Acceleration of age-related learning and memory decline in middle-aged CD-1 mice due to maternal exposure to lipopolysaccharide during late pregnancy

Previous studies have shown that inflammation process involves pathogenesis of Alzheimer's disease (AD). But, the natural AD model of inflammation has not been obtained yet. In the present study, CD-1 mothers intraperitoneally received a 50 μg/kg lipopolysaccharide (LPS) or normal saline daily during gestational days 15-17. Body weight of the offspring was recorded at ages of 4-33 weeks. A different battery of behavioral tasks was, respectively, completed at ages of 35, 290 and 400 days. The results showed that there was no significant difference in body weight between LPS-treated and control mice during ages of 4-33 weeks. LPS-treated offspring had similar anxiety and locomotor behaviors, and spatial ability of learning and memory at the age of 35 days compared to the controls. At an age of 290 days, the LPS-treated offspring had similar sensorimotor ability, locomotor activity and anxiety, species-typical behaviors, and spatial ability of learning and memory. At an age of 400 days, there were similar sensorimotor ability, locomotor activity and anxiety between the LPS-treated offspring and controls. However, there were impaired species-typical behaviors, and spatial and non-spatial abilities of learning and memory in the LPS-treated offspring. Our results suggested that maternal exposure to LPS in adequate dose in late gestation can deliver term offspring which experience a normal duration of development and maturation, and an accelerated aged-related impairment in memory (spatial and non-spatial) and species-typical behaviors in middle-aged. These meet with the criteria of AD model in behaviors.     

Effects of exposure period and nutrition on the developmental neurotoxicity of anticonvulsants in rats: short and long-term effects

The results of three experiments on the functional neuroteratogenicity of anticonvulsants in rats are presented. Two of the experiments have been reported previously and are reviewed here, while the third experiment is presented here for the first time. The first experiment examined prenatal phenytoin (200 mg/kg), trimethadione (250 mg/kg), and phenobarbital (80 mg/kg) for critical period effects by exposing separate groups of rats to the drugs or to vehicle on embryonic (E) days 7-10, 11-14, or 15-18. Phenytoin produced effects in the E11-14 offspring, but few effects in the E15-18 offspring, and almost no effects in the E7-10 offspring. Phenytoin's E11-14 effects in the offspring were increased pivoting, delayed swimming ontogeny, hyperactivity, impaired water maze learning, and impaired passive avoidance retention. The second experiment looked for phenytoin's long-term effects. Phenytoin-exposed offspring administered 200 mg/kg on E7-18 exhibited numerous postnatal dysfunctions, including water maze learning deficits that persisted to beyond 501 days of age. The learning deficits were neither increased nor decreased in severity at this age compared to those seen in littermates tested at 50 days of age. The third experiment assessed the role of manganese in counteracting phenytoin-induced postnatal dysfunction and the possible confounding effects of maternal undernutrition associated with the drug's administration. The typical pattern of phenytoin-induced behavioral effects was observed in rat offspring. The results demonstrated that undernutrition was not a confound, since pair-feeding and pair-watering controls did not diminish the phenytoin-induced dysfunction in the offspring. Also, administration of a manganese supplementation (200 ppm in the drinking water) during gestation did not significantly alter the pattern of phenytoin-induced postnatal effects.     

Pervasive hyperactivity and long-term learning impairments in rats with induced micrencephaly from prenatal exposure to methylazoxymethanol

Pregnant Long-Evans rats were given a single i.p. injection of 30 mg/kg of methylazoxymethanol (MAM) acetate or saline on day 14 of gestation (vaginal plug = day 0). All litters were reduced to 8 at birth and were reared by their biological dams. Between 49-192 days of age all offspring were examined on open-field, figure-8 (at two different ages), and hole-board tests of activity, as well as passive avoidance and Biel water maze tests of learning (also at two different ages). The MAM offspring showed no increase in mortality, but weighed less than controls, a difference that remained relatively constant throughout the experiment. At 204-215 days of age the MAM offspring were confirmed to be micrencephalic, a known effect of this drug at this dose and exposure period. On all tests of activity the MAM offspring were markedly hyperactive. The female progeny also exhibited a pronounced impairment of normal activity habituation patterns. The MAM males, however, showed a marked impairment of passive avoidance performance, while the females did not. At 2 months of age the MAM offspring also showed a pronounced deficit in learning a water maze. This maze deficit had not abated when tested again at 6 months of age. The MAM induced brain and behavioral abnormalities provide a potentially useful animal model of congenital micrencephaly and associated mental retardation.     

