Prenatal stress on the kinetic properties of Ca2+ and K+ channels in offspring hippocampal CA3 pyramidal neurons

Prenatal stress is known to cause neuronal loss and oxidative damage in the hippocampus of offspring rats. To further understand the mechanisms, the present study was undertaken to investigate the effects of prenatal stress on the kinetic properties of high-voltage-activated (HVA) Ca(2+) and K(+) channels in freshly isolated hippocampal CA3 pyramidal neurons of offspring rats. Pregnant rats in the prenatal stress group were exposed to restraint stress on days 14-20 of pregnancy three times daily for 45 min. The patch clamp technique was employed to record HVA Ca(2+) and K(+) channel currents. Prenatal stress significantly increased HVA Ca(2+) channel disturbance including the maximal average HVA calcium peak current amplitude (-576.52+/-7.03 pA in control group and -702.05+/-6.82 pA in prenatal stress group, p<0.01), the maximal average HVA Ca(2+) current density (-40.89+/-0.31 pA/pF in control group and -49.44+/-0.37 pA/pF in prenatal stress group, p<0.01), and the maximal average integral current of the HVA Ca(2+) channel (106.81+/-4.20 nA ms in control group and 133.49+/-4.59 nA ms in prenatal stress group, p<0.01). The current-voltage relationship and conductance--voltage relationship of HVA Ca(2+) channels and potassium channels in offspring CA3 neurons were not affected by prenatal stress. These data suggest that exposure of animals to stressful experience during pregnancy can exert effects on calcium ion channels of offspring hippocampal neurons and that the calcium channel disturbance may play a role in prenatal stress-induced neuronal loss and oxidative damage in offspring brain.     

The effects of prenatal stress on expression of CaMK-II and L-Ca2+ channel in offspring hippocampus

The purpose of the present study was to characterize the expressions of phosphorylated Ca(2+)/calmodulin-dependent protein kinase II (p-CaMK-II), total CaMK-II, and L-type Ca(2+) channel in offspring hippocampus that was induced by prenatal restraint stress. Pregnant rats were divided into two groups: the control group and the prenatal stress (PNS) group. Pregnant rats in the PNS group were exposed to restraint stress on day 14-20 of pregnancy three times daily for 45 min. Adult offspring rats were used in this study. The results demonstrated that prenatal restraint stress induced a significant increase in the expression of p-CaMK-II, total CaMK-II, and L-Ca(2+) channel by western blot analysis in offspring hippocampus. The immunohistochemistry results revealed that PNS increased the expressions of CaMK-II and L-Ca(2+) channel in the hippocampal CA3 of offspring rats. These data suggest that PNS can have long-term neuronal effects within hippocampal structure involved in the feedback mechanisms of the hypothalamo-pituitary-adrenal axis.     

Neurotoxic Effects of Methamphetamine on Rat Hippocampus Pyramidal Neurons

Methamphetamine (MAP) is known to alter behavior and cause deficits in learning and memory. While the major site of action of MAP is on mesolimbic dopaminergic pathways, the effects on learning and memory raise the possibility of important actions in the hippocampus. We have studied electrophysiologic and morphologic effects of MAP in the CA1 region of hippocampus from young male rats chronically exposed to MAP, male rats exposed during gestation only and the effects of bath perfusion of MAP onto brain slices from control rats. Pyramidal neurons in brain slices from chronically exposed rats had reduced membrane potential and membrane resistance. Long-term potentiation (LTP) was reduced as compared to control, but when MAP was acutely perfused over control slices the amplitude of LTP was increased. LTP in young adult animals that had been gestationally exposed to MAP showed reduced LTP as compared to controls. Morphologically CA1 pyramidal neurons in chronically exposed animals showed a high prevalence of extensive blebbing of dendrites. We conclude that the NMDA receptor and the process of LTP are also targets of MAP dysfunction, at least in the hippocampus.     

