P21

Neonatal Freeze Lesion-Induced Cortical Malformation Alters Hippocampal Gene Expression and Leads to Persistent Cognitive and Emotional Deficits in Adult Male Wistar Rats.

Olga E Zubareva, Anna A Kovalenko, Denis S Sinyak +4 more

Cortical malformations, including microgyria, are often associated with neurodevelopmental comorbidities such as epilepsy and cognitive impairments in humans. To investigate how early cortical disruption leads to persistent behavioral impairments, we employed a neonatal neocortical focal freeze lesion (FFL) model of polymicrogyria in male Wistar rats. Unilateral cortical lesions were induced at postnatal day 0 (P0), and molecular changes in hippocampal gene expression (glutamatergic signaling: Grin1, Grin2a, Grin2b, Gria1, Gria2; neuroinflammation: Nlrp3, Il1b, Il1rn; glial markers: Gfap, Aif1; neurotrophic factors: Bdnf, Fgf2) were analyzed at P21. Behavioral outcomes, including locomotor activity, exploratory behavior, anxiety-like behavior, social interaction, and recognition memory, were assessed in adulthood (P70-P90). Neonatal cortical lesions induced subregion-specific alterations in hippocampal gene expression: Grin2b and Gria1 expression decreased in the ipsilateral dorsal hippocampus, while Grin2a, Bdnf, and Fgf2 increased in the contralateral ventral hippocampus. These molecular changes were associated with subsequent cognitive deficits (impaired recognition memory) and emotional dysregulation (heightened anxiety-like behavior) in adult rats, alongside reduced exploratory activity. Basic motor functions and sociability remained unaffected, and seizure susceptibility (assessed via maximal electroshock threshold) was unchanged, highlighting the specificity of the observed impairments. Our findings suggest a potential mechanistic link between early-life cortical malformations with microgyrus formation, dysregulation of hippocampal synaptic plasticity and neurotrophic signaling, and persistent neurobehavioral deficits. These results underscore the translational relevance of the freeze lesion model for studying the neurodevelopmental trajectory of cortical malformation-related comorbidities.

Neonatal citalopram treatment inhibits the 5-HT depleting effects of MDMA exposure in rats.

Tori L Schaefer, Curtis E Grace, Matthew R Skelton +4 more

Neonatal exposure to 3,4-methylenedioxymethamphetamine (MDMA) produces long-term learning and memory deficits and increased anxiety-like behavior. The mechanism underlying these behavioral changes is unknown but we hypothesized that it involves perturbations to the serotonergic system as this is the principle mode of action of MDMA in the adult brain. During development 5-HT is a neurotrophic factor involved in neurogenesis, synaptogenesis, migration, and target region specification. We have previously showed that MDMA exposure (4×10 mg/kg/day) from P11-20 (analogous to human third trimester exposure) induces ~50% decreases in hippocampal 5-HT throughout treatment. To determine whether MDMA-induced 5-HT changes are determinative, we tested if these changes could be prevented by treatment with a selective serotonin reuptake inhibitor (citalopram: CIT). In a series of experiments we evaluated the effects of different doses and dose regimens of CIT on MDMA-induced 5-HT depletions in three brain regions (hippocampus, entorhinal cortex, and neostriatum) at three time-points (P12, P16, P21) during the treatment interval (P11-20) known to induce behavioral alterations when animals are tested as adults. We found that 5 mg/kg CIT administered twice daily significantly attenuated MDMA-induced 5-HT depletions in all three regions at all three ages but that the protection was not complete at all ages. Striatal dopamine was unaffected. We also found increases in hippocampal NGF and plasma corticosterone following MDMA treatment on P16 and P21, respectively. No changes in BDNF were observed. CIT treatment may be a useful means of interfering with MDMA-induced 5-HT reductions and thus permit tests of the hypothesis that the drug's cognitive and/or anxiety effects are mediated through early disruptions to 5-HT dependent developmental processes.

Noise Exposure Promotes Alzheimer's Disease-Like Lesions and DNA Damage.

