Prepulse Inhibition Test Research Articles

Hippocampal chloride transporter KCC2 contributes to excitatory GABA dysregulation in the developmental rat model of schizophrenia

Recent studies have revealed an altered expression of NKCC1 and KCC2 in prefrontal cortex (PFC) and hippocampus of schizophrenic patients. Despite extensive considerations, the alteration of NKCC1 and KCC2 co-transporters at different stages of development has not been fully studied. Therefore, we evaluated the expression of these transporters in PFC and hippocampus at time points of four, eight, and twelve weeks in post-weaning social isolation rearing rat model. For this purpose, 23–25 days-old rats were classified into social- or isolation-reared groups. The levels of NKCC1 and KCC2 mRNA expression were evaluated at hippocampus or PFC regions at the time-points of four, eight, and twelve weeks following housing. Post-weaning isolation rearing decreased the hippocampal KCC2 mRNA expression level, but does not affect the NKCC1 mRNA expression. However, no significant difference was observed in the PFC mRNA levels of NKCC1 and KCC2 in the isolation-reared group compared to the socially-reared group during the course of modeling. Further, we assessed the therapeutic effect of selective NKCC1 inhibitor bumetanide (10 mg/kg), on improvement of prepulse inhibition (PPI) test on twelve weeks isolation-reared rats. Intraperitoneal administration of bumetanide (10 mg/kg) did not exert beneficial effects on PPI deficit. Our findings show that isolation rearing reduces hippocampal KCC2 expression level and may underlie hippocampal GABA excitatory. In addition, 10 mg/kg bumetanide is not effective in improving the reduced PPI of twelve weeks isolation-reared rats.Collectively, our findings show that hippocampal chloride transporter KCC2 contributes to excitatory GABA dysregulation in the developmental rat model of schizophrenia.

The effects of galangin in prepulse inhibition test and experimental schizophrenia models.

Acetylcholinesterase inhibitors are the focus of interest in the management of schizophrenia. We aimed to investigate the effects of acute galangin administration, a flavonoid compound with acetylcholinesterase inhibiting activity, on schizophrenia-associated cognitive deficits in rats and schizophrenia models in mice. Apomorphine-induced prepulse inhibition (PPI) disruption for cognitive functions, nicotinic, muscarinic, and serotonergic mechanism involvement, and brain acetylcholine levels were investigated in Wistar rats. Apomorphine-induced climbing, MK-801-induced hyperlocomotion, and catalepsy tests were used as schizophrenia models in Swiss albino mice. The effects of galangin were compared with acetylcholinesterase inhibitor donepezil, and typical and atypical antipsychotics haloperidol and olanzapine, respectively. Galangin (50,100 mg/kg) enhanced apomorphine-induced PPI disruption similar to donepezil, haloperidol, and olanzapine (p < 0.05). This effect was not altered in the combination of galangin with the nicotinic receptor antagonist mecamylamine (1 mg/kg), the muscarinic receptor antagonist scopolamine (0.05 mg/kg), or the serotonin-1A receptor antagonist WAY-100635 (1 mg/kg) (p > 0.05). Galangin (50,100 mg/kg) alone increased brain acetylcholine concentrations (p < 0.05), but not in apomorphine-injected rats (p > 0.05). Galangin (50 mg/kg) decreased apomorphine-induced climbing and MK-801-induced hyperlocomotion similar to haloperidol and olanzapine (p < 0.05), but did not induce catalepsy, unlike them. We suggest that galangin may help enhance schizophrenia-associated cognitive deficits, and nicotinic, muscarinic cholinergic, and serotonin-1A receptors are not involved in this effect. Galangin also exerted an antipsychotic-like effect without inducing catalepsy and may be considered as an advantageous antipsychotic agent.

Treatment with Autophagy Inducer Trehalose Alleviates Memory and Behavioral Impairments and Neuroinflammatory Brain Processes in db/db Mice.

