Neonatal Brain Development Research Articles

Coexposure of Neonatal Mice to a Flame Retardant PBDE 99 (2,2′,4,4′,5-Pentabromodiphenyl Ether) and Methyl Mercury Enhances Developmental Neurotoxic Defects

Epidemiological studies indicate that exposure to environmental pollutants during early human development can have deleterious effects on cognitive development. The interaction between environmental pollutants is suggested as one reason for the observed defective neurological development in children from the Faeroe Islands as compared to children from the Seychelles. We have previously seen in mice that polychlorinated biphenyls (PCBs) can interact together with methyl mercury (MeHg), as well as PCB together with polybrominated diphenyl ether (PBDE 99) to exacerbate developmental neurotoxic effects when present during a critical period of neonatal brain development. PBDEs are a new class of global environmental contaminants. The present study shows that neonatal coexposure to PBDE 99 (0.8 mg/kg body weight) and MeHg (0.4 or 4.0 mg/kg body weight) can exacerbate developmental neurotoxic effects. These effects are manifested as disrupted spontaneous behavior, reduced habituation, and impaired learning/memory abilities. This is seen in the low dose range, where the sole compounds do no give rise to developmental neurotoxic effects. The effects seen are more than just additive. Furthermore, a significant effect of interaction was seen on the cholinergic nicotinic receptors in the cerebral cortex and hippocampus. This suggests that a mechanism for the observed cognitive defects is via the cholinergic system. Furthermore, PBDE can interact with MeHg causing developmental neurotoxic effects similar to those we previously have observed between PCB 153 + MeHg and PCB 52 + PBDE 99. This is of vital importance, as the levels of PBDEs are increasing in mother's milk and in the environment generally.

Neonatal exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) causes neurobehavioural defects in adult mice

Perfluorinated compounds (PFCs) are found in applications such oil/water repellents for clothing fabrics, carpets, food packaging, lubricants, surfactants and fire extinguishers. PFCs are persistent in the environment. They have been found in humans and in wildlife. We reported earlier that persistent organic pollutants (POPs), such as DDT, PCBs and BFRs, caused developmental neurotoxic defects in mice, manifested as persistent aberrations in spontaneous behaviour, habituation capability, learning and memory, and changes in the cholinergic system in adults, when mice were exposed during a critical period of neonatal brain development. The present study was conducted to see whether PFCs can cause similar developmental neurotoxic effects as earlier observed for POPs as PCBs and PBDEs. NMRI male mice were exposed to a single-oral dose, either 1.4 or 21 μmol/kg body weight of PFOS (0.75 or 11.3 mg), PFOA (0.58 or 8.70 mg), or PFDA (0.72 or 10.8 mg), via a metal gastric-tube at the age of 10 days. The control animals received in the same manner 10 ml/kg body weight of the 20% fat emulsion vehicle. Spontaneous behaviour (locomotion, rearing, and total activity), and habituation were observed in 2- and 4-month-old mice. The susceptibility of the cholinergic system was explored in a nicotine-induced spontaneous behaviour test in 4-month-old mice. Deranged spontaneous behaviour was observed in mice exposed to PFOS and PFOA, manifested as reduced and/or lack of habituation and hyperactivity in adult mice. These effects were also seen to worse with age. Neonatal exposure to PFOS and PFOA affected the cholinergic system, manifested as a hypoactive response to nicotine, compared to a hyperactive response to nicotine in controls. These developmental neurotoxic effects are similar to those we reported earlier for PCBs and PBDEs. This suggests that PFOS and PFOA be included in the group of POPs known to be developmental neurotoxicants.

Suppressive Effects of Bisphenol A on the Proliferation of Neural Progenitor Cells

Endocrine disruptors (EDs) exert adverse effects on reproductive and immune function or neurological behavior. Bisphenol A (BPA), one of the environmental EDs, is widely used in the manufacture of plastics and epoxy resins. Studies reported that BPA affects reproductive organ growth and development. However, the potential adverse effects of BPA on neuronal development have not been fully explored. In this study, the potent harmful effects of BPA were investigated on the murine-derived multipotent neural progenitor cells (NPCs). Pretreatment of BPA significantly decreased proliferation of NPCs in a concentration-dependent manner. Moreover, at a high concentration (> 400 μM), BPA was cytotoxic to NPCs. However, the low concentrations of BPA, previously shown to exert estrogenic actions, did not affect the proliferation of NPCs. BPA altered the activation of extracellular signal-regulated kinases and c-Jun-N-Kinases in a different manner without affecting activities of p38 kinases. It was also found that reactive oxygen species (ROS) were elevated in NPCs exposed to high concentrations of BPA, indicating oxidative stress-related cytotoxicity. These data show adverse effects of BPA on the nervous system and potentially on neonatal brain development.