Xiao-Jie Dai, Jun-Hua Liao, Yi Jia +2 more

This study aimed to explore the mechanism by which noise contributes to the development of Alzheimer's disease (AD)-like lesions.

Early Movement Restriction Affects FNDC5/Irisin and BDNF Levels in Rat Muscle and Brain.

Orlane Dupuis, Julien Girardie, Mélanie Van Gaever +4 more

Interaction with the environment appears necessary for the maturation of sensorimotor and cognitive functions in early life. In rats, a model of sensorimotor restriction (SMR) from postnatal day 1 (P1) to P28 has shown that low and atypical sensorimotor activities induced the perturbation of motor behavior due to muscle weakness and the functional disorganization of the primary somatosensory and motor cortices. In the present study, our objective was to understand how SMR affects the muscle-brain dialogue. We focused on irisin, a myokine secreted by skeletal muscles in response to exercise. FNDC5/irisin expression was determined in hindlimb muscles and brain structures by Western blotting, and irisin expression in blood and cerebrospinal fluid was determined using an ELISA assay at P8, P15, P21 and P28. Since irisin is known to regulate its expression, Brain-Derived Neurotrophic Factor (BDNF) levels were also measured in the same brain structures. We demonstrated that SMR increases FNDC5/irisin levels specifically in the soleus muscle (from P21) and also affects this protein expression in several brain structures (as early as P15). The BDNF level was increased in the hippocampus at P8. To conclude, SMR affects FNDC5/irisin levels in a postural muscle and in several brain regions and has limited effects on BDNF expression in the brain.

Lactate Improves Long-term Cognitive Impairment Induced By Repeated Neonatal Sevoflurane Exposures Through SIRT1-mediated Regulation of Adult Hippocampal Neurogenesis and Synaptic Plasticity in Male Mice.

Li-Li Qiu, Xiao-Xiang Tan, Jiao-Jiao Yang +5 more

Repeated neonatal exposures to sevoflurane induce long-term cognitive impairment that has been reported to have sex-dependent differences. Exercise promotes learning and memory by releasing lactate from the muscle. The study tested the hypothesis that lactate may improve long-term cognitive impairment induced by repeated neonatal exposures to sevoflurane through SIRT1-mediated regulation of adult hippocampal neurogenesis and synaptic plasticity. C57BL/6 mice of both genders were exposed to 3% sevoflurane for 2 h daily from postnatal day 6 (P6) to P8. In the intervention experiments, mice received lactate at 1 g/kg intraperitoneally once daily from P21 to P41. Behavioral tests including open field (OF), object location (OL), novel object recognition (NOR), and fear conditioning (FC) tests were performed to assess cognitive function. The number of 5-Bromo-2'- deoxyuridine positive (BrdU+) cells and BrdU+/DCX+ (doublecortin) co-labeled cells, expressions of brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeletal-associated protein (Arc), early growth response 1 (Egr-1), SIRT1, PGC-1α and FNDC5, and long-term potentiation (LTP) were evaluated in the hippocampus. Repeated exposures to sevoflurane induced deficits in OL, NOR and contextual FC tests in male but not female mice. Similarly, adult hippocampal neurogenesis, synaptic plasticity-related proteins and hippocampal LTP were impaired after repeated exposures to sevoflurane in male but not female mice, which could rescue by lactate treatment. Our study suggests that repeated neonatal exposures to sevoflurane inhibit adult hippocampal neurogenesis and induce defects of synaptic plasticity in male but not female mice, which may contribute to long-term cognitive impairment. Lactate treatment rescues these abnormalities through activation of SIRT1.

Lipopolysaccharide-induced endotoxaemia during adolescence promotes stress vulnerability in adult mice via deregulation of nuclear factor erythroid 2-related factor 2 in the medial prefrontal cortex.

Yan-Chen Chen, Yan-Hua Huang, Li Song +7 more

Sepsis is a severe inflammatory response to infection that leads to long-lasting cognitive impairment and depression after resolution. The lipopolysaccharide (LPS)-induced endotoxaemia model is a well-established model of gram-negative bacterial infection and recapitulates the clinical characteristics of sepsis. However, whether LPS-induced endotoxaemia during adolescence can modulate depressive and anxiety-like behaviours in adulthood remains unclear.