Autophagy attenuation has been found in neurodegenerative diseases, aging, diabetes mellitus, and atherosclerosis. In experimental models of neurodegenerative diseases, the correction of autophagy in the brain reverses neuronal and behavioral deficits and hence seems to be a promising therapy for neuropathologies. Our aim was to study the effect of an autophagy inducer, trehalose, on brain autophagy and behavior in a genetic model of diabetes with signs of neuronal damage (db/db mice). A 2% trehalose solution was administered as drinking water during 24 days of the experiment. Expressions of markers of autophagy (LC3-II), neuroinflammation (IBA1), redox state (NOS), and neuronal density (NeuN) in the brain were assessed by immunohistochemical analysis. For behavioral phenotyping, the open field, elevated plus-maze, tail suspension, pre-pulse inhibition, and passive avoidance tests were used. Trehalose caused a slight reduction in increased blood glucose concentration, considerable autophagy activation, and a decrease in the neuroinflammatory response in the brain along with improvements of exploration, locomotor activity, anxiety, depressive-like behavior, and fear learning and memory in db/db mice. Trehalose exerted some beneficial peripheral and systemic effects and partially reversed behavioral alterations in db/db mice. Thus, trehalose as an inducer of mTOR-independent autophagy is effective at alleviating neuronal and behavioral disturbances accompanying experimental diabetes.

Duration of Social Isolation Affects Production of Nitric Oxide in the Rat Brain.

Social isolation deprives rodents of social interactions that are critical for normal development of brain and behavior. Several studies have indicated that postweaning isolation rearing may affect nitric oxide (NO) production. The aim of this study was to compare selected behavioral and biochemical changes related to NO production in the brain of rats reared in social isolation for different duration. At the age of 21 days, male Sprague Dawley rats were randomly assigned into four groups reared in isolation or socially for 10 or 29 weeks. At the end of the rearing, open-field and prepulse inhibition (PPI) tests were carried out. Furthermore, in several brain areas we assessed NO synthase (NOS) activity, protein expression of nNOS and iNOS isoforms and the concentration of conjugated dienes (CD), a marker of oxidative damage and lipid peroxidation. Social isolation for 10 weeks resulted in a significant decrease in PPI, which was accompanied by a decrease in NOS activity in the cerebral cortex and the cerebellum, an increase in iNOS in the hippocampus and an increase in CD concentration in cortex homogenate. On the other hand, a 29 week isolation had an opposite effect on NOS activity, which increased in the cerebral cortex and the cerebellum in animals reared in social isolation, accompanied by a decrease in CD concentration. The decrease in NOS activity after 10 weeks of isolation might have been caused by chronic stress induced by social isolation, which has been documented in previous studies. The increased oxidative state might result in the depleted NO bioavailability, as NO reacts with superoxide radical creating peroxynitrite. After 29 weeks of isolation, this loss of NO might be compensated by the subsequent increase in NOS activity.

Endogenous Estrogen Influences Predator Odor-Induced Impairment of Cognitive and Social Behaviors in Aromatase Gene Deficiency Mice.

Epidemiological studies have suggested that traumatic stress increases vulnerability to various mental disorders, such as dementia and psychiatric disorders. While women are more vulnerable than men to depression and anxiety, it is unclear whether endogenous estrogens are responsible for the underlying sex-specific mechanisms. In this study, the aromatase gene heterozygous (Ar+/-) mice were used as an endogenous estrogen deficiency model and age- and sex-matched wild type mice (WT) as controls to study the predator odor 2,3,5-trimethyl-3-thiazoline- (TMT-) induced short- and long-term cognitive and social behavior impairments. In addition, the changes in brain regional neurotransmitters and their associations with TMT-induced changes in behaviors were further investigated in these animals. Our results showed TMT induced immediate fear response in both Ar+/- and WT mice regardless of sexes. TMT induced an acute impairment of novel object recognition memory and long-term social behavior impairment in WT mice, particularly in females, while Ar+/- mice showed impaired novel object recognition in both sexes and TMT-elevated social behaviors, particularly in males. TMT failed to induce changes in the prepulse inhibition (PPI) test in both groups. TMT resulted in a slight increase of DOPAC/DA ratio in the cortex and a significant elevation of this ratio in the striatum of WT mice. In addition, the ratio of HIAA/5-HT was significantly elevated in the cortex of TMT-treated WT mice, which was not found in TMT-treated Ar+/- mice. Taken together, our results indicate that TMT exposure can cause cognitive and social behavior impairments as well as change catecholamine metabolism in WT mice, and endogenous estrogen deficiency might desensitize the behavioral and neurochemical responses to TMT in Ar+/- mice.