Sex differences in the control of neuronal nitric oxide synthase by GABA-A receptors in the developing rat diencephalon

The nitric oxide free radical (NO ), which is synthesized by neuronal nitric oxide synthase (nNOS), is known to play an important morphogenetic role in the developing rat brain. In the cortex, the levels of nNOS are regulated by phosphorylated cAMP response element binding protein (pCREB) downstream of GABA-A receptor activation. During early stages of neonatal development, binding of GABA to its type A receptors leads to depolarization of the neuronal membrane. One of the developmental processes mediated through GABA-A receptors is the sexual differentiation of the brain. In the present work, we investigated the effect of GABA-A receptor activation on nNOS and pCREB immunoreactivity in the developing diencephalon of 5-day-old male and female rats. Our results showed that in the bed nucleus of the stria terminalis activation of GABA-A receptors leads to increased numbers of nNOS, and pCREB as well as nNOS-pCREB doubly immunopositive cells only in the males while in the posterior hypothalamus this effect is observed in both sexes. The GABA-A receptor-mediated increase in nNOS and pCREB is abolished when L-type voltage-gated Ca 2+ channels are blocked. These results indicate that the following mechanism could be operating in a gonadal hormone-dependent and brain area-specific manner during neonatal rat brain development: Depolarization following GABA-A receptor activation leads to opening of L-type voltage-gated calcium channels, resulting in an increased Ca 2+ influx, which in turn leads to phosphorylation, and thus activation of the transcription factor CREB; the phosphorylated CREB can then induce nNOS.

Population Living in the Red Sea State of Sudan May Need Urgent Intervention to Correct the Excess Dietary Iodine Intake

Both inadequate and high intakes of iodine are associated with thyroid disease and associated abnormalities. Consumption of foods deficient in iodine induces hypothyroidism. Conversely, excessive intake of the nutrient precipitates hyperthyroidism. Iodine deficiency causes impairment of thyroid hormonogenesis resulting in goiter (struma), cretinism which is associated with increased prenatal and infant mortality, deafness, motor disabilities and mental retardation due to damage during fetal and neonatal brain development. We have assessed the iodine status of school children from the locality of Port Sudan, Red Sea State of Eastern Sudan. The primary sources of iodine of the children are mainly iodized salt and rations supplied by local donors and various aid agencies operating in the Sudan. Male and female children (n=141), aged 6 to 12 years (median age 9.8 years), were selected for the survey using a multistage random sampling technique, between May 22 and August 25, 2006. All the children were assessed for urinary iodine and visible goiter. In addition, the iodine content of twenty salt samples was determined using the lodometric titration method and spot test kits. The components of other foods that are routinely consumed by the children and households were noted using a questionnaire form. Urinary iodine concentration exceeded 300 microg/l and 1000 microg/l in 65% and 9.9% of the children, respectively. The highest urinary iodine level was 1470 microg/l. The prevalence of visible goiter was 17%. All the salt samples collected from the schools had more than 150mg potassium iodate per kg of salt. The results of this pilot survey reveal that excessive intake of iodine in children exists in Port Sudan. Inappropriate and unregulated local fortification of salt and lack of monitoring of the imported and donated salt is the primary reason for the excessive intake. There is an urgent need for a regulatory mechanism during the process of iodine fortification and at the point of entry of imported and donated iodized salt as well as the mode of delivery in order to avoid hyperthyroidism and associated disorders. In addition, independent professionals should critically evaluate the health impact of excessive consumption of the nutrient.