Studies on noradrenergic alterations in relation to early phenobarbital-induced behavioral changes

Mice were exposed to phenobarbital prenatally (B offspring) by feeding their mother 3 g/kg phenobarbital in milled food on gestation days 9-18; control dams received unadulterated milled food. At age 50 days, B offspring had fewer fluorescing noradrenergic (NE) cells in the locus coeruleus than control (P less than 0.001). Hippocampal NE levels were also lower in B than in control offspring, while the cerebellar NE levels of B offspring remained normal. Since B offspring are known to be deficient in their hippocampal eight-arm maze behavior, an attempt was made to reverse the behavioral deficit by transplantation of normal embryonic locus coeruleus NE cells into the impaired hippocampus of B offspring. While sham and NE-transplanted controls needed approximately 2 days to reach criterion in the maze, sham-transplanted B required approximately 5 days to reach criterion (P less than 0.01). The scores of NE-transplanted B mice were similar to B and differed significantly from control (P less than 0.01). Thus, it appears that the hippocampal behavioral deficits studied may not be related to alterations in locus coeruleus-hippocampal NE innervations.     

Maternal ethanol consumption: binding of L-glutamate to synaptic membranes from whole brain, cortices, and cerebella of offspring

We examined the influence of chronic maternal ethanol consumption on the Na+- and Ca2+-independent binding of L-glutamate to synaptic plasma membranes from whole brain as well as from cortices and cerebella of developing offspring. The maximum specific binding (Bmax) of L-glutamate to the Na+- and Ca2+-independent binding sites in synaptic plasma membranes of brain peaked at 17 days of age in the offspring of both control and ethanol-fed rats, although at that age there were significantly fewer binding sites in the brains of the offspring of ethanol-fed rats. The regional localization of this deficit is not now known. However, it appears that one major glutamatergic region (the cortex) does not reflect the transient deficiency of L-glutamate sites in brain. In fact, the concentration of L-glutamate binding sites in cortical synaptic plasma membranes was significantly increased in the 20-day-old offspring of ethanol-fed rats. In contrast to the cortex, binding to cerebellar synaptic plasma membranes was comparable in 20-day-old offspring of control and ethanol-fed rats. Despite transient alterations in the concentrations of L-glutamate binding sites in brain and synaptic plasma membranes, the affinity of the sites for L-glutamate (Kd) was consistently normal in the 14- to 26-day-old offspring of ethanol-fed rats.     

Prenatal Stress Increases the Hypothalamo-Pituitary-Adrenal Axis Response in Young and Adult Rats

Prenatal stress is considered as an early epigenetic factor able to induce long-lasting alterations in brain structures and functions. It is still unclear whether prenatal stress can induce long-lasting modifications in the hypothalamo-pituitary-adrenal axis. To test this possibility the effects of restraint stress in pregnant rats during the third week of gestation were investigated in the functional properties of the hypothalamo-pituitary-adrenal axis and hippocampal type I and type II corticosteroid receptors in the male offspring at 3, 21 and 90 days of age. Plasma corticosterone was significantly elevated in prenatally-stressed rats at 3 and 21 days after exposure to novelty. At 90 days of age, prenatally-stressed rats showed a longer duration of corticosterone secretion after exposure to novelty. No change was observed for type I and type II receptor densities 3 days after birth, but both receptor subtypes were decreased in the hippocampus of prenatally-stressed offspring at 21 and 90 days of life. These findings suggest that prenatal stress produces long term changes in the hypothalamo-pituitary-adrenal axis in the offspring.     

Maternal infection during late pregnancy increases anxiety- and depression-like behaviors with increasing age in male offspring

Scientific reports suggest that the exposure to long-term stressors throughout or during late gestation increase anxiety- and depression-like behaviors of offspring in their later life. Moreover, several studies concluded that increasing age correlates with increased anxiety behaviors in humans and rodents. In the present study, we assessed the effects of prenatally administration of equal lipopolysaccharide (LPS) doses in various points of late gestation (days 15, 16, and 17) period, on neuroendocrine and immunological responses of pregnant mice, and subsequent long-lasting consequences of anxiety and depression with increasing age in male offspring at postnatal days (PD) 40 and 80. Four hours after the LPS injection, levels of corticosterone (COR) and pro-inflammatory cytokines (PIC) in pregnant mice, as compared to the control dams, were increased significantly. Furthermore, maternal inflammation raised the levels of COR, anxiety- and depression-like behaviors with increasing age in male offspring in comparison with saline male offspring. These data support other studies demonstrating that maternal stress increases the levels of anxiety and depression in offspring. Additionally, our data confirm other findings indicating that increasing age correlates with increased anxiety or depression behaviors in humans and rodents. Findings of this study suggest that time course of an inflammation response or stressor application during various stages of gestation and ages of offspring are important factors for assessing neuropsychiatric disorders.     