Microinjection of Reelin into the mPFC prevents MK-801-induced recognition memory impairment in mice

Reelin, a large extracellular matrix protein, helps to regulate neuronal plasticity and cognitive function. Several studies have shown that Reelin dysfunction, resulting from factors such as mutations in gene RELN or low Reelin expression, is associated with schizophrenia (SCZ). We previously reported that microinjection of Reelin into cerebral ventricle prevents phencyclidine-induced cognitive and sensory-motor gating deficits. However, it remains unclear whether and how Reelin ameliorates behavioral abnormalities in the animal model of SCZ. In the present study, we evaluated the effect of recombinant Reelin microinjection into the medial prefrontal cortex (mPFC) on abnormal behaviors induced by MK-801, an N-methyl-D-aspartate receptor antagonist. Microinjection of Reelin into the mPFC prevented impairment of recognition memory of MK-801-treated mice in the novel object recognition test (NORT). On the other hand, the same treatment had no effect on deficits in sensory-motor gating and short-term memory in the pre-pulse inhibition and Y-maze tests, respectively. To establish the neural substrates that respond to Reelin, the number of c-Fos-positive cells in the mPFC was determined. A significant increase in c-Fos-positive cells in the mPFC of MK-801-treated mice was observed when compared with saline-treated mice, and this change was suppressed by microinjection of Reelin into the mPFC. A K2360/2467A Reelin that cannot bind to its receptor failed to ameliorate MK-801-induced cognitive deficits in NORT. These results suggest that Reelin prevents MK-801-induced recognition memory impairment by acting on its receptors to suppress neural activity in the mPFC of mice.

Ameliorating schizophrenia-like symptoms in vasopressin deficient male Brattleboro rat by chronic antipsychotic treatment

Due to its various function vasopressin has been associated with many psychiatric disorders, including schizophrenia. Our previous study confirmed that vasopressin-deficient (di/di) Brattleboro rat can be a good genetic model for schizophrenia. Our present aim was to confirm whether the treatment effects of marketed antipsychotics are similar in di/di rats to those seen in human schizophrenic patients.Chronic subcutaneous administration of aripiprazole (5 mg/kg), clozapine (1 mg/kg), haloperidol (0.1 mg/kg), olanzapine (0.3 mg/kg) or risperidone (0.25 mg/kg) was used for 15 days in control (+/+ Brattleboro) and di/di rats. Social discrimination, social avoidance and prepulse inhibition tests were conducted on day 1, 8 and 15 of the treatment.Vasopressin-deficient rats showed social memory- and sensorimotor gating deficit. All used antipsychotics successfully normalized the reduced prepulse inhibition of di/di animals. However, most were effective only after prolonged treatment. Aripiprazole, clozapine, and olanzapine normalized the social memory deficit, while the effects of haloperidol and risperidone were not unequivocal. All drugs reduced social interest to some extent both in control and in di/di animals, aripiprazole being the less implicated in this regard during the social avoidance test.The restoration of schizophrenia-like behavior by antipsychotic treatment further support the utility of the vasopressin-deficient Brattleboro rat as a good preclinical model. Reduced social interest might be a general side-effect of antipsychotics, and aripiprazole has the most favorable profile in this regard.

Sodium valproate improves sensorimotor gating deficit induced by sleep deprivation at low doses

Background/aim Sleep deprivation disrupts prepulse inhibition of acoustic startle reflex and can be used to mimic psychosis in experimental animals. On the other hand, it is also a model for other disorders of sensory processing, including migraine. This study aims to assess the effects of sodium valproate, a drug that is used in a variety of neuropsychiatric disorders, on normal and disrupted sensorimotor gating in rats.Materials and methods Sixty-two Wistar albino rats were randomly distributed into 8 groups. Subchronic and intraperitoneal sodium valproate were administrated to the sleep-deprived and nonsleep-deprived rats by either 50–100 or 200 mg/kg/day. Prepulse inhibition test and locomotor activity test were performed. Sleep deprivation induced by the modified multiple platform method.Results Sleep deprivation impaired prepulse inhibition, decreased startle amplitude, and increased locomotor activity. Sodium valproate did not significantly alter prepulse inhibition and locomotor activity in nonsleep-deprived and sleep-deprived groups. On the other hand, all doses decreased locomotor activity in drug-treated groups, and low dose improved sensorimotor gating and startle amplitude after sleep deprivation.Conclusion Low-dose sodium valproate improves sleep deprivation-disrupted sensorimotor gating, and this finding may rationalize the use of sodium valproate in psychotic states and other sensory processing disorders. Dose-dependent effects of sodium valproate on sensorimotor gating should be investigated in detail.

