nVHL also displayed increased NO levels in PFC, striatum and occipital cortex. Clozapine administration selectively reversed these abnormal levels of NO in striatum in nVHL rat while NO levels were increased in the PFC of sham animals. Our results further extend the usefulness of the nVHL as a model of schizophrenia-related behavior and suggest that clozapine reverses behavioral deficits in these animals by modulating neuronal reorganization and NO levels in the brain.

Spontaneous object recognition and its relevance to schizophrenia: a review of findings from pharmacological, genetic, lesion and developmental rodent models

Spontaneous (novel) object recognition (SOR) is one of the most widely used rodent behavioural tests. The opportunity for rapid data collection has made SOR a popular choice in studies that explore cognitive impairment in rodent models of schizophrenia, and that test the efficacy of drugs intended to reverse these deficits. We provide an overview of the many recent studies that have used SOR to explore the mnemonic effects of manipulation of the key transmitter systems relevant to schizophrenia-the dopamine, glutamate, GABA, acetylcholine, serotonin and cannabinoid systems-alone or in combination. We also review the use of SOR in studying memory in genetically modified mouse models of schizophrenia, as well as in neurodevelopmental and lesion models. We end by discussing the construct and predictive validity, and translational relevance, of SOR with respect to cognitive impairment in schizophrenia. Perturbation of the dopamine or glutamate systems can generate robust and reliable impairment in SOR. Impaired performance is also seen following antagonism of the muscarinic acetylcholine system, or exposure to cannabinoid agonists. Cognitive enhancement has been reported using alpha7-nicotinic acetylcholine receptor agonists and 5-HT(6) antagonists. Among non-pharmacological models, neonatal ventral hippocampal lesions and maternal immune activation can impair SOR, while mixed results have been obtained with mice carrying mutations in schizophrenia risk-associated genes, including neuregulin and COMT. While SOR is not without its limitations, the task represents a useful method for studying manipulations with relevance to cognitive impairment in schizophrenia, as well as the interactions between them.

Chronic administration of the neurotrophic agent cerebrolysin ameliorates the behavioral and morphological changes induced by neonatal ventral hippocampus lesion in a rat model of schizophrenia.

Neonatal ventral hippocampal lesion (nVHL) in rats has been widely used as a neurodevelopmental model to mimic schizophrenia-like behaviors. Recently, we reported that nVHLs result in dendritic retraction and spine loss in prefrontal cortex (PFC) pyramidal neurons and medium spiny neurons of the nucleus accumbens (NAcc). Cerebrolysin (Cbl), a neurotrophic peptide mixture, has been reported to ameliorate the synaptic and dendritic pathology in models of aging and neurodevelopmental disorder such as Rett syndrome. This study sought to determine whether Cbl was capable of reducing behavioral and neuronal alterations in nVHL rats. The behavioral analysis included locomotor activity induced by novel environment and amphetamine, social interaction, and sensoriomotor gating. The morphological evaluation included dendritic analysis by using the Golgi-Cox procedure and stereology to quantify the total cell number in PFC and NAcc. Behavioral data show a reduction in the hyperresponsiveness to novel environment- and amphetamine-induced locomotion, with an increase in the total time spent in social interactions and in prepulse inhibition in Cbl-treated nVHL rats. In addition, neuropathological analysis of the limbic regions also showed amelioration of dendritic retraction and spine loss in Cbl-treated nVHL rats. Cbl treatment also ameliorated dendritic pathology and neuronal loss in the PFC and NAcc in nVHL rats. This study demonstrates that Cbl promotes behavioral improvements and recovery of dendritic neuronal damage in postpubertal nVHL rats and suggests that Cbl may have neurotrophic effects in this neurodevelopmental model of schizophrenia. These findings support the possibility that Cbl has beneficial effects in the management of schizophrenia symptoms.