Intracranial Hemorrhage in Asymptomatic Neonates: Prevalence on MR Images and Relationship to Obstetric and Neonatal Risk Factors

To retrospectively evaluate the prevalence of neonatal intracranial hemorrhage (ICH) and its relationship to obstetric and neonatal risk factors. Pregnant women were recruited for a prospective study of neonatal brain development; the study was approved by the institutional review board and complied with HIPAA regulations. After informed consent was obtained from a parent, neonates were imaged with 3.0-T magnetic resonance (MR) imaging without sedation. The images were reviewed by a neuroradiologist with 12 years of experience for the presence of ICH. Medical records were prospectively and retrospectively reviewed for selected risk factors, which included method of delivery, duration of labor, and evidence of maternal or neonatal birth trauma. Risk factors were assessed for relationship to ICH by using Fisher exact test statistics. Ninety-seven neonates (mean age at MR imaging, 20.8 days +/- 6.9 [standard deviation]) underwent MR imaging between the ages of 1 and 5 weeks. Eighty-eight (44 male and 44 female) neonates (65 with vaginal delivery and 23 with cesarean delivery) completed the MR imaging evaluation. Seventeen neonates with ICHs (16 subdural, two subarachnoid, and six parenchymal hemorrhages) were identified. Seven infants had two or more types of hemorrhages. All neonates with ICH were delivered vaginally, with a prevalence of 26% in vaginal births. ICH was significantly associated with vaginal birth (P < .005) but not with prolonged duration of labor or with traumatic or assisted vaginal birth. Asymptomatic ICH following vaginal birth in full-term neonates appears to be common, with a prevalence of 26% in this study.

Fetal and Neonatal Brain Development

Fetal and Neonatal Brain Development

Fetal and Neonatal Brain Development

Fetal and Neonatal Brain Development

Polybrominated Diphenyl Ethers, A Group of Brominated Flame Retardants, Can Interact with Polychlorinated Biphenyls in Enhancing Developmental Neurobehavioral Defects

The present study shows that polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) can interact and enhance developmental neurobehavioral defects when the exposure occurs during a critical stage of neonatal brain development. PBDEs are used in large quantities as flame-retardant additives in polymers, especially in the manufacture of a great variety of electrical appliances, and textiles. In contrast to the well-known persistent compounds PCBs and DDT, the PBDEs have been found to increase in the environment and in human mother's milk. We have previously shown that low-dose exposure to environmental toxic agents such as PCB can cause developmental neurotoxic effects when present during a critical stage of neonatal brain development. Epidemiological studies indicate the adverse neurobehavioral impact of PCBs. Recently, we reported that neonatal exposure to PBDEs causes developmental neurotoxic effects. In the present study, 10-day-old Naval Medical Research Institute male mice were given one single oral dose of PCB 52 (1.4 micromol/kg body weight [bw]) + PBDE 99 (1.4 micromol), PCB 52 (1.4 micromol or 14 micromol), or PBDE 99 (1.4 micromol or 14 micromol). Controls received a vehicle (20% fat emulsion). Animals exposed to the combined dose of PCB 52 (1.4 micromol) + PBDE 99 (1.4 micromol) and the high dose of PCB 52 (14 micromol) or PBDE 99 (14 micromol) showed significantly impaired spontaneous motor behavior and habituation capability at the age of 4 and 6 months. The neurobehavioral defects were also seen to worsen with age in mice neonatally exposed to PCB 52 + PBDE 99.

Prenatal stress reduces S100B in the neonatal rat hippocampus

Prenatal stress has been shown to disturb neonatal rat brain development. The astroglial-specific neurotrophic factor S100B is known to play an important role in normal brain development. In the present study, we investigated the effects of prenatal stress on S100B concentrations in the hippocampus of 1-day-old Fischer 344 rats. Overall, prenatal stress resulted in a 25% reduction in hippocampal S100B content. Further, male hippocampal S100B content was negatively correlated with plasma corticosterone levels. Positive correlations were found between female S100B levels and fetal growth, and hippocampal brain-derived neurotrophic factor content. In conclusion, the observed reduction in neonatal hippocampal S100B levels, as a consequence of prenatal stress, may be involved in affecting postnatal brain development.