Prenatal stress causes dendritic atrophy of pyramidal neurons in hippocampal CA3 region by glutamate in offspring rats

A substantial number of human epidemiological data, as well as experimental studies, suggest that adverse maternal stress during gestation is involved in abnormal behavior, mental, and cognition disorder in offspring. To explore the effect of prenatal stress (PS) on hippocampal neurons, in this study, we observed the dendritic field of pyramidal neurons in hippocampal CA3, examined the concentration of glutamate (Glu), and detected the expression of synaptotagmin‐1 (Syt‐1) and N‐methyl‐D ‐aspartate receptor 1 (NR1) in hippocampus of juvenile female offspring rats. Pregnant rats were divided into two groups: control group (CON) and PS group. Female offspring rats used were 30‐day old. The total length of the apical dendrites of pyramidal neurons in hippocampal CA3 of offspring was significantly shorter in PS than that in CON (p < 0.01). The number of branch points of the apical dendrites of pyramidal neurons in hippocampal CA3 of offspring was significantly less in PS (p < 0.01). PS offspring had a higher concentration of hippocampal Glu compared with CON (p < 0.05). PS offspring displayed increased expression of Syt‐1 and decreased NR1 in hippocampus compared with CON (p < 0.001 and p < 0.01, respectively). The expression of NR1 in different hippocampus subfields of offspring was significantly decreased in PS than that in CON (p < 0.05‐0.01). This study shows that PS increases the Glu in hippocampus and causes apical dendritic atrophy of pyramidal neurons of hippocampal CA3 in offspring rats. The decline of NR1 in hippocampus may be an adaptive response to the increased Glu. © 2009 Wiley Periodicals, Inc. Develop Neurobiol, 2010     

Anxiety induced by prenatal stress is associated with suppression of hippocampal genes involved in synaptic function

Exposure of pregnant women or animals to stress during a critical period of foetal brain development increases the likelihood of anxiety, depression and learning deficits that are associated with structural alterations in the offspring hippocampus. In this study, we report the effect of gestational stress in rats on anxiogenic behaviour and hippocampal gene expression of their 23-day-old female offspring. As the rat brain continues to develop after birth, we also used the procedure of handling (H) during the first 10 days of life to reverse the anxiogenic behaviour of prenatally stressed (PS) rats. By means of micro-array analysis on hippocampal extracts, we found that the expression of about 6.1% of 9505 valid genes was significantly altered by prenatal stress (p<0.05). Of these, 48% were over-expressed and 52% under-expressed. The latter included approximately 300 genes that participate in axonal growth, regulation of ion channels and transporters, trafficking of synaptic vesicles and neurotransmitter release. About 30% of the genes that were down-regulated in PS rats were restored to control levels by H. These include genes that play a role in pre-synaptic organization and function. Our results provide a possible relationship between hippocampal gene expression and changes in behaviour resulting from prenatal stress.     

Maternal infection and fever during late gestation are associated with altered synaptic transmission in the hippocampus of juvenile offspring rats

Prenatal exposure to infection is known to affect brain development and has been linked to increased risk for schizophrenia. The goal of this study was to investigate whether maternal infection and associated fever near term disrupts synaptic transmission in the hippocampus of the offspring. We used LPS to mimic bacterial infection and trigger the maternal inflammatory response in near-term rats. LPS was administered to rats on embryonic days 15 and 16 and hippocampal synaptic transmission was evaluated in the offspring on postnatal days 20-25. Only offspring from rats that showed a fever in response to LPS were tested. Schaffer collateral-evoked field excitatory postsynaptic potentials (fEPSPs) and fiber volleys in CA1 of hippocampal slices appeared smaller in offspring from the LPS group compared with controls, but, when the fEPSPs were normalized to the amplitude of fiber volleys, they were larger in the LPS group. In addition, intrinsic excitability of CA1 pyramidal neurons was heightened, as antidromic field responses in the LPS group were greater than those from control. Short-, but not long-term plasticity was impaired since paired-pulse facilitation of the fEPSP was attenuated in the LPS group, whereas no differences in long-term potentiation were noted. These results suggest that LPS-induced inflammation during pregnancy produces in the offspring a reduction in presynaptic input to CA1 with compensatory enhancements in postsynaptic glutamatergic response and pyramidal cell excitability. Neurodevelopmental disruption triggered by prenatal infection can have profound effects on hippocampal synaptic transmission, likely contributing to the memory and cognitive deficits observed in schizophrenia.     