Combined glyoxalase 1 dysfunction and vitamin B6 deficiency in a schizophrenia model system causes mitochondrial dysfunction in the prefrontal cortex

Methylglyoxal (MG) is a reactive and cytotoxic α-dicarbonyl byproduct of glycolysis. Our bodies have several bio-defense systems to detoxify MG, including an enzymatic system by glyoxalase (GLO) 1 and GLO2. We identified a subtype of schizophrenia patients with novel mutations in the GLO1 gene that results in reductions of enzymatic activity. Moreover, we found that vitamin B6 (VB6) levels in peripheral blood of the schizophrenia patients with GLO1 dysfunction are significantly lower than that of healthy controls. However, the effects of GLO1 dysfunction and VB6 deficiency on the pathophysiology of schizophrenia remains poorly understood. Here, we generated a novel mouse model for this subgroup of schizophrenia patients by feeding Glo1 knockout mice VB6-deficent diets (KO/VB6(−)) and evaluated the combined effects of GLO1 dysfunction and VB6 deficiency on brain function. KO/VB6(−) mice accumulated homocysteine in plasma and MG in the prefrontal cortex (PFC), hippocampus, and striatum, and displayed behavioral deficits, such as impairments of social interaction and cognitive memory and a sensorimotor deficit in the prepulse inhibition test. Furthermore, we found aberrant gene expression related to mitochondria function in the PFC of the KO/VB6(−) mice by RNA-sequencing and weighted gene co-expression network analysis (WGCNA). Finally, we demonstrated abnormal mitochondrial respiratory function and subsequently enhanced oxidative stress in the PFC of KO/VB6(−) mice in the PFC. These findings suggest that the combination of GLO1 dysfunction and VB6 deficiency may cause the observed behavioral deficits via mitochondrial dysfunction and oxidative stress in the PFC.

A Characterization of the Effects of Minocycline Treatment During Adolescence on Structural, Metabolic, and Oxidative Stress Parameters in a Maternal Immune Stimulation Model of Neurodevelopmental Brain Disorders.

BackgroundMinocycline (MIN) is a tetracycline with antioxidant, anti-inflammatory, and neuroprotective properties. Given the likely involvement of inflammation and oxidative stress (IOS) in schizophrenia, MIN has been proposed as a potential adjuvant treatment in this pathology. We tested an early therapeutic window, during adolescence, as prevention of the schizophrenia-related deficits in the maternal immune stimulation (MIS) animal model.MethodsOn gestational day 15, Poly I:C or vehicle was injected in pregnant Wistar rats. A total 93 male offspring received MIN (30 mg/kg) or saline from postnatal day (PND) 35–49. At PND70, rats were submitted to the prepulse inhibition test. FDG-PET and T2-weighted MRI brain studies were performed at adulthood. IOS markers were evaluated in frozen brain tissue.ResultsMIN treatment did not prevent prepulse inhibition test behavioral deficits in MIS offspring. However, MIN prevented morphometric abnormalities in the third ventricle but not in the hippocampus. Additionally, MIN reduced brain metabolism in cerebellum and increased it in nucleus accumbens. Finally, MIN reduced the expression of iNOS (prefrontal cortex, caudate-putamen) and increased the levels of KEAP1 (prefrontal cortex), HO1 and NQO1 (amygdala, hippocampus), and HO1 (caudate-putamen).ConclusionsMIN treatment during adolescence partially counteracts volumetric abnormalities and IOS deficits in the MIS model, likely via iNOS and Nrf2–ARE pathways, also increasing the expression of cytoprotective enzymes. However, MIN treatment during this peripubertal stage does not prevent sensorimotor gating deficits. Therefore, even though it does not prevent all the MIS-derived abnormalities evaluated, our results suggest the potential utility of early treatment with MIN in other schizophrenia domains.

TrkB agonist 7,8-dihydroxyflavone reverses an induced prepulse inhibition deficit selectively in maternal immune activation offspring: implications for schizophrenia.