Iron in the Brain

After completing this article, readers should be able to: 1. Describe the role of iron in proteins involved in neuronal and glial energy metabolism, myelin production, and monoamine neurotransmitter metabolism. 2. Indicate the neonates who are at risk for iron deficiency. 3. Explain how iron deficiency affects the biochemistry, structure, signaling molecules, and electrophysiology of the hippocampus. 4. Describe the primary causes of iron overload in the neonate. 5. Explain why the preterm infant is at particular risk for iron deficiency. This article is designed to acquaint readers with the role of iron in early brain development. Several important principles that govern the effects of nutrients on the immature brain are discussed, followed by an explanation of the roles of iron during development. Because the developing brain is sensitive to iron overload as well as iron deficiency, both are discussed in the context of human studies and in model systems. The first guiding principle of nutrient-brain interactions during development is the concept of timing, dose, and duration. (1) The positive or negative effects of any nutrient depend on which brain regions or processes are developing at the time that nutrient status is altered and the requirements of those regions for the nutrient during that time of development. Generally, the more rapidly an area is developing, the more vulnerable it is. Dependence on specific nutrients during phases of rapid proliferation or differentiation results in the second principle, a regionalization of brain effects during periods of nutrient deficiency. In the case of iron deficiency, certain brain areas that are dependent on iron for proper development are more vulnerable than areas that are less dependent on iron. Additionally, these same brain areas are likely to be more vulnerable at certain time points than at others. To exert a maximal effect on regional brain development, the timing of iron …

Lowering the dose of antenatal steroids: The effects of a single course of betamethasone on somatic growth and brain cell proliferation in the rat

We investigated the effects of a single course of antenatal betamethasone on neonatal somatic and brain development. On day 20 of gestation, pregnant rats were injected with either with 170 microg kg(-1) body weight of betamethasone ("clinically-equivalent dose," equivalent to 12 mg twice, 24 hours apart) or half this dose or vehicle. Pups (8-11 animals per experimental group per timepoint per gender) were analyzed at 1 (P1), 2, and 21 days after birth. We report that betamethasone induced a significant dose-dependent decrease of somatic measurements in both genders. At P1 cell proliferation was affected by the "clinically equivalent dose" only in the subventricular zone in both genders and in the hippocampus in males. In summary, we show for the first time that a lower dose (equivalent to 6 mg) induces fewer and less severe effects on somatic growth, whereas it does not affect cell proliferation within the brain.

Prenatal stress and neonatal rat brain development

Chronic or repeated stress during human fetal brain development has been associated with various learning, behavioral, and/or mood disorders, including depression in later life. The mechanisms accounting for these effects of prenatal stress are not fully understood. The aim of this study was to investigate the effects of prenatal stress on early postnatal brain development, a disturbance of which may contribute to this increased vulnerability to psychopathology. We studied the effects of prenatal stress on fetal growth, stress-induced corticosterone secretion, brain cell proliferation, caspase-3-like activity and brain-derived neurotrophic factor protein content in newborn Fischer 344 rats. In addition to a slight reduction in birth weight, prenatal stress was associated with elevated corticosterone levels (33.8%) after 1 h of maternal deprivation on postnatal day 1, whereas by postnatal day 8 this pattern was reversed (−46.5%). Further, prenatal stress resulted in an approximately 50% decrease in brain cell proliferation just after birth in both genders with a concomitant increase in caspase-3-like activity within the hippocampus at postnatal day 1 (36.1%) and at postnatal day 5 (females only; 20.1%). Finally, brain-derived neurotrophic factor protein content was reduced in both the olfactory bulbs (−24.6%) and hippocampus (−28.2%) of prenatally stressed male offspring at postnatal days 1 and 5, respectively. These detrimental central changes observed may partly explain the increased susceptibility of prenatally stressed subjects to mood disorders including depression in later life.

Early Developmental Changes in IGF-I, IGF-II, IGF Binding Protein-1, and IGF Binding Protein-3 Concentration in the Cerebrospinal Fluid of Children

IGF-I and IGF-II are ubiquitously expressed growth factors that have profound effects on the growth and differentiation of many cell types and tissues, including cells of the CNS. In biologic fluids, most IGFs are bound to one of six IGF binding proteins (IGFBPs 1-6). Increasing evidence strongly supports a role for IGF-I in CNS development, as it promotes neuronal proliferation and survival. However, little is known about IGF-I and its homolog IGF-II and their carrier proteins, IGFBPs, during the neonatal period in which brain size increases dramatically, myelination takes place, and neurons show limited capacity to proliferate. Herein, we have determined the concentrations of IGF-I, IGF-II, IGFBP-1, and IGFBP-3 in cerebral spinal fluid (CSF) samples that were collected from children who were 1 wk to 18 y of age. The concentrations of IGF-I, IGFBP-1, and IGFBP-3 in CSF from children <6 mo of age were significantly higher than in older children, whereas IGF-II was higher in the older group. This is in contrast to what is observed in the peripheral circulation, where IGF-I and IGFBP-3 are low at birth and rise rapidly during the first year, reaching peak levels during puberty. Higher concentrations of IGF-I, IGFBP-1, and IGFBP-3 in the CSF of very young children suggest that these proteins might participate in the active processes of myelination and synapse formation in the developing nervous system. We propose that IGF-I and certain IGFBPs are likely necessary for normal CNS development during critical stages of neonatal brain growth and development.