Effects of prenatal exposure to cocaine or related drugs on rat developmental and neurological indices

Although increasing numbers of infants born to cocaine abusing mothers are of grave concern, little is known of the long term development of these children. To determine the long term effects of cocaine on a developing fetus, gravid rats were dosed SC throughout pregnancy with either saline, amfonelic acid (AFA, 1.5 mg/kg), amitriptyline (10 mg/kg) or cocaine (15 mg/kg b.i.d.) and the male pups fostered by surrogate rats. Compared to saline offspring, cocaine- and amitriptyline-exposed litters were underweight at birth, but there were no differences between groups at 15 or 30 days of age. There were more birth defects and stillbirths in cocaine-exposed offspring, however, there were no differences in male/female sex ratios or litter size in any group. Number of days to righting reflex was delayed in the cocaine-exposed group, but there were no changes in time to eye opening. Cocaine- and amitriptyline-exposed pups were hyperactive at 30 days of age, though no differences were found in an initial 15-min exploration period. Only the AFA-exposed offspring were hyperactive at 60 days postnatal. Since cocaine and amitriptyline decreased birth weights, this effect may be related to the nondopaminergic effects of cocaine. These data demonstrate that cocaine exposure in utero at relevant doses can affect neonatal outcome and long term development in rat offspring.     

Effect of prenatal and neonatal chronic exposure to phenobarbital on central and peripheral benzodiazepine receptors

Phenobarbital (PhB) was administered to pregnant mice during days 9-18 of gestation. [3H]Muscimol binding to cerebellum, [3H]flunitrazepam binding to cerebellum and olfactory bulb, and [3H]PK 11195 binding to olfactory bulb, heart and kidney were assay in the of offspring at 22 and 50 days of age. The chronic prenatal administration of PhB did not affect either gamma-aminobutyric acid (GABA) receptors, central benzodiazepine receptors (CBR), or peripheral benzodiazepine binding sites (PBS) in these tissues. In the next stage of the study, we investigated a possible modulatory effect of chronic postnatal PhB treatment during days 2-21 of age on the same receptors measured at 22 and 50 days of age. PhB exposure of neonates resulted in a significant down-regulation of GABA receptors and CBR in the cerebellum and of PBS in the heart. The effects were demonstrated on day 22 of age and were undetectable by day 50 of age. CBR at the olfactory bulb and PBS at the olfactory bulb and kidney were not altered by the drug treatment. It is concluded that in utero exposure to PhB does not affect benzodiazepine receptor ontogenesis, and the effects of postnatal treatment are transitory only.     

Glycoproteins and proteins in an axolemma-enriched fraction and myelin from developing rats: effect of maternal ethanol consumption

The present study examined proteins and glycoproteins from an axolemma-enriched fraction from the developing offspring of female rats that were pair-fed control or 6.6% (50 g/liter) ethanol liquid diets on a chronic basis prior to parturition. In addition, this study examined the synthesis of the major CNS myelin-associated glycoprotein (MAG) as an index of myelin maturation. The results of the latter study demonstrated normal MAG maturation in ethanol-treated rats. However, a significant decrease in the proportion of radioactivity associated with MAG was found in the developing offspring of ethanol-treated rats. The major axolemmal proteins from 32-day rats included those with molecular weights of 105 K, 81 K, 62 K, 55 K, 52 K, 36 K, and 33 K. Major peaks of radioactivity were associated with fucosylated axolemmal glycoproteins with apparent molecular weights of 150 K, 130 K, 85 K, 76 K, and 64 K. Several development-related changes in the protein composition of axolemma-enriched fractions were observed in control animals. Between 22 and 32 days of age control rats exhibited a significant (P less than .05) decrease in the proportion of axolemmal proteins that had apparent molecular weights of 150 K, 105 K, and 62 K. A development-related decrease in the 105 K axolemma-associated protein did not occur during the 22-32 day age period in the offspring of ethanol-treated animals. At 22 days the proportion of this 105 K protein in affected offspring was significantly (P less than .05) less than that in age-matched control rats and comparable to that in 32-day control rats. The relative distribution of radioactivity among fucosylated axolemmal glycoproteins also changed significantly between 22 and 32 days of age. These changes include a decrease in the proportion of radioactivity associated with the 110 K, 55 K, and 52 K fucosylated glycoproteins and an increase in the proportion of radioactivity associated with the 85 K and 67 K glycoproteins. Several small, but significant (P less than .05) alterations were found associated with glycoproteins in an axolemma-enriched fraction from 22- and 32-day ethanol-treated rats.     