Reduced brain-derived neurotrophic factor (BDNF) signalling has been implicated in schizophrenia endophenotypes, including deficits in prepulse inhibition (PPI). Maternal immune activation (MIA) is a widely used neurodevelopmental animal model for schizophrenia but it is unclear if BDNF and its receptor, tropomyosin receptor kinase B (TrkB), are involved in PPI regulation in this model. Pregnant Long Evans rats were treated with the viral mimetic, polyinosinic-polycytidylic acid (poly I:C; 4 mg/kg i.v.), and nine male offspring from these dams were compared in adulthood to 11 male Long Evans controls. Offspring underwent PPI testing following injection with the TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF) (10 mg/kg i.p.), with or without the dopamine receptor agonist, apomorphine (APO; 1 mg/kg s.c.), or the dopamine releasing drug, methamphetamine (METH; 2 mg/kg s.c.). Acute administration of APO and METH caused the expected significant reduction of PPI. Acute administration of 7,8-DHF did not alter PPI on its own; however, it significantly reversed the effect of APO on PPI in poly I:C rats, but not in controls. A similar trend was observed in combination with METH. Western blot analysis of frontal cortex revealed significantly increased levels of BDNF protein, but not TrkB or phosphorylated TrkB/TrkB levels, in poly I:C rats. These findings suggest that, selectively in MIA offspring, 7,8-DHF has the ability to reverse PPI deficits caused by dopaminergic stimulation. This effect could be associated with increased BDNF expression in the frontal cortex. These data suggest that targeting BDNF signalling may have therapeutic potential for the treatment of certain symptoms of schizophrenia.

Omega-3 fatty acids during adolescence prevent schizophrenia-related behavioural deficits: Neurophysiological evidences from the prenatal viral infection with PolyI:C

The likely involvement of inflammation and oxidative stress (IOS) in mental disease has led to advocate anti-oxidant and anti-inflammatory drugs as therapeutic strategies in the treatment of schizophrenia. Since omega-3 fatty acids (ω-3) show anti-inflammatory/neuroprotective properties, we aim to evaluate whether ω-3 treatment during adolescence in the maternal immune stimulation (MIS) animal model of schizophrenia could prevent the brain and behavioural deficits described in adulthood. At gestational day 15, PolyI:C (4 mg/kg) or saline (VH) were injected to pregnant Wistar rats. Male offspring received ω-3 (800 mg/kg) or saline (Sal) daily from postnatal day (PND) 35–49, defining 4 groups: MIS-ω-3; MIS-Sal; VH-ω-3 and VH-Sal. At PND70, rats were submitted to prepulse inhibition test (PPI). FDG-PET and T2-weighted MRI brain studies were performed in adulthood and analyzed by means of SPM12. IOS markers were measured in selected brain areas. MIS-offspring showed a PPI deficit compared with VH-offspring and ω-3 treatment prevented this deficit. Also, ω-3 reduced the brain metabolism in the deep mesencephalic area and prevented the volumetric abnormalities in the hippocampus but not in the ventricles in MIS-offspring. Besides, ω-3 reduced the expression of iNOS and Keap1 and increased the activity/concentration of HO1, NQO1 and GPX. Our study demonstrates that administration of ω-3 during adolescence prevents PPI behavioural deficits and hippocampal volumetric abnormalities, and partially counteracts IOS deficits via iNOS and Nrf2–ARE pathways in the MIS model. This study highlights the need for novel strategies based on anti-inflammatory/anti-oxidant compounds to alter the disease course in high-risk populations at early stages.

Role of Polyinosinic:Polycytidylic Acid-Induced Maternal Immune Activation and Subsequent Immune Challenge in the Behaviour and Microglial Cell Trajectory in Adult Offspring: A Study of the Neurodevelopmental Model of Schizophrenia.