Developmental changes induced by graded prenatal systemic hypoxic–ischemic insults in rats

In infants, a common consequence of systemic perinatal insults is disruption of neonatal brain development. Such insults can cause cerebral palsy, cognitive delay, epilepsy and other chronic neurologic deficits in children. The mechanisms underlying disruption of brain development after perinatal insults are poorly defined. To mimic human systemic insults, a transient prenatal hypoxic-ischemic insult model was developed in rodents. Ischemic animals showed reproducible histological lesions including oligodendrocyte loss, gliosis, and axonal disruption. Ischemic animals displayed persistent postnatal loss of oligodendrocyte lineage cells and cortical neurons, decreased cell proliferation, increased cell death, elevated pro-inflammatory cytokine levels, and impaired motor skills as young adults. Progressive ischemic intervals produced a graded pattern of injury. This systemic rodent prenatal hypoxic-ischemic insult accurately models human perinatal brain injury in several important criteria, including functional association of altered brain development with motor delay, and consequently provides novel insights into the pathogenesis of human perinatal brain insults.

The role of thyroid hormone in fetal and neonatal brain development

To understand how thyroid hormone regulates brain development it is important to identify thyroid hormone-responsive brain genes; determine how regulated expression of these genes affects brain cell development, physiology, and function; and determine how these physiologic changes affect brain function. The authors summarize recent studies contributing to the understanding of these processes and discuss important new studies that assess thyroid hormone metabolism in the developing brain. Specific thyroid hormone transporters are expressed in the developing brain. Recent data suggest that regulated expression of these transporters may control brain thyroid hormone influx and efflux. Additional data support a role for deiodinases in controlling local iodothyronine concentrations in the developing brain. A series of recent reports assesses the role of thyroid hormone in oligodendrocyte development and axonal myelination. These data provide a cellular and molecular explanation for the hypomyelination observed in neonates that have developed in a hypothyroid state. The cerebellar Purkinje cell is another well-described target of thyroid hormone in the developing brain. A recent study provides evidence that thyroid hormone acts directly on the Purkinje cell to regulate dendritic arborization. Finally, important new data provide insight regarding the functional effects of thyroid hormone deficiency on neuronal activity. Recent work has provided exciting new insights regarding the mechanisms controlling thyroid hormone action in the developing brain. It seems likely that regulation of thyroid hormone metabolism and transport during brain development is a critically important mechanism of control. Additionally, important new findings have furthered our understanding of the structural and physiologic effects of thyroid hormone deficiency and excess on brain cell function.

Manganese‐enhanced magnetic resonance imaging (MEMRI) of mouse brain development

Given the importance of genetically modified mice in studies of mammalian brain development and human congenital brain diseases, MRI has the potential to provide an efficient in vivo approach for analyzing mutant phenotypes in the early postnatal mouse brain. The combination of reduced tissue contrast at the high magnetic fields required for mice, and the changing cellular composition of the developing mouse brain make it difficult to optimize MRI contrast in neonatal mouse imaging. We have explored an easily implemented approach for contrast-enhanced imaging, using systemically administered manganese (Mn) to reveal fine anatomical detail in T1-weighted MR images of neonatal mouse brains. In particular, we demonstrate the utility of this Mn-enhanced MRI (MEMRI) method for analyzing early postnatal patterning of the mouse cerebellum. Through comparisons with matched histological sections, we further show that MEMRI enhancement correlates qualitatively with granule cell density in the developing cerebellum, suggesting that the cerebellar enhancement is due to uptake of Mn in the granule neurons. Finally, variable cerebellar defects in mice with a conditional mutation in the Gbx2 gene were analyzed with MEMRI to demonstrate the utility of this method for mutant mouse phenotyping. Taken together, our results indicate that MEMRI provides an efficient and powerful in vivo method for analyzing neonatal brain development in normal and genetically engineered mice.

The fragile X protein controls microtubule-associated protein 1B translation and microtubule stability in brain neuron development.