Long-term behavioral and electrophysiological changes associated with lead exposure at different stages of brain development in the rat

The present investigation was conducted to assess the behavioral and electrophysiological impairments exhibited by adult male rats as a function of the developmental stage during which lead exposure occurred. Dams were given either a lead acetate (0.3%) or a control drinking solution during days 16-23 of gestation, days 1-8 or days 9-16 of nursing. The temporal and spatial activity patterns exhibited by gestationally exposed offspring in the open field between 42-45 days of age was distinguished from all other groups by the absence of a decrement in peripheral field activity across days and by increased exploration of the center field. Although open field activity proved sensitive to the timing of lead exposure, power spectral analyses of hippocampal and cortical EEG activity at 70-72 days of age revealed that lead selectively depressed 6-7 Hz energy in the hippocampus, independent of the developmental stage of exposure; cortical EEG and other hippocampal theta frequencies were unaffected. The differential sensitivity of open field activity and select hippocampal theta frequencies to the timing of lead administration suggests that the identification of toxic consequences depends on the function assessed and the developmental stage during which lead exposure occurred.     

孕期脉冲电磁场与子代大鼠海马神经干细胞增殖及巢蛋白的表达

背景：电磁场能对机体产生影响,尤其对于神经系统。研究已发现了脉冲电磁场对神经干细胞的影响。 目的：观察产前脉冲电磁场对子代大鼠海马神经干细胞增殖及巢蛋白表达的影响。 方法：选用体质量240~260 g SD雌性大鼠为母鼠,随机分为2组。对照组孕期不给任何干预;产前脉冲电磁场组于怀孕14~20 d,给予脉冲电磁场刺激,3次/d,10 min/次。于雌、雄仔鼠1月龄时每组随机各组6只行脑组织切片,应用免疫组织化学方法检测海马中Nestin蛋白和Brdu阳性细胞的表达。 结果与结论：产前脉冲电磁场组雌雄子代海马Nestin蛋白和Brdu阳性细胞表达均较对照组多(P < 0.001),,且产前脉冲电磁场组雌性子代海马Nestin蛋白和Brdu阳性细胞表达较雄性子代的多,差异具有非常显著性意义(P < 0.001),对照组雌雄子代之间差异无显著性意义(P > 0.05)。结果表明,产前脉冲磁场能引起子代海马神经干细胞数增多及增殖能力增加,这可能是机体对产前脉冲电磁场所致脑损伤的代偿性反应。     

The synthesis of myelin and brain subcellular membrane proteins in the offspring of rats fed ethanol during pregnancy

Pregnant Long-Evans rats received either: (1) liquid diet containing 5.15% ethanol; (2) liquid diet pair fed to (1) for total calories; or (3) liquid diet ad libitum. These special diets were administered from the 5th through the 18th days of gestation. Dams received standard laboratory chow and water ad libitum before and after the test interval. Additional dams received standard chow and water throughout the study. Birth weights of offspring in the ethanol group were lower than for offspring of the pair-fed or control groups, and their subsequent growth lagged behind the other groups. Neonate deaths in the ethanol group outnumbered other deaths. Eye opening was delayed, and brain weights appeared low from 16 to 30 days postnatal age. The onset of myelin synthesis was delayed by several days; however, by 30 days of age, the rate of myelin synthesis and net accumulation was comparable to the offspring of pairfed controls. Thus, the effect of ethanol on brain myelination in the offspring of subject females appears as a delay in myelin initiation and cannot be fully explained by caloric undernourishment. An unexpected observation involved offspring of females fed standard chow throughout the study. The brain myelin concentration in this group was lower than for any of the other groups, which may relate to the higher fat content of the liquids diets and/or the comparatively slow weight gain of pregnant rats on standard chow.     