产前应激对子代大鼠海马CA3区神经元Ca2+和K+通道的影响

本研究的目的在于探讨产前应激对子代大鼠海马CA3神经元高电压激活(HVA)钙通道、延迟整流钾电流(delayedrectifierpotassiumcurrents,IKD)的影响。产前应激(prenatalstress,PNS)组孕鼠孕晚期给予束缚应激,应用全细胞膜片钳技术进行研究。结果显示产前应激增加了子代海马CA3神经元HVA钙通道峰电流幅值,对照组和产前应激组子代CA3神经元平均最大HVA钙电流峰值分别为-576.52±7.03pA和-702.05±6.82pA(P<0.01)。同时未改变其电导-电压关系,也未改变延迟整流钾通道电流-电压关系、电导-电压关系。结果提示,在胎儿发育的关键时期,给予母体产前应激,引起子代海马神经元HVA钙电流增加,其机制一方面PNS导致皮质酮升高,从而可能增加HVA钙通道mRNA表达;另一方面PNS所致反应性氧化产物(reactiveoxygenspecies,ROS)增多,后者可能通过磷酸化HVACa2 通道亚单位,从而提高HVA钙电流幅值。     

Prenatal ethanol exposure persistently impairs NMDA receptor-dependent activation of extracellular signal-regulated kinase in the mouse dentate gyrus

The dentate gyrus (DG) is the central input region to the hippocampus and is known to play an important role in learning and memory. Previous studies have shown that prenatal alcohol is associated with hippocampal-dependent learning deficits and a decreased ability to elicit long-term potentiation (LTP) in the DG in adult animals. Given that activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling cascade by NMDA receptors is required for various forms of learning and memory, as well as LTP, in hippocampal regions, including the DG, we hypothesized that fetal alcohol-exposed adult animals would have deficits in hippocampal NMDA receptor-dependent ERK1/2 activation. We used immunoblotting and immunohistochemistry techniques to detect NMDA-stimulated ERK1/2 activation in acute hippocampal slices prepared from adult fetal alcohol-exposed mice. We present the first evidence linking prenatal alcohol exposure to deficits in NMDA receptor-dependent ERK1/2 activation specifically in the DG of adult offspring. This deficit may account for the LTP deficits previously observed in the DG, as well as the life-long cognitive deficits, associated with prenatal alcohol exposure.     

Prenatal Nicotine and Maternal Deprivation Stress De-Regulate the Development of CA1, CA3, and Dentate Gyrus Neurons in Hippocampus of Infant Rats

Adverse experiences by the developing fetus and in early childhood are associated with profound effects on learning, emotional behavior, and cognition as a whole. In this study we investigated the effects of prenatal nicotine exposure (NIC), postnatal maternal deprivation (MD) or the combination of the two (NIC+MD) to determine if hippocampal neuron development is modulated by exposure to drugs of abuse and/or stress. Growth of rat offspring exposed to MD alone or NIC+MD was repressed until after weaning. In CA1 but not CA3 of postnatal day 14 (P14) pups, MD increased pyramidal neurons, however, in dentate gyrus (DG), decreased granule neurons. NIC had no effect on neuron number in CA1, CA3 or DG. Unexpectedly, NIC plus MD combined caused a synergistic increase in the number of CA1 or CA3 neurons. Neuron density in CA regions was unaffected by treatment, but in the DG, granule neurons had a looser packing density after NIC, MD or NIC+MD exposure. When septotemporal axes were analyzed, the synergism of stress and drug exposure in CA1 and CA3 was associated with rostral, whereas MD effects were predominantly associated with caudal neurons. TUNEL labeling suggests no active apoptosis at P14, and doublecortin positive neurons and mossy fibers were diminished in NIC+MD relative to controls. The laterality of the effect of nicotine and/or maternal deprivation in right versus left hippocampus was also analyzed and found to be insiginificant. We report for the first time that early life stressors such as postnatal MD and prenatal NIC exposure, when combined, may exhibit synergistic consequences for CA1 and CA3 pyramidal neuron development, and a potential antagonistic influence on developing DG neurons. These results suggest that early stressors may modulate neurogenesis, apoptosis, or maturation of glutamatergic neurons in the hippocampus in a region-specific manner during critical periods of neurodevelopment.     