Effects of early-life zinc deficiency on learning and memory in offspring and the changes in DNA methylation patterns.

Yu-Gang Jiang, Yong-Hui Wang, Han Zhang +2 more

To investigate the effect of maternal zinc deficiency on learning and memory in offspring and the changes in DNA methylation patterns.

Effect of metformin treatment on memory and hippocampal neurogenesis decline correlated with oxidative stress induced by methotrexate in rats.

Nataya Sritawan, Kornrawee Suwannakot, Salinee Naewla +6 more

Metformin is currently used as a first-line drug to treat patients with type 2 diabetes. Previous studies have demonstrated that metformin has antioxidant properties and reduces neuroinflammation and hippocampal neuronal cell loss, which eventually improves memory. Methotrexate (MTX) is an antimetabolite chemotherapeutic agent reported to activate cognitive impairment found in many patients. Moreover, MTX negatively affects the spatial working memory, related to neurogenesis reduction in animal models. Therefore, the present study aimed to investigate the antioxidant effect of metformin on the reduction of memory and neurogenesis caused by MTX. Male Sprague-Dawley rats were divided into four groups: control, MTX, metformin, and MTX+metformin. MTX (75 mg/kg, i.v.) was administered on days 7 and 14. Rats were administered metformin (200 mg/kg, i.p.) for 14 days. Memory was determined using novel object location (NOL) and novel object recognition (NOR) tests. Furthermore, cell cycle arrest was quantified by p21 immunostaining. Levels of neuronal protein expression, scavenging enzymes activity, and malondialdehyde (MDA) level changes in the hippocampus and prefrontal cortex were investigated. Rats receiving only MTX showed memory impairment. Decreases in scavenging enzyme activity and BDNF, DCX, and Nrf2 protein expressions levels were detected in the MTX-treated rats. In addition, MTX significantly increased p21-positive cell numbers and MDA levels. However, these adverse MTX effects were counteracted by co-administration with metformin. These results demonstrate that metformin can improve memory impairments, increase BDNF, DCX and Nrf2 protein expressions and antioxidant capacities, and decrease MDA levels in MTX-treated rats.

Transplantation of gut microbiota derived from Alzheimer's disease mouse model impairs memory function and neurogenesis in C57BL/6 mice.

Namkwon Kim, Seung Ho Jeon, In Gyoung Ju +4 more

Alzheimer's disease (AD) is a neurodegenerative disease that causes memory and cognitive decline. Although many studies have attempted to clarify the causes of AD occurrence, it is not clearly understood. Recently, the emerging role of the gut microbiota in neurodegenerative diseases, including AD, has received much attention. The gut microbiota composition of AD patients and AD mouse models is different from that of healthy controls, and these changes may affect the brain environment. However, the specific mechanisms by which gut microbiota that influence memory decline are currently unclear. In this study, we performed fecal microbiota transplantation (FMT) to clarify the role of 5xFAD mouse-derived microbiota in memory decline. We observed that FMT from 5xFAD mice into normal C57BL/6 mice (5xFAD-FMT) decreased adult hippocampal neurogenesis and brain-derived neurotrophic factor expression and increased p21 expression, resulting in memory impairment. Microglia in the hippocampus of the 5xFAD-FMT mice were activated, which caused the elevation of pro-inflammatory cytokines (tumor necrosis factor-α and interleukin-1β). Moreover, we observed that pro-inflammatory cytokines increased in the colon and plasma of 5xFAD-FMT mice. The gut microbiota composition of the 5xFAD-FMT mice was different from that of the control mice or wild type-FMT mice. Collectively, 5xFAD mouse-derived microbiota decreased neurogenesis by increasing colonic inflammation, thereby contributing to memory loss. Our findings provide further evidence concerning the role of gut microbial dysbiosis in AD pathogenesis and suggest that targeting the gut microbiota may be a useful therapeutic strategy for the development of novel candidates for the treatment of AD.