Multiple lines of evidence support the pathogenic role of maternal immune activation (MIA) in the occurrence of the schizophrenia-like disturbances in offspring. While in the brain the homeostatic role of neuron-microglia protein systems is well documented, the participation of the CX3CL1-CX3CR1 and CD200-CD200R dyads in the adverse impact of MIA often goes under-recognized. Therefore, in the present study, we examined the effect of MIA induced by polyinosinic:polycytidylic acid (Poly I:C) on the CX3CL1-CX3CR1 and CD200-CD200R axes, microglial trajectory (MhcII, Cd40, iNos, Il-1β, Tnf-α, Il-6, Arg1, Igf-1, Tgf-β and Il-4), and schizophrenia-like behaviour in adult male offspring of Sprague-Dawley rats. Additionally, according to the “two-hit” hypothesis of schizophrenia, we evaluated the influence of acute challenge with Poly I:C in adult prenatally MIA-exposed animals on the above parameters. In the present study, MIA evoked by Poly I:C injection in the late period of gestation led to the appearance of schizophrenia-like disturbances in adult offspring. Our results revealed the deficits manifested as a diminished number of aggressive interactions, presence of depressive-like episodes, and increase of exploratory activity, as well as a dichotomy in the sensorimotor gating in the prepulse inhibition (PPI) test expressed as two behavioural phenotypes (MIAPPI-low and MIAPPI-high). Furthermore, in the offspring rats subjected to a prenatal challenge (i.e., MIA) we noticed the lack of modulation of behavioural changes after the additional acute immune stimulus (Poly I:C) in adulthood. The important finding reported in this article is that MIA affects the expression and levels of the neuron-microglia proteins in the frontal cortex and hippocampus of adult offspring. We found that the changes in the CX3CL1-CX3CR1 axis could affect microglial trajectory, including decreased hippocampal mRNA level of MhcII and elevated cortical expression of Igf-1 in the MIAPPI-high animals and/or could cause the up-regulation of an inflammatory response (Il-6, Tnf-α, iNos) after the “second hit” in both examined brain regions and, at least in part, might differentiate behavioural disturbances in adult offspring. Consequently, the future effort to identify the biological background of these interactions in the Poly I:C-induced MIA model in Sprague-Dawley rats is desirable to unequivocally clarify this issue.

ZFP804A mutant mice display sex-dependent schizophrenia-like behaviors

Genome-wide association studies uncovered the association of ZNF804A (Zinc-finger protein 804A) with schizophrenia (SZ). In vitro data have indicated that ZNF804A might exert its biological roles by regulating spine and neurite morphogenesis. However, no in vivo data are available for the role of ZNF804A in psychiatric disorders in general, SZ in particular. We generated ZFP804A mutant mice, and they showed deficits in contextual fear and spatial memory. We also observed the sensorimotor gating impairment, as revealed by the prepulse inhibition test, but only in female ZFP804A mutant mice from the age of 6 months. Notably, the PPI difference between the female mutant and control mice was no longer existed with the administration of Clozapine or after the ovariectomy. Hippocampal long-term potentiation was normal in both genders of the mutant mice. Long-term depression was absent in male mutants, but facilitated in the female mutants. Protein levels of hippocampal serotonin-6 receptor and GABAB1 receptor were increased, while those of cortical dopamine 2 receptor were decreased in the female mutants with no obvious changes in the male mutants. Moreover, the spine density was reduced in the cerebral cortex and hippocampus of the mutant mice. Knockdown of ZFP804A impaired the neurite morphogenesis of cortical and hippocampal neurons, while its overexpression enhanced neurite morphogenesis only in the cortical neurons in vitro. Our data collectively support the idea that ZFP804A/ZNF804A plays important roles in the cognitive functions and sensorimotor gating, and its dysfunction may contribute to SZ, particularly in the female patients.

Subclass imbalance of parvalbumin-expressing GABAergic neurons in the hippocampus of a mouse ketamine model for schizophrenia, with reference to perineuronal nets

Impairments of parvalbumin-expressing GABAergic neurons (PV+ neurons) and specialized extracellular structures called perineuronal nets (PNNs) have been found in schizophrenic patients. In this study, we examined potential alterations in four subclasses of PV+ neurons colocalized with PNNs in the hippocampus of a mouse ketamine model for schizophrenia. Because biosynthesis of human natural killer-1 (HNK-1) is shown to be associated with the risk of schizophrenia, here we used mouse monoclonal Cat-315 antibody, which recognizes HNK-1 glycans on PNNs. Once-daily intraperitoneal injections of ketamine for seven consecutive days induced hyper-locomotor activity in the open field tests. The prepulse inhibition (PPI) test showed that PPI scores declined in ketamine-treated mice compared to vehicle-treated mice. The densities of PV+ neurons and Cat-315+ PNNs declined in the CA1 region of ketamine-treated mice. Interestingly, the density of Cat-315+/PV+ neurons was lower in ketamine-treated mice than in vehicle-treated mice, whereas the density of Cat-315−/PV+ neurons was not affected by ketamine. Among the four subclasses of PV+ neurons, the densities of Cat-315+/PV+ basket cells and Cat-315−/PV+ axo-axonic cells were lower in ketamine-treated mice than in vehicle-treated mice, while the densities of Cat-315−/PV+ basket cells and Cat-315+/PV+ axo-axonic cells were not affected by ketamine. Taken together, PNNs may not play a simple neuroprotective role against ketamine. Because different subclasses of PV+ neurons are considered to play distinct roles in the hippocampal neuronal network, the ketamine-induced subclass imbalance of PV+ neurons may result in abnormal network activity, which underlies the pathophysiology of schizophrenia.