Effects of prenatal low-dose beta radiation from tritiated water on learning and memory in rats and their possible mechanisms.

Pregnant adult Wistar rats were randomly divided into four groups. Three of these groups were irradiated with beta rays by a single intraperitoneal injection of tritiated water ((3)H(2)O) administered on the 13th day of gestation. The doses absorbed by their offspring were estimated to be 4.6, 9.2 and 27.3 cGy. The influence of radiation on the postnatal learning ability and memory behavior and on brain development of the offspring was investigated. The number of pyramidal cells (in areas CA1, CA2, CA3 and CA4) and neurons in the hippocampus of the offspring was also measured. In addition, the Ca(++) conductance of hippocampal pyramidal cells cultured in vitro was observed. The results showed that an exposure to 4.6 cGy could prolong avoidance response time significantly and decrease the number of hippocampal pyramidal cells in the CA1 area compared to controls. An exposure to 9.2 cGy significantly decreased the establishment of conditioned reflexes and the number of hippocampal pyramidal cells in the CA3 area. This exposure also induced the degeneration and malformation of hippocampal neurons cultured in vitro, in addition to decreasing the number of hippocampal neurons observed on each culture day. A dose of 27.3 cGy significantly decreased brain and body weights and the maximum electric conductance of Ca(++) in hippocampal pyramidal neurons. In general, dose-dependent effects were observed for most of the parameters assessed in the present study. Possible mechanisms are discussed.     

产前束缚应激子代大鼠海马神经颗粒素表达降低

神经颗粒素（neurogranin,NG）是脑特异性突触后蛋白,参与在学习记忆功能中起核心作用的信号转导通路及突触可塑性。本研究旨在探讨产前束缚应激对子代大鼠海马NG表达的影响。连续7d对孕晚期大鼠进行束缚应激,建立产前束缚应激模型,分为对照雌、雄组,应激雌、雄组。采用免疫组化方法观察NG在产前束缚应激子代大鼠海马不同亚区的分布特点;采用蛋白免疫印迹方法检测产前束缚应激子代大鼠海马NG蛋白的表达。结果显示：各组子代大鼠海马各区均有NG蛋白表达,CA1和CA3区表达高于齿状回（dentate gyrus,DG）;应激组雌、雄子代大鼠海马NG的表达明显低于对照组（P〈0．01）,应激组雌性子代比雄性子代减少更显著,对照组雌、雄子代之间无差异。免疫组化与蛋白免疫印迹方法所得结果一致。上述结果表明,NG在产前束缚应激子代大鼠海马表达降低,并且雌性比雄性降低明显,NG对产前束缚应激子代大鼠有差异性调制,NG表达减少可能与产前束缚应激子代大鼠学习记忆能力下降有关。     