Voluntary Exercise Rescues the Spatial Memory Deficit Associated With Early Life Isoflurane Exposure in Male Rats.

Gregory A Chinn, Jennifer M Sasaki Russell, Esther T Banh +2 more

Early life anesthesia exposure results in long-term cognitive deficits in rats. Environmental enrichment consisting of social housing, a stimulating environment, and voluntary exercise can rescue this deficit. We hypothesized that exercise alone is sufficient to rescue the cognitive deficit associated with perinatal anesthesia.

Effect of early postnatal exposure to valproate on neurobehavioral development and regional BDNF expression in two strains of mice.

Kevin G Bath, Tiare Pimentel

Valproate has been used for over 30years as a first-line treatment for epilepsy. In recent years, prenatal exposure to valproate has been associated with teratogenic effects, limiting its use in women that are pregnant or of childbearing age. However, despite its potential detrimental effects on development, valproate continues to be prescribed at high rates in pediatric populations in some countries. Animal models allow us to test hypotheses regarding the potential effects of postnatal valproate exposure on neurobehavioral development, as well as identify potential mechanisms mediating observed effects. Here, we tested the effect of early postnatal (P4-P11) valproate exposure (100mg/kg and 200mg/kg) on motor and affective development in two strains of mice, SVE129 and C57Bl/6N. We also assessed the effect of early valproate exposure on regional BDNF protein levels, a potential target of valproate, and mediator of neurodevelopmental outcomes. We found that early life valproate exposure led to significant motor impairments in both SVE129 and C57Bl/6N mice. Both lines of mice showed significant delays in weight gain, as well as impairments in the righting reflex (P7-8), wire hang (P17), open field (P12 and P21), and rotarod (P25 and P45) tasks. Interestingly, some of the early locomotor effects were strain- and dose-dependent. We observed no effects of valproate on early markers of anxiety-like behavior. Importantly, early life valproate exposure had significant effects on regional BDNF expression, leading to a near 50% decrease in BDNF levels in the cerebellum of both strains of mice, while not impacting hippocampal BDNF protein levels. These observations indicate that postnatal exposure to valproate may have significant, and region-specific effects, on neural and behavioral development, with specific consequences for cerebellar development and motor function.

Hippocampal Astrocyte Cultures from Adult and Aged Rats Reproduce Changes in Glial Functionality Observed in the Aging Brain.

Bruna Bellaver, Débora Guerini Souza, Diogo Onofre Souza +1 more

Astrocytes are dynamic cells that maintain brain homeostasis, regulate neurotransmitter systems, and process synaptic information, energy metabolism, antioxidant defenses, and inflammatory response. Aging is a biological process that is closely associated with hippocampal astrocyte dysfunction. In this sense, we demonstrated that hippocampal astrocytes from adult and aged Wistar rats reproduce the glial functionality alterations observed in aging by evaluating several senescence, glutamatergic, oxidative and inflammatory parameters commonly associated with the aging process. Here, we show that the p21 senescence-associated gene and classical astrocyte markers, such as glial fibrillary acidic protein (GFAP), vimentin, and actin, changed their expressions in adult and aged astrocytes. Age-dependent changes were also observed in glutamate transporters (glutamate aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1)) and glutamine synthetase immunolabeling and activity. Additionally, according to in vivo aging, astrocytes from adult and aged rats showed an increase in oxidative/nitrosative stress with mitochondrial dysfunction, an increase in RNA oxidation, NADPH oxidase (NOX) activity, superoxide levels, and inducible nitric oxide synthase (iNOS) expression levels. Changes in antioxidant defenses were also observed. Hippocampal astrocytes also displayed age-dependent inflammatory response with augmentation of proinflammatory cytokine levels, such as TNF-α, IL-1β, IL-6, IL-18, and messenger RNA (mRNA) levels of cyclo-oxygenase 2 (COX-2). Furthermore, these cells secrete neurotrophic factors, including glia-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), S100 calcium-binding protein B (S100B) protein, and transforming growth factor-β (TGF-β), which changed in an age-dependent manner. Classical signaling pathways associated with aging, such as nuclear factor erythroid-derived 2-like 2 (Nrf2), nuclear factor kappa B (NFκB), heme oxygenase-1 (HO-1), and p38 mitogen-activated protein kinase (MAPK), were also changed in adult and aged astrocytes and are probably related to the changes observed in senescence marker, glutamatergic metabolism, mitochondrial dysfunction, oxidative/nitrosative stress, antioxidant defenses, inflammatory response, and trophic factors release. Together, our results reinforce the role of hippocampal astrocytes as a target for understanding the mechanisms involved in aging and provide an innovative tool for studies of astrocyte roles in physiological and pathological aging brain.