Thiamine deficiency encephalopathy in the developing rat

The body and brain growth of the offspring of rats fed a low-thiamine diet from the 14th day of pregnancy was drastically impaired and characteristic neurological signs appeared by 25 days of age. The normal developmental increase in brain transketolase activity, a thiamine-dependent enzyme of the pentose phosphate pathway, occured between 5 and approximately 18 days of age. During this same interval, enzyme activity of the thiamine deficient group declined markedly and by 25 days of age enzyme values were depressed by 73% compared to controls. The pair-fed control offspring, which were markedly undernourished as a result of the anorexia accompanying dietary thiamine deficiency, showed an essentially normal developmental increase in transketolase activity. Of the brain regions, which included those particularly sensitive to thiamine deprivation, transketolase activity was depleted by 85% in the cerebellum, 77% in the brain stem and 68% in the diencephalon of the deficient offspring. In contrast to the developing young, the deficient mothers remained asymptomatic and brain transketolase activity declined by only 20% even after 5 weeks on a low-thiamine diet. Changes in cerebral nucleic acid were a result of undernutrition. The relationship of the altered transketolase activity to the neurological disorder is discussed.     

Fetal ethanol exposure diminishes hippocampal beta-adrenergic receptor density while sparing muscarinic receptors during development

Because of ostensible effects of fetal exposure to ethanol on cardiac and memory functions, beta-adrenergic and muscarinic receptor binding were surveyed in hippocampus and heart in 8- and 17-day-old rat pups. Pregnant, multiparous rats were intubated with either 6 g/kg ethanol or isocaloric dextrose twice daily from gestational days 10-16. At birth, offspring were fostered to untreated mothers. Pups exposed to ethanol had diminished birth weights, although there was no difference in the amount of weight gain by ethanol and control dams during gestation, nor in litter size. Ethanol pups remained smaller than control pups, but this difference was significant only until 8 days of age. At 17 days of age, ethanol pups had fewer hippocampal beta-adrenergic receptors than age-matched controls; muscarinic receptors and CA1 cell densities were not disparate. Parallel studies suggested that approximately 50% of the hippocampal beta-adrenergic receptors in 8-day-olds were of the beta 1 and beta 2 subtypes, while by 17 days of age approximately 70% of the receptors were beta 1. There was an ontogenetic increment in both beta-adrenergic and muscarinic binding from 8 to 17 days of age in hippocampus. No differences between age or drug groups were found in the binding measures in heart tissue. The present findings indicate that fetal ethanol treatment affects developmental measures and beta-adrenergic receptors in the hippocampus in a quasi-selective manner, but not hippocampal CA1-cell density.     

Prenatal caffeine causes long lasting behavioral and neurochemical changes

The effects of prenatal exposure to caffeine were studied on later physical development, behavior and brain neurochemistry. Daily doses (150, 300 or 450 mg/L) of caffeine were given to rat dams during the last week of pregnancy. Prenatal caffeine exposure resulted in a number of behavioral and neurochemical changes in the offspring which were long lasting and dose related. The low dose (150 mg/L) of prenatal caffeine caused hyperactivity in an open-field. The high dose of caffeine caused learning disabilities in complex visual and auditory discrimination learning paradigms while simple motor learning or a spatial orientation task were not affected. Both male and female offspring showed some behavioral effects of caffeine exposure. The medium and high doses of caffeine resulted in weight gain that was observable as early as 35 days of age and increased progressively with age. This weight gain was associated with increased food intake. The neurochemical studies carried out at 2-3 months of age revealed an increase in choline uptake in hippocampus, mainly in the animals treated with the lower doses of caffeine and higher protein concentration (microgram/mg wet tissue) in the cortex or hippocampus of offspring exposed to the higher doses of caffeine. At 15 months of age, choline uptake in the frontal cortex was significantly reduced in the animals prenatally exposed to the 300 and 450 mg/L dose.     