右美托咪定对异丙酚麻醉所致新生大鼠脑损伤的保护作用及机制

高浓度的异丙酚可导致动物和人类发生脑损伤,而右美托咪定对多种脑损伤动物模型具有一定的神经保护作用。为了考察右美托咪定对异丙酚麻醉所致新生大鼠脑损伤的保护作用及机制,本研究对7日龄清洁级SD大鼠分别腹腔注射异丙酚(60 mg/kg)、右美托咪定(80μg/kg)和异丙酚(60 mg/kg)+右美托咪定(80μg/kg)。Morris水迷宫实验发现高剂量的异丙酚可显著增加大鼠的逃避潜伏期并减少穿越平台次数,然而右美托咪定预处理则可显著降低大鼠的逃避潜伏期并提高穿越平台次数(p<0.05)。异丙酚单独处理导致大鼠的海马神经元细胞凋亡程度显著增加,而右美托咪定预处理则可显著抑制神经元细胞的凋亡(p<0.05)。异丙酚单独处理可显著下调PSD95蛋白的表达,但右美托咪定预处理则可有效抑制PSD95蛋白的下调(p<0.05)。高剂量的异丙酚可明显下调大鼠海马组织P13K、Akt和GSK-3βmRNA的表达,而右美托咪定预处理则可抑制P13K、Akt和GSK-3βmRNA的下调。此外,右美托咪定预处理可显著提高p-Akt/Akt和p-GSK-3β/GSK-3β蛋白比值。本研究表明,右美托咪定可有效抑制异丙酚诱导的神经元细胞凋亡,改善大鼠的学习和记忆能力。右美托咪定的神经保护作用与其对PI3K/AKT/GSK-3β信号通路的激活有关。     

Prenatal stress in rat causes long-term spatial memory deficit and hippocampus MRI abnormality: differential effects of postweaning enriched environment

Prenatal stress (PS) can cause long-term hippocampus alternations in structure and plasticity in adult offspring. Enriched environment (EE) has an effect in rescuing a variety of neurological disorders. Pregnant dams were left undisturbed (prenatal control, PC) or restrained 6h per day from days 14 to 21 (prenatal stress, PS). Control and prenatal stressed offspring rats were subjected to a standard rearing environment (SE) or an EE on postnatal days 22-120 (PC/SE PC/EE, PS/SE, and PS/EE; n=5, each group). At ～4 months of age, all rats underwent Morris water maze test and brain MRI examination. Hippocampi were then dissected for biochemical analyses, including, Western blot for NMDA receptor (NR) subunits and synaptophysin and RT-PCR forβ1 integrin and tissue-plasminogen activator (t-PA). MRI showed all 5 rats in the PS/SE group and 5 in the PS/EE group exhibited increased signals in bilateral hippocampus and increased T2 time in the PS/SE group. Exposure to EE treatment on postnatal days 22-120 counteracted the deficit in spatial memory and increased NR1 protein expression, but it did not affect the rate of high signals and increased T2 time, decreased NR2, synaptophysin, β1 integrin and t-PA mRNA expressions in PS adult offspring. The results of this study indicate PS in rats causes long-term spatial memory deficits and gross hippocampus pathology. Postnatal EE treatment has differential benefits in terms of spatial learning, signaling molecules, and gross hippocampus pathology.     

Altered dipsogenic responses and expression of angiotensin receptors in the offspring exposed to prenatal high sucrose

The present study determined water and salt intake as well as expression of AT₁ and AT₂ receptors in the brain and kidney in the adult offspring rats prenatally exposed to high sucrose. Following the exposure during pregnancy, water intake and salt intake at baseline levels were not changed in the adult offspring. However, after 24 h water deprivation, consumption of water and salt was significantly increased compared to that of the control. Plasma sodium and osmolality levels remained the same between the offspring in the control and the exposed groups, while hematocrit was higher in the offspring exposed to prenatal high sucrose immediately following water deprivation. Density of renal AT₁ receptor protein was the same between the control and the exposed group, while AT₂ receptor protein in the kidney was significantly increased in the offspring exposed to prenatal high sucrose in association of thicker basal membrane of glomerular. In the forebrain, both AT₁ and AT₂ receptor levels were significantly increased in the offspring with history of prenatal high sucrose. In addition, water deprivation induced more c-fos expression in the central dipsogenic areas, including the paraventricular and supraoptic nuclei in the offspring exposed to prenatal high sucrose. The results suggested that prenatal high intake of sucrose may affect development of pathways in regulation of dipsogenic behavior in face of dehydration, which was associated with altered expression of AT₁ or/and AT₂ receptors in the kidney and brain.     