Impaired Reality Testing in an Animal Model of Schizophrenia

Schizophrenia is a chronic and devastating brain disorder characterized by hallucinations and delusions, symptoms reflecting impaired reality testing. Although animal models have captured negative symptoms and cognitive deficits associated with schizophrenia, none have addressed these defining, positive symptoms. Here we tested the performance of adults given neonatal ventral hippocampal lesions (NVHL), a neurodevelopmental model of schizophrenia, in two taste aversion procedures. Normal and NVHL rats formed aversions to a palatable food when the food was directly paired with nausea, but only NVHL rats formed a food aversion when the cue predicting that food was paired with nausea. The failure of NVHL rats to discriminate fully real from imagined food parallels the failure of people with schizophrenia to differentiate internal thoughts and beliefs from reality. These results further validate the NVHL model of schizophrenia and provide a means to assess impaired reality testing in variety of animal models.

Differential Effect of the DopamineD3Agonist (±)-7-Hydroxy-2-(N,N-di-n-propylamino) Tetralin (7-OH-DPAT) on Motor Activity between Adult Wistar and Sprague-Dawley Rats after a Neonatal Ventral Hippocampus Lesion

The neonatal ventral hippocampal lesion (nVHL) has been widely used as an animal model for schizophrenia. Rats with an nVHL show several delayed behavioral alterations that mimic some symptoms of schizophrenia. Sprague-Dawley (SD) rats with an nVHL have a decrease in D3 receptors in limbic areas, but the expression of D3 receptors in Wistar (W) rats with an nVHL is unknown. The 7-Hydroxy-2-(N,N-di-n-propylamino) tetralin (7-OH-DPAT) has been reported as a D3-preferring agonist. Thus, we investigated the effect of (±)-7-OH-DPAT (0.25 mg/kg) on the motor activity in male adult W and SD rats after an nVHL. The 7-OH-DPAT caused a decrease in locomotion of W rats with an nVHL, but it did not change the locomotion of SD rats with this lesion. Our results suggest that the differential effect of 7-OH-DPAT between W and SD rats with an nVHL could be caused by a different expression of the D3 receptors. These results may have implications for modeling interactions of genetic and environmental factors involved in schizophrenia.

The HDAC Inhibitor Phenylbutyrate Reverses Effects of Neonatal Ventral Hippocampal Lesion in Rats.

Recent evidence suggests that epigenetic mechanisms play a role in psychiatric diseases. In this study, we considered rats with neonatal ventral hippocampal lesions (NVHL) that are currently used for modeling neurodevelopmental aspects of schizophrenia. Contribution of epigenetic regulation to the effects of the lesion was investigated, using a histone deacetylase (HDAC) inhibitor. Lesioned or sham-operated rats were treated with the general HDAC inhibitor phenylbutyrate, which was injected daily from the day after surgery until adulthood. Changes in the volume of the lesion were monitored by magnetic resonance imaging (MRI). Anxiety was analyzed in the Plus Maze Test. Hypersensitivity of the dopaminergic system was evaluated by measuring the locomotor response to apomorphine. An associative conditioning test rewarded with food was used to evaluate learning abilities. The volume of the lesions expanded long after surgery, independently of the treatment, as assessed by MRI. Removal of the ventral hippocampus reduced anxiety, and this remained unchanged when animals were treated with phenylbutyrate. In contrast, NVHL rats’ hypersensitivity to apomorphine and deterioration of the associative learning were reduced by the treatment. Global HDAC activity, which was increased in the prefrontal cortex of lesioned non-treated rats, was found to be reversed by HDAC inhibition. The study provides evidence that chromatin remodeling may be useful for limiting behavioral consequences due to lesioning of the ventral hippocampus at an early age. This represents a novel approach for treating disorders resulting from insults occurring during brain development.

Alcohol seeking and consumption in the NVHL neurodevelopmental rat model of schizophrenia

Alcohol abuse in schizophrenia exceeds rates in the general population and worsens illness outcomes. Neonatal ventral hippocampal lesion (NVHL) rats model multiple schizophrenia dimensions including addiction vulnerability. This study compared NVHL vs. SHAM-controls in operant alcohol seeking and consumption. NVHLs enhanced consumption of combined ethanol/sucrose solution but neither ethanol or sucrose only solutions, consistent with increased vulnerability specific to carbohydrate-laden alcohol beverages typically consumed in early stages of human alcoholism.