Mitogen-activated protein kinase (MAPK) signalling corresponds with distinct behavioural profiles in a rat model of maternal immune activation

Dysfunction within the mitogen-activated protein kinase (MAPK) cascade has been recognised as a pathological feature of schizophrenia, however the possible mechanistic connection to the disease phenotype remains unexplored. Using the maternal immune activation (MIA) rat model of schizophrenia, the present study investigated the involvement of prefrontal cortex (PFC) MAPK in sensorimotor gating and adaptive learning deficits via western blot, pre-pulse inhibition (PPI) testing, and a contingency degradation operant task, respectively. Principle findings identified a negative relationship between basal MAPK expression and PPI exclusively in MIA rats, suggesting a modulatory role for MAPK in sensorimotor gating pathology. In addition, the correlation between MAPK and adaptive learning capacity observed in control rats was absent for rats exposed to MIA. Findings are considered with respect to the glutamatergic NMDA hypofunction theory of schizophrenia, as well as the critical role of PFC in contingency learning.

Quetiapine Attenuates Schizophrenia-Like Behaviors and Demyelination in a MK-801-Induced Mouse Model of Schizophrenia.

Brain demyelination is possibly one of the main pathological factors involved in schizophrenia, and targeting on myelination may be a useful strategy for schizophrenia treatment. Quetiapine, a widely used atypical antipsychotic drug for schizophrenia treatment, has been reported to have neuroprotective effects on cerebral myelination in a demyelination animal model. The objective of the present study was to evaluate the effect and underlying neuroprotective mechanism of quetiapine on the schizophrenia-like behaviors and possible cerebral demyelination induced by MK-801, an N-methyl-D-aspartate glutamate receptor antagonist. Mice were treated with chronic quetiapine (10 mg/kg/day, intraperitoneally) for 28 days. From day 22 to 28, 1 h after the administration of quetiapine, the mice were administered MK-801 (2 mg/kg/day, subcutaneously). The positive symptom of schizophrenia was measured in a locomotor activity test on day 29, the memory was evaluated by a Y-maze test on day 30, and the sensorimotor gating deficit in mice was measured by prepulse inhibition test on day 31. After the behavioral tests, the protein expression of myelin basic protein (MBP) was measured by Western Blot, and the protein expression of brain-derived neurotrophic factor (BDNF) was measured by ELISA in the frontal cortex of mice. Our results showed quetiapine attenuated schizophrenia-like behaviors including hyperactivity, memory impairment, and sensorimotor gating deficit in the MK-801 mice. In the same time, quetiapine attenuated demyelination, concurrent with attenuated BDNF decrease in the brain of MK-801-injected mice. These results suggest that the beneficial effects of quetiapine on schizophrenia might be partly related to its neuroprotective effect on brain myelin basic protein and its upregulating neuroprotective proteins such as BDNF, and indicate that modulation of cerebral demyelination could be a novel treatment target of schizophrenia.

Loss of Cochlear Ribbon Synapse Is a Critical Contributor to Chronic Salicylate Sodium Treatment-Induced Tinnitus without Change Hearing Threshold.

Tinnitus is a common auditory disease worldwide; it is estimated that more than 10% of all individuals experience this hearing disorder during their lifetime. Tinnitus is sometimes accompanied by hearing loss. However, hearing loss is not acquired in some other tinnitus generations. In this study, we injected adult rats with salicylate sodium (SS) (200 mg/kg/day for 10 days) and found no significant hearing threshold changes at 2, 4, 8, 12, 14, 16, 20, or 24 kHz (all p > 0.05). Tinnitus was confirmed in the treated rats via Behaviour Testing of Acoustic Startle Response (ASR) and Gap Prepulse Inhibition Test of Acoustic Startle Reflex (GPIAS). A immunostaining study showed that there is significant loss of anti-CtBP2 puncta (a marker of cochlear inner hair cell (HC) ribbon synapses) in treated animals in apical, middle, and basal turns (all p < 0.05). The ABR wave I amplitudes were significantly reduced at 4, 8, 12, 14, 16, and 20 kHz (all p < 0.05). No significant losses of outer HCs, inner HCs, or HC cilia were observed (all p > 0.05). Thus, our study suggests that loss of cochlear inner HC ribbon synapse after SS exposure is a contributor to the development of tinnitus without changing hearing threshold.