Effects of isoflurane exposure during pregnancy on postnatal memory and learning in offspring rats

Emerging evidence has demonstrated that exposure to anesthetics early in life caused neurohistopathologic changes and persistent behavioral impairments. In this study, a maternal fetal rat model was developed to study the effects of isoflurane exposure during pregnancy on postnatal memory and learning in the offspring. Pregnant rats at gestational day 14 were either exposed to 1.3% isoflurane in a humidified 100% oxygen carrier gas or simply humidified 100% oxygen without any inhalational anesthetic for 2 h every day before delivery. Four weeks later, spatial learning and memory of the offspring were examined using the Morris Water Maze. The expression levels of GAP-43 and NPY in the hippocampal CA1 region of the pups were determined by immunohistochemistry and RT-PCR. Simultaneously, the ultrastructure changes in synapse of the hippocampus were also observed by transmission electron microscopy (TEM). Isoflurane exposure during pregnancy impaired postnatal spatial memory and learning in the offspring as shown by the longer escape latency and the fewer original platform crossings in the Morris Water Maze test. The number and optical densities of GAP-43 and NPY positive cells, as well as the levels of GAP-43 and NPY mRNA, decreased significantly in the hippocampus of isoflurane-exposed pups. Furthermore, TEM studies showed remarkable changes in synaptic ultrastructure of hippocampus. These results indicate that isoflurane exposure during pregnancy could cause postnatal spatial memory and learning impairments in offspring rats, which may be partially explained by the down-regulation of GAP-43 and NPY in the hippocampal area.     

Prenatal corticosteroid exposure affects hippocampal plasticity and reduces lifespan

Synthetic corticosteroids, such as dexamethasone, are frequently administered to pregnant women at risk for preterm delivery. Endogenous corticosteroids are essential for normal development, but exposure to therapeutic doses at critical developmental stages may have adverse effects on the central nervous system. Major concern has arisen about long-term effects of corticosteroid treatment on brain plasticity, particularly in the hippocampus. Therefore, we analyzed the molecular, cellular, and behavioral effects of prenatal dexamethasone treatment on the adult hippocampus. Pregnant mice were treated at embryonic day 15.5 with a single dose of dexamethasone or saline. Adult offspring was analyzed for hippocampal neuron loss, cell proliferation, and NMDA receptor subunit expression. Hippocampal function was assessed in the Morris water maze and synaptic plasticity in the CA1 field by determining frequency dependence of LTP and LTD in hippocampal slices. Prenatal dexamethasone treatment decreased hippocampal cell proliferation in the dentate gyrus. Treated mice showed reduced LTD, impaired spatial learning, and a marked reduction in lifespan. Our data show long-term adverse effects of prenatal dexamethasone treatment on hippocampal function in mice and suggest accelerated aging. These findings indicate that it is important to be restrictive with corticosteroid administration during fetal development because of the lifelong consequences.     

Prenatal exposure to interleukin-6 results in inflammatory neurodegeneration in hippocampus with NMDA/GABA(A) dysregulation and impaired spatial learning

During pregnancy, infection or immune responses induce cytokine release, which might influence fetal neurodevelopment, leading to neurodegenerative disease in adulthood. Because the hippocampus is a key area for learning and memory, we evaluated 4- and 24-wk-old rats for the effects of early and late prenatal exposure to interleukin-6 (IL-6) on hippocampal morphology, expression of mRNA for IL-6, the gamma-aminobutyric acid receptor (GABA(Aalpha5)), the NR1 subunit of the N-methyl-D-aspartate receptor, and glial fibrillary acidic protein (GFAP), caspase-3 protein and mRNA levels, and learning abilities. Late exposure increased serum IL-6 and hippocampal expression of IL-6 mRNA at 4 and 24 wk. All adult rats showed neuronal loss in the hilus and astrogliosis; males had losses mainly in the CA2 and CA3 regions, and females in CA1. Expression of GABA(Aalpha5), NR1, and GFAP mRNA increased in late-exposed males and females at 4 and 24 wk. mRNA and protein levels of the apoptosis marker caspase-3 were increased in all late-exposed rats except males at 4 wk. Evaluation of hippocampus-dependent working memory in the Morris water maze at 20 wk of age showed increases in escape latency and time spent near the pool wall in all IL-6 adult rats, especially females. These findings suggest that fetal IL-6 exposure, especially in late pregnancy, leads to increased IL-6 levels in the circulation and hippocampus, abnormalities of hippocampal structural and morphology, and decreased learning during adulthood.     