Protective Effect of Hyperbaric Oxygen on Cognitive Impairment Induced by D-Galactose in Mice.

Xiaoyu Chen, Yaoxuan Li, Wan Chen +3 more

Memory decline is characteristic of aging and age-related neurodegenerative disorders. This study was designed to investigate the protective effect of hyperbaric oxygen (HBO) against cognitive impairment induced by D-galactose (D-gal) in mice. D-gal was intraperitoneally injected into mice daily for 8 weeks to establish the aging model. HBO was simultaneously administered once daily. The results indicate that HBO significantly reversed D-gal-induced learning and memory impairments. Studies on the potential mechanisms of this action showed that HBO significantly reduced oxidative stress by increasing superoxide dismutase, glutathione peroxidase, and catalase levels, as well as the total anti-oxidation capability, while decreasing the content of malondialdehyde, nitric oxide, and nitric oxide synthase in the hippocampal CA1 region. HBO also inhibited advanced glycation end-product formation and decreased levels of tumor necrosis factor-α and interleukin-6. Moreover, HBO significantly attenuated D-gal-induced pathological injury in the hippocampus, as well as β-amyloid protein1-42 expression and retained BDNF expression. Furthermore, HBO decreased p16, p21 and p53 gene and protein expression in the hippocampus of D-gal-treated mice. In conclusion, the protective effect of HBO against D-gal-induced cognitive impairment was mainly due to its ability to reduce oxidative damage, suppress inflammatory responses, and regulate aging-related gene expression.

Epigenetic Manipulation of Brain-derived Neurotrophic Factor Improves Memory Deficiency Induced by Neonatal Anesthesia in Rats.

Jiang Wu, Bihua Bie, Mohamed Naguib

Although neonatal exposure to anesthetic drugs is associated with memory deficiency in rodent models and possibly in pediatric patients, the underlying mechanisms remain elusive. The authors tested their hypothesis that exposure of the developing brain to anesthesia triggers epigenetic modification, involving the enhanced interaction among transcription factors (histone deacetylase 2, methyl-cytosine-phosphate-guanine-binding protein 2, and DNA methyltransferase 1) in Bdnf promoter region(s) that inhibit brain-derived neurotrophic factor (BDNF) expression, resulting in insufficient drive for local translation of synaptic mRNAs. The authors further hypothesized that noninvasive environmental enrichment (EE) will attenuate anesthesia-induced epigenetic inhibition of BDNF signaling and memory loss in rodent models.

Neurobehavioural abnormalities induced by repeated exposure of neonatal rats to sevoflurane can be aggravated by social isolation and enrichment deprivation initiated after exposure to the anaesthetic.

M Q Zhang, M H Ji, Q S Zhao +6 more

We tested the hypothesis that developmental effects of repeated neonatal exposure to sevoflurane in rats are exacerbated by stressful experiences received later in life.

Temporal manipulation of transferrin-receptor-1-dependent iron uptake identifies a sensitive period in mouse hippocampal neurodevelopment.