More is less: a disinhibited prefrontal cortex impairs cognitive flexibility.

The prefrontal cortex (PFC) is critical for decision making, and it becomes dysfunctional in many neuropsychiatric disorders. Studies in schizophrenia patients and relevant animal models suggest loss of PFC inhibitory interneuron function. For instance, rats with a neonatal ventral hippocampal lesion (NVHL) show a deficient modulation of PFC interneurons by dopamine (DA). Whether the PFC becomes disinhibited in this model and alters decision making remains to be determined. Here, we recorded neural activity in the medial PFC of NVHL rats during a reward-discounting choice task that activated DA systems. Rats were trained to sample odors that instructed them to select one of two feeders that delivered unequal amounts of liquid. Putative pyramidal neurons in the PFC were hyperactive whereas task-related field potential oscillations were significantly reduced in NVHL rats, consistent with impaired interneuron activation by DA during odor sampling leading to disorganized processing. Cognitive flexibility was tested by examining response bias and errors after reversing reward outcomes. NVHL rats demonstrated impaired flexibility as they were less able to track changes in reward outcome and made more response errors than controls did. Reducing cortical excitability with the metabotropic glutamate receptor 2/3 agonist LY379268 (1 mg/kg, i.p.) improved behavioral flexibility in NVHL rats but not controls. Furthermore, D2 dopamine receptors were involved, as the antagonist eticlopride (0.02 mg/kg, i.p.) reduced the ability to switch only in control animals. We conclude that NVHL rats present PFC disinhibition, which affects neural information processing and the selection of appropriate behavioral responses.

Nitric oxide in neonatal ventral hippocampus lesion rats

Dear Dr. Flores: In a recent Letter to the Editor published in this journal, Bernstein and coworkers performed a valuable integration of results obtained in his laboratory (Bernstein et al., 1999), our laboratory (Negrete-Diaz et al., 2010) and others about the role of nitric oxide (NO) in the pathophysiology of schizophrenia, and summarized them in a very comprehensive review (Bernstein et al., 2005). Using the same animal model of schizophrenia, adult rats with a neonatal ventral hippocampus (nVH) lesion, Bernstein and coworkers and our group found an alteration of the nitrergic system (an increase in the number of cortical neurons expressing neuronal nitric oxide synthase (nNOS) and NADPH diaphorase and increased production of NO respectively, in the prefrontal cortex of adult animals with nVH-lesions). Therefore, both works are complementary to each other and reinforce our view of the role of the nitrergic system in the pathophysiology of schizophrenia. The results are also consistent with postmortem studies in humans with schizophrenia, because the chronic treatment with haloperidol may produce a decrease in the expression of nNOS (see Bernstein et al., 2005 for review), and our results show that subchronic doses of the typical neuroleptic haloperidol (0.5 mg /kg) administrated to nVH-lesion animals result in a decrease of higher NO activity (NegreteDiaz et al., 2010). This suggests that haloperidol exerts in part its therapeutic effect through its action on the activity of NO. It is interesting to note that compared to other models, the animal model of the nVH lesion is one of the best characterized, having been published to date in around a hundred works (see Tseng et al., 2009 for review). This is a neurodevelopmental model in which the behavioral changes mimic some of the symptoms of schizophrenia and are clearly observable after puberty. In summary, we believe that our findings support the integration of the results of previous works and facilitate our understanding of the role of NO in the pathophysiology of schizophrenia, as described by Bernstein and coworkers quite clearly in his letter to the editor of this journal (Bernstein et al., 2010).

Neuroinflammation is associated with changes in glial mGluR5 expression and the development of neonatal excitotoxic lesions.