Maternal Immune Activation Sensitizes Male Offspring Rats to Lipopolysaccharide-Induced Microglial Deficits Involving the Dysfunction of CD200-CD200R and CX3CL1-CX3CR1 Systems.

Early life challenges resulting from maternal immune activation (MIA) may exert persistent effects on the offspring, including the development of psychiatric disorders, such as schizophrenia. Recent evidence has suggested that the adverse effects of MIA may be mediated by neuron–microglia crosstalk, particularly CX3CL1–CX3CR1 and CD200–CD200R dyads. Therefore, the present study assessed the behavioural parameters resembling schizophrenia-like symptoms in the adult male offspring of Sprague-Dawley rats that were exposed to MIA and to an additional acute lipopolysaccharide (LPS) challenge in adulthood, according to the “two-hit” hypothesis of schizophrenia. Simultaneously, we aimed to clarify the role of the CX3CL1–CX3CR1 and CD200–CD200R axes and microglial reactivity in the brains of adult offspring subjected to MIA and the “second hit” wit LPS. In the present study, MIA generated a range of behavioural changes in the adult male offspring, including increased exploratory activity and anxiety-like behaviours. The most intriguing finding was observed in the prepulse inhibition (PPI) test, where the deficit in the sensorimotor gating was age-dependent and present only in part of the rats. We were able to distinguish the occurrence of two groups: responsive and non-responsive (without the deficit). Concurrently, based on the results of the biochemical studies, MIA disrupted mainly the CD200–CD200R system, while the changes of the CX3CL1–CX3CR1 axis were less evident in the frontal cortex of adult non-responsive offspring. MIA markedly affected the immune regulators of the CD200–CD200R pathway as we observed an increase in cortical IL-6 release in the responsive group and IL-4 in the non-responsive offspring. Importantly, the “second hit” generated disturbances at the behavioural and biochemical levels mostly in the non-responsive adult animals. Those offspring were characterized both by disturbed PPI and “priming” microglia. Altogether, the exposure to MIA altered the immunomodulatory mechanisms, including the CD200–CD200R axis, in the brain and sensitized animals to subsequent immunological challenges, leading to the manifestation of schizophrenia-like alterations.

Effect of gabapentin on sleep-deprivation-induced disruption of prepulse inhibition.

There are controversial reports on the effects of gabapentin in respect to psychotic symptoms. Prepulse inhibition of the acoustic startle response is an operational measure of sensorimotor gating. In laboratory rodents, deficits in sensorimotor gating are used to model behavioral endophenotypes of schizophrenia. Sleep deprivation disrupts prepulse inhibition and can be used as a psychosis model to evaluate effects of gabapentin. This study aimed to investigate behavioral effects of gabapentin in both naïve and sleep-deprived rats. Sleep deprivation was induced in male Wistar rats by using the modified multiple platform technique in a water tank for 72h. The effect of water tank itself was studied in a sham group. The effects of oral acute and subchronic (4.5days) gabapentin doses (25, 100, or 200mg/kg/day) on sensorimotor gating and locomotor activity was evaluated by prepulse inhibition test and locomotor activity test, respectively. Plasma gabapentin levels of some groups and body weights of all groups were also assessed. Sleep deprivation disrupted prepulse inhibition, increased locomotor activity, reduced gabapentin plasma levels, and body weights. Some gabapentin doses disrupted sensorimotor gating irrespective of sleep condition. Some gabapentin doses increased locomotor activity in non-sleep-deprived rats and decreased locomotor activity in sleep-deprived rats. On the contrary, gabapentin did not normalize sleep deprivation-induced disruption in sensorimotor gating. Sleep deprivation via modified multiple platform technique could be used as an animal model for psychosis. Gabapentin may have dose- and duration-dependent effects on sensorimotor gating and locomotor activity.