Maternal behavior regulates long-term hippocampal expression of BAX and apoptosis in the offspring

Naturally occurring variations in maternal care influence hippocampal development in the rat. In the present study we found that variations in maternal licking/grooming (LG) during the first week of life are associated with altered hippocampal expression of BAX (group-1 tumor necrosis factor family mediated cell death effector) in 90-day-old male offspring. BAX-like immunoreactivity on western blots is significantly increased in the adult offspring of low-level LG mothers. There is no effect of maternal care on levels of either B-cell lymphoma-2 (BCL-2) (group-II mitochondria mediated cell death suppressor) or BAD (group-III endoplasmic reticulum mediated cell death effector). The most striking biochemical event in apoptosis is DNA fragmentation. Terminal deoxynucleotidyl transerferase (Tdt)-mediated dUTP-biotin nick-end labeling (TUNEL) and 4',6'-diamidino-2-phenylindole hydrochloride (DAPI) staining showed that the number of TUNEL-positive cells in both the dentate gyrus and CA1 region of the hippocampus is significantly increased in the adult offspring of low-level LG mothers. In conclusion, we propose that hippocampal neurons in the offspring of low-level LG mothers may be more vulnerable to loss through apoptosis.     

Thyroxine administration prevents matrilineal intergenerational consequences of in utero ethanol exposure in rats

The neurodevelopmental fetal alcohol spectrum disorder (FASD) is characterized by cognitive and behavioral deficits in the offspring. Conferring the deficits to the next generation would increase overall FASD disease burden and prevention of this transmission could be highly significant. Prior studies showed the reversal of these behavioral deficits by low dose thyroxine (T4) supplementation to the ethanol-consuming mothers. Here we aim to identify whether prenatal ethanol (PE) exposure impairs hippocampus-dependent learning and memory in the second-generation (F2) progeny, and whether T4 administration to the ethanol-consuming dam can prevent it. Sprague-Dawley (S) dams received control diets (ad libitum and nutritional control) or ethanol containing liquid diet with and without simultaneous T4 (0.3 mg/L diet) administration. Their offspring (SS F1) were mated with naive Brown Norway (B) males and females generating the SB F2 and BS F2 progeny. Hippocampus-dependent contextual fear memory and hippocampal expression of the thyroid hormone-regulated type 3 deiodinase, (Dio3) and neurogranin (Nrgn) were assessed. SS F1 PE-exposed females and their SB F2 progeny exhibited fear memory deficits. T4 administration to the mothers of F1 females reversed these deficits. Although SS F1 PE-exposed males also experienced fear memory deficit, this was neither transmitted to their BS F2 offspring nor reversed by prenatal T4 treatment. Hippocampal Dio3 and Nrgn expression showed similar pattern of changes. Grandmaternal ethanol consumption during pregnancy affects fear memory of the matrilineal second-generation progeny. Low dose T4 supplementation prevents this process likely via altering allele-specific and total expression of Dio3 in the hippocampus.     

Effect of L-deprenyl treatment on electrical activity, Na+, K+ ATPase, and protein kinase C activities in hippocampal subfields (CA1 and CA3) of aged rat brain

L-deprenyl is considered to protect against age-related cognitive deficits by improving long-term learning/memory in the aged brain. The CA1 and CA3 hippocampal areas are the sites at which initial learning and memory processes occur. Chronic deprenyl treatment significantly augmented the basal electrical firing rate (multiple-unit action potentials), and Na+, K(+)-ATPase and protein kinase C activities of both CA1 and CA3 indicating that the drug increased the excitability of CA1 and CA3. The increase, however, was much greater in CA1 than in CA3 suggesting that deprenyl can improve longer-term learning in aged animals by its excitability-enhancing action in CA1. The drug also countered the ageing-related loss of hippocampal protein kinase C activity.