It has been hypothesized that neuroinflammation triggered during brain development can alter brain functions later in life. We investigated the contribution of inflammation to the alteration of normal brain circuitries in the context of neuroexcitotoxicity following neonatal ventral hippocampal lesions in rats with ibotenic acid, an NMDA glutamate receptor agonist. Excitotoxic ibotenic acid lesions led to a significant and persistent astrogliosis and microglial activation, associated with the production of inflammatory mediators. This response was accompanied by a significant increase in metabotropic glutamate receptor type 5 (mGluR5) expression within two distinct neuroinflammatory cell types; astrocytes and microglia. The participation of inflammation to the neurotoxin-induced lesion was further supported by the prevention of hippocampal neuronal loss, glial mGluR5 expression and some of the behavioral perturbations associated to the excitotoxic lesion by concurrent anti-inflammatory treatment with minocycline. These results indicate that neuroinflammation significantly contributes to long-lasting excitotoxic effects of the neurotoxin and to some behavioral phenotypes associated with this model. Thus, the control of the inflammatory response may prevent the deleterious effects of excitotoxic processes that are triggered during brain development, limiting the risk to develop some of the behavioral manifestations related to these processes in adulthood.

Neonatal ventral hippocampus lesion induces increase in no levels which is attenuated by subchronic haloperidol treatment

Haloperidol is a potent dopamine receptor antagonist and used to treat psychotic disorders, such as schizophrenia. Recent clinical and preclinical studies demonstrated the overactivity of the nitric oxide (NO) system in schizophrenia. Neonatal ventral hippocampal (nVH) lesions in rats have been widely used as a neurodevelopmental model that mimics schizophrenia-like behaviors. Here, we investigate first whether the nVH lesion causes changes in NO levels in different limbic brain regions in young adults, postnatal day (PD) 81, and second, whether haloperidol treatment from PD60 to PD81 reverses these changes, by determining the accumulation of nitrites. The results show that NO levels at the level of the prefrontal cortex, occipital cortex, and cerebellum are higher in the nVH lesion animals, and that the haloperidol, in part, attenuates these altered NO levels. The NO levels observed in the nVH lesion animals with and without haloperidol treatment may be relevant to behaviors observed in schizophrenia.

Selective deficits in spatial working memory in the neonatal ventral hippocampal lesion rat model of schizophrenia

The neonatal ventral hippocampal lesion (NVHL) manipulation is a neurodevelopmental animal model of schizophrenia that produces abnormalities in the prefrontal cortex and nucleus accumbens, both efferent targets of the hippocampus, and leads to spatial working memory impairments. To investigate the neuroanatomical basis of spatial working memory in NVHL animals, we assessed performance in two radial arm maze tasks known to be differentially sensitive to the two hippocampal efferent pathways, and measured levels of neuronal activation (Fos immunoreactivity [Fos-IR]) in the prefrontal cortex and nucleus accumbens following task performance. Neonatal rats (postnatal day 6–8) received excitotoxic lesions of the ventral hippocampus (n = 25), or a sham procedure (infusions of artificial cerebrospinal fluid; n = 22). Upon reaching adulthood, animals were trained in either a non-delayed random foraging task or a spatial delayed win-shift task. NVHL animals were impaired on the spatial delayed win-shift task, which depends on communication between hippocampus and prefrontal cortex, but were unimpaired on the non-delayed random foraging task, which requires connections between hippocampus and nucleus accumbens. Fos-IR in the nucleus accumbens was greater in NVHL animals than in shams following the random foraging task, despite similar levels of performance, while no group differences in Fos-IR in either the nucleus accumbens or prefrontal cortex were observed following win-shift performance. These results suggest that although the NVHL manipulation disrupts development of hippocampal efferents to both the prefrontal cortex and the nucleus accumbens, the disruption of hippocampal–prefrontal pathways has the dominant behavioral effect on spatial performance in NVHL rats.