S J B Fretham, E S Carlson, J Wobken +3 more

Iron is a necessary substrate for neuronal function throughout the lifespan, but particularly during development. Early life iron deficiency (ID) in humans (late gestation through 2-3 yr) results in persistent cognitive and behavioral abnormalities despite iron repletion. Animal models of early life ID generated using maternal dietary iron restriction also demonstrate persistent learning and memory deficits, suggesting a critical requirement for iron during hippocampal development. Precise definition of the temporal window for this requirement has been elusive due to anemia and total body and brain ID inherent to previous dietary restriction models. To circumvent these confounds, we developed transgenic mice that express tetracycline transactivator regulated, dominant negative transferrin receptor (DNTfR1) in hippocampal neurons, disrupting TfR1 mediated iron uptake specifically in CA1 pyramidal neurons. Normal iron status was restored by doxycycline administration. We manipulated the duration of ID using this inducible model to examine long-term effects of early ID on Morris water maze learning, CA1 apical dendrite structure, and defining factors of critical periods including parvalbmin (PV) expression, perineuronal nets (PNN), and brain-derived neurotrophic factor (BDNF) expression. Ongoing ID impaired spatial memory and resulted in disorganized apical dendrite structure accompanied by altered PV and PNN expression and reduced BDNF levels. Iron repletion at P21, near the end of hippocampal dendritogenesis, restored spatial memory, dendrite structure, and critical period markers in adult mice. However, mice that remained hippocampally iron deficient until P42 continued to have spatial memory deficits, impaired CA1 apical dendrite structure, and persistent alterations in PV and PNN expression and reduced BDNF despite iron repletion. Together, these findings demonstrate that hippocampal iron availability is necessary between P21 and P42 for development of normal spatial learning and memory, and that these effects may reflect disruption of critical period closure by early life ID.

Early exercise promotes positive hippocampal plasticity and improves spatial memory in the adult life of rats.

Sérgio Gomes da Silva, Nicolas Unsain, Daniel Hugo Mascó +9 more

There is a great deal of evidence showing the capacity of physical exercise to enhance cognitive function, reduce anxiety and depression, and protect the brain against neurodegenerative disorders. Although the effects of exercise are well documented in the mature brain, the influence of exercise in the developing brain has been poorly explored. Therefore, we investigated the morphological and functional hippocampal changes in adult rats submitted to daily treadmill exercise during the adolescent period. Male Wistar rats aged 21 postnatal days old (P21) were divided into two groups: exercise and control. Animals in the exercise group were submitted to daily exercise on the treadmill between P21 and P60. Running time and speed gradually increased over this period, reaching a maximum of 18 m/min for 60 min. After the aerobic exercise program (P60), histological and behavioral (water maze) analyses were performed. The results show that early-life exercise increased mossy fibers density and hippocampal expression of brain-derived neurotrophic factor and its receptor tropomyosin-related kinase B, improved spatial learning and memory, and enhanced capacity to evoke spatial memories in later stages (when measured at P96). It is important to point out that while physical exercise induces hippocampal plasticity, degenerative effects could appear in undue conditions of physical or psychological stress. In this regard, we also showed that the exercise protocol used here did not induce inflammatory response and degenerating neurons in the hippocampal formation of developing rats. Our findings demonstrate that physical exercise during postnatal development results in positive changes for the hippocampal formation, both in structure and function.

Perinatal undernutrition modifies cell proliferation and brain-derived neurotrophic factor levels during critical time-windows for hypothalamic and hippocampal development in the male rat.