Release of [3H]norepinephrine: alteration by early developmental exposure to diazepam

The effect of prenatal exposure to diazepam (over gestational days 13-20) on the release of tritiated norepinephrine [( 3H]NE) from selected brain regions was analyzed to determine mechanisms whereby such exposure could disrupt functioning in specific NE neurons, as previously observed. Pregnant rats were administered diazepam (DZ) once daily at doses of 1.0, 2.5 or 10.0 mg/kg and the offspring studied as adults at 70-90 days of age and during development at 14, 21, 35 and 56 days of age. Release of [3H]NE was measured during in vitro incubation using 25 mM potassium as the depolarizing stimulus. As noted previously, prenatal exposure to DZ induced an effect only on NE neurons innervating the hypothalamus, sparing the NE innervation to the hippocampus and cerebellum. Prenatal exposure to DZ had no effect on the depolarized release of [3H]NE in the hypothalamus until after 35 days of age, a developmental pattern previously observed with respect to endogenous NE levels. In adult rat offspring, however, the depolarization-induced release of [3H]NE from the hypothalamus decreased 28%, 32% and 64% (relative to uninjected control values) in animals prenatally exposed to DZ at 1.0, 2.5 or 10 mg/kg/day respectively. Concurrent exposure of the pregnant dam to benzodiazepine antagonists (Ro 15-1788 or ethyl-beta-carboline-3-carboxylate) prevented the effects of DZ (2.5 mg/kg/day) on [3H]NE release, demonstrating again the importance of the benzodiazepine binding site to the effects induced by the early DZ exposure. The initial accumulation of the [3H]NE was not altered by the prenatal exposure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of litter size, sex and periconceptional ewe nutrition on side preference and cognitive flexibility in the offspring

Maternal undernutrition during pregnancy alters the physiology, behaviour and cognitive abilities of the offspring in sheep. Undernutrition restricted to the time around conception alters the physiology of the offspring, but effects on the behaviour and cognitive abilities are unknown. We studied the effects of mild periconceptional undernutrition in sheep on side preference and cognitive flexibility in the offspring. Ewes were well fed (controls) or mildly undernourished from 60 days before until 30 days after mating (PCUN; 10–15% body weight reduction). Offspring were evaluated at 4 and 18 months of age in a left–right choice maze using social and feeding motivation as rewards. We determined side preference, and assessed cognitive flexibility as the ability to improve runs required to reach criterion during two reversal learning episodes.Side preference in the PCUN offspring was close to neutrality in singleton males (p ≤ 0.05) and twin females (p ≤ 0.05) at 4 but not 18 months of age. Twin offspring tended to be more likely to change side preference between 4 and 18 months (p = 0.07). Performance on reversal learning was similar in PCUN and control offspring, but speed of learning improved faster in female than in male lambs (p ≤ 0.05) at 4 but not 18 months of age. These findings suggest that mild periconceptional undernutrition in sheep can alter behavioural laterality of the offspring, and that singleton/twin status, sex and postnatal age are all important factors to consider in evaluating the effects of prenatal insults on postnatal behaviour.     

环境富集对孕期应激子代青年期大鼠海马突触损害的影响

Environmental enrichment attenuates hippocampal synaptic injury induced by prenatal stress in offspring. However, the influence of hippocampal synaptic changes and regional differences in prenatal stress remains poorly understood. The present study induced stress in Sprague Dawley rats, which were at gestational age 13-19 days. Following weaning, the offspring were raised in an enriched environment to establish models of stress + enriched environment. Dendritic spine density and synaptophysin expression were detected in hippocampal neurons using Golgi staining and western blot analysis, respectively. Results showed that enriched environment increased dendritic spine density of apical dendrites in CA1 pyramidal cells and basal dendrites of granular cells in the outer layer of the dentate gyrus. In addition, hippocampal synaptophysin expression increased and the effects of prenatal stress on neuronal dendritic spines were reversed in adolescence.     

The stamp of ancestry: roots of behavioral and neuronal impairment in adulthood

Exposure of pregnant animals to noxious conditions affects neuronal function in the offspring. However, exposure or treatment of the maternal animal during pregnancy affects both ancestor and offspring. In the present study, female CD-1 mice were repetitively treated with 3-nitropropionate (3-np), a selective inhibitor of succinic dehydrogenase, exclusively prior to mating. Clinically, mice appeared normal during treatment. Five days after cessation of treatment animals were mated with control male animals. At 4 months of age spatial learning, LTP, NADH autofluorescence, and hypoxic tolerance were alike in controls and the offspring of treated female ancestors. However, an additional metabolic challenge in the offspring unmasks impairment of spatial learning, diminution of long-term potentiation (LTP), an altered protein microenvironment of mitochondrial enzymes, and reduced hypoxic tolerance. We conclude that the exposure of maternal ancestors to subclinical repetitive impairment of oxidative phosphorylation fosters impairment of behavior and neuronal function in the adult offspring, becoming apparent only on additional challenge. This finding may ultimately help to understand the causes of neuronal impairment or even neuropsychiatric disease in old age.