Ventral and dorsal striatal dopamine efflux and behavior in rats with simple vs. co-morbid histories of cocaine sensitization and neonatal ventral hippocampal lesions

RationalExposing animal models of mental illness to addictive drugs provides an approach to understanding the neural etiology of dual diagnosis disorders. Previous studies have shown that neonatal ventral hippocampal lesions (NVHL) in rats produce features of both schizophrenia and addiction vulnerability.ObjectiveThis study investigated ventral and dorsal striatal dopamine (DA) efflux in NVHL rats combined with behavioral sensitization to cocaine.MethodsAdult NVHL vs. SHAM-operated rats underwent a 5-day injection series of cocaine (15 mg/kg/day) vs. saline. One week later, rats were cannulated in nucleus accumbens SHELL, CORE, or caudate–putamen. Another week later, in vivo microdialysis sampled DA during locomotor testing in which a single cocaine injection (15 mg/kg) was delivered.ResultsNVHLs and cocaine history significantly increased behavioral activation approximately 2-fold over SHAM-saline history rats. DA efflux curves corresponded time dependently with the cocaine injection and locomotor curves and varied significantly by striatal region: Baseline DA levels increased 5-fold while cocaine-stimulated DA efflux decreased by half across a ventral to dorsal striatal gradient. However, NVHLs, prior cocaine history, and individual differences in behavior were not underpinned by differential DA efflux overall or within any striatal region.ConclusionDifferences in ventral/dorsal striatal DA efflux are not present in and are not required for producing differential levels of acute cocaine-induced behavioral activation in NVHLs with and without a behaviorally sensitizing cocaine history. These findings suggest other neurotransmitter systems, and alterations in striatal network function post-synaptic to DA transmission are more important to understanding the interactive effects of addictive drugs and mental illness.

Neurodegeneration in schizophrenia

The neurodegenerative aspect of schizophrenia presupposes gene–environmental interactions involving chromosomal abnormalities and obstetric/perinatal complications that culminate in predispositions that impart a particular vulnerability for drastic and unpredictable precipitating factors, such as stress or chemical agents. The notion of a neurodevelopmental progression to the disease state implies that early developmental insults, with neurodegenerative proclivities, evolve into structural brain abnormalities involving specific regional circuits and neurohumoral agents. This neurophysiological orchestration is expressed in the dysfunctionality observed in premorbid signs and symptoms arising in the eventual diagnosis, as well as the neurobehavioral deficits reported from animal models of the disorder. The relative contributions of perinatal insults, neonatal ventral hippocampus lesion, prenatal methylazoxymethanol acetate and early traumatic experience, as well as epigenetic contributions, are discussed from a neurodegenerative view of the essential neuropathology. It is implied that these considerations of factors that exert disruptive influences upon brain development, or normal aging, operationalize the central hub of developmental neuropathology around which the disease process may gain momentum. Nonetheless, the status of neurodegeneration in schizophrenia is somewhat tenuous and it is possible that brain imaging studies on animal models of the disorder, which may describe progressive alterations to cortical, limbic and ventricular structures similar to those of schizophrenic patients, are necessary to resolve the issue.

Metabolic activity in the brain of juvenile and adult rats with a neonatal ventral hippocampal lesion

Longitudinal studies on patients for schizophrenia suggest that functional brain perturbations precede the onset of symptoms. Rats with a neonatal ventral hippocampal lesion (NVHL) are considered as a heuristic neurodevelopmental model of schizophrenia. We characterized basal metabolic changes observed in NVHL rats before and after the age when known behavioral alterations have been reported. Male pups were lesioned with ibotenic acid at postnatal day 7 (PD7). We measured local cerebral metabolic rates for glucose (LCMRglc) by the quantitative autoradiographic [(14)C]2-deoxyglucose technique at pre- (PD21) and postpubertal (PD42) ages when NVHL rats do not express abnormal dopamine related behaviors, and at adulthood (PD70). We observed a widespread increase in LCMRglcs in PD21 NVHL indicative of an ongoing intense reorganization of the brain while at PD42, increases were less extended. At PD70, changes in glucose metabolism were restricted to specific systems, such as the auditory system, the cerebellum, the serotonergic median raphe, and median septum. These data show in a heuristic animal model of schizophrenia that functional metabolic changes within the brain could precede the onset of dopamine-related behavioral alterations and lead to a distinct ensemble of functional changes in adulthood in systems that may be relevant to schizophrenia.