B Coupé, I Dutriez-Casteloot, C Breton +7 more

Maternal perinatal undernutrition (MPU) modifies the activity of the hypothalamic-pituitary-adrenal axis and sensitises to the development of metabolic and cognitive adult diseases. Because the hypothalamus and hippocampus are involved in the regulation of neuroendocrine activity, energy metabolism and cognition, we hypothesised that a maternal 50% food restriction (FR50) from day 14 of pregnancy (E14) until postnatal day 21 (P21) would affect the development of these structures in male rat offspring. Protein and mRNA levels of brain-derived neurotrophic factor (BDNF) and cell proliferation [analysed by 5-bromodeoxyuridine (BrdU) incorporation] were compared in both control and FR50 rats from E21 to P22. Although the pattern of the evolution of BDNF concentration and cell proliferation throughout development was not strikingly different between groups, several disturbances at specific developmental stages were observed. FR50 rats exhibited a delayed increase of hippocampal BDNF content whereas, in the hypothalamus, BDNF level was augmented from E21 to P14 and associated, at this latter stage, with an increased mRNA expression of TRkB-T2. In both groups, a correlation between BDNF content and the number of BrdU positive cells was noted in the dentate gyrus, whereas opposite variations were observed in CA1, CA2 and CA3 layers, and in the arcuate and ventromedial nuclei. In the hippocampus, P15-FR50 rats showed an increased number of BrdU positive cells in all regions, whereas, at P22, a decrease was observed in the CA2. In the hypothalamus, between E21 and P8, MPU increases the number of BrdU positive cells in all regions analysed and, until P15, marked differences were noticed in the median eminence, the paraventricular nucleus and the arcuate nucleus. Taken together, the results obtained in the present study show that MPU changes the time course of production of BDNF and cell proliferation in specific hippocampal and hypothalamic areas during sensitive developmental windows, suggesting that these early perinatal modifications may have long-lasting consequences.

The effects of adulthood olanzapine treatment on cognitive performance and neurotrophic factor content in male and female rats neonatally treated with quinpirole.

Stephanie K Thacker, Marla K Perna, Jeffery J Ward +4 more

Male and female Sprague-Dawley rats were administered quinpirole (1 mg/kg, i.p.) or saline once daily from postnatal day (P)1 to P21. This drug treatment has been shown to produce long-term priming of the D2 receptor. Beginning on P62, rats were administered the atypical antipsychotic olanzapine (2.5 mg/kg) or saline twice daily (i.p.) for 28 days. One day after olanzapine treatment ceased, rats were tested on the place and match-to-place versions of the Morris water maze (MWM) for seven consecutive days. Dopamine D2 receptor priming was verified through a yawning behavioural test, a D2 receptor-mediated event, before olanzapine was administered as well as after olanzapine treatment and behavioural testing were complete. Results showed that neonatal quinpirole treatment induced D2 priming that was eliminated by olanzapine treatment. On the MWM place version, D2-primed rats demonstrated a significant impairment that was eliminated by olanzapine treatment, but olanzapine treatment to animals neonatally treated with saline produced a significant deficit on the place version of the MWM. There were no significant deficits on the match-to-place version. Brain tissue analyses revealed that neonatal quinpirole treatment produced a significant decrease in hippocampal NGF, BDNF and ChAT that was eliminated by olanzapine treatment. Neonatal quinpirole treatment produced a significant decrease in BDNF and ChAT in the frontal cortex that was unaffected by olanzapine treatment. These results show that olanzapine eliminates D2 receptor priming and cognitive impairment and also alleviates decreases in neurotrophins and acetylcholinergic markers produced by D2 priming in the hippocampus.

Neonatal quinpirole treatment impairs Morris water task performance in early postweanling rats: relationship to increases in corticosterone and decreases in neurotrophic factors.

Russell W Brown, Timothy J Flanigan, Kimberly N Thompson +3 more

Past studies from this laboratory have shown that quinpirole administration from postnatal day (P) 1-21 produces persistent supersensitization of the dopamine D2 receptor that persists throughout the animal's lifetime.

Activity-dependent regulation of genes implicated in X-linked non-specific mental retardation.

B Boda, C Mas, D Muller

X-linked forms of non-specific mental retardation are complex disorders, for which mutations in several genes have recently been identified. These include OPHN1, GDI1, PAK3, IL1RAPL, TM4SF2, FMR2 and RSK2. To investigate the mechanisms through which alterations of these gene products could result in cognitive impairment, we analyzed their expression using quantitative PCR technique in two in vitro models of activity-dependent gene regulation: kainate-induced seizures and long-term synaptic potentiation (LTP). We found that the level of expression of four genes, PAK3, IL1RAPL, RSK2 and TM4SF2, was significantly up-regulated following kainate treatment. Furthermore we observed a significant increase in mRNA levels of PAK3 and IL1RAPL following LTP induction. These results suggest a possible role for these four genes in activity-dependent brain plasticity.