The fragile X mental retardation protein (FMRP) is a selective RNA-binding protein implicated in regulating translation of its mRNA ligands. The absence of FMRP results in fragile X syndrome, one of the leading causes of inherited mental retardation. Delayed dendritic spine maturation was found in fragile X mental retardation patients as well as in Fmr1 knockout (KO) mice, indicating the functional requirement of FMRP in synaptic development. However, the biochemical link between FMRP deficiency and the neuronal impairment during brain development has not been defined. How FMRP governs normal synapse development in the brain remains elusive. We report here that the developmentally programmed FMRP expression represses the translation of microtubule associated protein 1B (MAP1B) and is required for the accelerated decline of MAP1B during active synaptogenesis in neonatal brain development. The lack of FMRP results in misregulated MAP1B translation and delayed MAP1B decline in the Fmr1 KO brain. Furthermore, the aberrantly elevated MAP1B protein expression leads to abnormally increased microtubule stability in Fmr1 KO neurons. Together, these results indicate that FMRP plays critical roles in controlling cytoskeleton organization during neuronal development, and the abnormal microtubule dynamics is a conceivable underlying factor for the pathogenesis of fragile X mental retardation.

Neurofunctional deficits and potentiated apoptosis by neonatal NMDA antagonist administration

The early postnatal brain development, when many potentially sensitive processes occur, has been shown to be vulnerable to different pharmacological and environmental compounds. In the present investigation, four groups of neonatal NMRI male mice were administered the glutamate NMDA receptor antagonist ketamine (50 mg/kg, s.c.), or the GABA A receptor agonist diazepam (5 mg/kg, s.c.), or co-administered ketamine (50 mg/kg, s.c.) and diazepam (5 mg/kg, s.c.), or vehicle (0.9% saline, s.c.) on day 10 after birth. On day 11, mice from each treatment group were sacrificed and brains were taken for analysis of neuronal cell degeneration, using Fluoro-Jade staining technique. Ketamine, but not diazepam, induced a severe degeneration of cells in the parietal cortex. The opposite was observed for diazepam in the laterodorsal thalamus. The most pronounced cell degeneration was seen in parietal cortex of mice exposed to both ketamine and diazepam. At 2 months of age each treatment group was tested for motor activity and learning performance. Ketamine and ketamine + diazepam treated mice displayed severe deficits of habituation to the test chamber in the spontaneous motor activity test, marked deficits of acquisition learning and retention memory in the radial arm maze-learning task and less shift learning in the circular swim maze-learning task. This study indicates that the observed functional deficits can be related to cell degeneration induced during a critical stage of neonatal brain development. The potentiated apoptosis induced by ketamine and diazepam may have implications for the selection of drugs used in neonatal paediatric anaesthesia.

Pre- and postnatal propylthiouracil-induced hypothyroidism impairs synaptic transmission and plasticity in area CA1 of the neonatal rat hippocampus.

Thyroid hormones are essential for neonatal brain development. It is well established that insufficiency of thyroid hormone during critical periods of development can impair cognitive functions. The mechanisms that underlie learning deficits in hypothyroid animals, however, are not well understood. As impairments in synaptic function are likely to contribute to cognitive deficits, the current study tested whether thyroid hormone insufficiency during development would alter quantitative characteristics of synaptic function in the hippocampus. Developing rats were exposed in utero and postnatally to 0, 3, or 10 ppm propylthiouracil (PTU), a thyroid hormone synthesis inhibitor, administered in the drinking water of dams from gestation d 6 until postnatal day (PN) 30. Excitatory postsynaptic potentials and population spikes were recorded from the stratum radiatum and the pyramidal cell layer, respectively, in area CA1 of hippocampal slices from offspring between PN21 and PN30. Baseline synaptic transmission was evaluated by comparing input-output relationships between groups. Paired-pulse facilitation, paired-pulse depression, long-term potentiation, and long-term depression were recorded to examine short- and long-term synaptic plasticity. PTU reduced thyroid hormones, reduced body weight gain, and delayed eye-opening in a dose-dependent manner. Excitatory synaptic transmission was increased by developmental exposure to PTU. Thyroid hormone insufficiency was also dose-dependently associated with a reduction paired-pulse facilitation and long-term potentiation of the excitatory postsynaptic potential and elimination of paired-pulse depression of the population spike. The results indicate that thyroid hormone insufficiency compromises the functional integrity of synaptic communication in area CA1 of developing rat hippocampus and suggest that these changes may contribute to learning deficits associated with developmental hypothyroidism.