MRI and X-ray scanning images of the brain of 3-, 6- and 9-month-old rats with bilateral neonatal ventral hippocampus lesions

Rats with bilateral neonatal ventral hippocampus lesions (NVHL) are commonly used for modeling developmental aspects of the pathophysiology of schizophrenia. Given that functional changes become significant only after puberty, NVHL as well as sham-operated rats were analyzed at the ages of 21, 42 and 63days (i.e. as pups, adolescents and adults), using MRI to examine the damage caused by surgery over time. Morphometric evaluations were considered and lesions were classified as small, medium and large. The volume of lesions increased regularly with age, to a greater extent than increases in overall brain size. This was relatively linear, corresponding to a gradually shrinking forebrain, and these observations held true for each class of lesions considered. Following the observation that the lesion procedure elicited calcifications in the brain, the same rats were subjected to 3D X-ray scanning the day after each MRI session, allowing precise measurements of skull size to be carried out. The NVHL rats had smaller skulls; however, the dimensions of the calcifications did not grow more than the skull size over time. The mechanisms underlying the progressive anatomical changes following surgery are discussed, and we propose this in vivo follow-up method to investigate therapeutic strategies aimed at countering or limiting the post-lesion consequences of a neonatal brain damage.

Sex differences in the activity of signalling pathways and expression of G-protein-coupled receptor kinases in the neonatal ventral hippocampal lesion model of schizophrenia

Animals with the neonatal ventral hippocampal lesion (NVHL) demonstrate altered responsiveness to stress and various drugs reminiscent of that in schizophrenia. Post-pubertal onset of abnormalities suggests the possibility of sex differences in NVHL effects that may model sex differences in schizophrenia. Here we demonstrate that novelty- and MK-801-induced hyperactivity is evident in both male and female NVHL rats, whereas only NVHL males were hyperactive in response to apomorphine. Next, we examined the sex- and NVHL-dependent differences in the activity of the ERK and Akt pathways. The basal activity of both pathways was higher in females than in males. NVHL reduces the level of phosphorylation of ERK1/2, Akt, and GSK-3 in both sexes, although males show more consistent down-regulation. Females had higher levels of G-protein-coupled kinases [G-protein-coupled receptor kinase (GRK)] 3 and 5, whereas the concentrations of other GRKs and arrestins were the same. In the nucleus accumbens, the concentration of GRK5 in females was elevated by NVHL to the male level. The data demonstrate profound sex differences in the expression and activity of signalling molecules that may underlie differential susceptibility to schizophrenia.

Adolescent Maturation of Cortical Dopamine

Dopamine is a critical modulator of prefrontal cortical function, and it is known to be dysfunctional in schizophrenia. Current hypotheses on schizophrenia highlight developmental aspects and genetic predisposition for the disease; yet, symptom onset typically occurs during adolescence. Several aspects of prefrontal cortical circuits and their modulation by dopamine mature postnatally, as late as during adolescence. Here we review studies assessing the postnatal trajectory of dopamine control of GABA interneurons, a neuronal population that has been long suspected to be critical for schizophrenia pathophysiology. Dopamine modulation of fast-spiking interneurons changes dramatically during adolescence (postnatal day 45-50 in rats) with D2 agonists switching from being mildly inhibitory in prepubertal rats to strongly excitatory in young adult rats. In vivo recordings in adult rats reveal that deep-layer pyramidal neurons respond to endogenous DA release with suppression of firing while interneurons are activated. In adult rats with a neonatal ventral hippocampal lesion (NVHL), an extensively studied developmental model of schizophrenia, the maturation in the D2 modulation of interneuron physiology fails to occur, rendering a disinhibited prefrontal cortex. Abnormal interneuron maturation may therefore impair cognitive function in the adult animal.