Genome-wide assessment of diversity and differentiation between original and modern Brown cattle populations.

Identifying genomic regions involved in the differences between breeds can provide information on genes that are under the influence of both artificial and natural selection. The aim of this study was to assess the genetic diversity and differentiation among four different Brown cattle populations (two original vs. two modern populations) and to characterize the distribution of runs of homozygosity (ROH) islands using the Illumina Bovine SNP50 BeadChip genotyping data. After quality control, 34 735 SNPs and 106 animals were retained for the analyses. Larger heterogeneity was highlighted for the original populations. Patterns of genetic differentiation, multidimensional scaling, and the neighboring joining tree distinguished the modern from the original populations. The FST -outlier identified several genes putatively involved in the genetic differentiation between the two groups, such as stature and growth, behavior, and adaptability to local environments. The ROH islands within both the original and the modern populations overlapped with QTL associated with relevant traits. In modern Brown (Brown Swiss and Italian Brown), ROH islands harbored candidate genes associated with milk production traits, in evident agreement with the artificial selection conducted to improve this trait in these populations. In original Brown (Original Braunvieh and Braunvieh), we identified candidate genes related with fat deposition, confirming that breeding strategies for the original Brown populations aimed to produce dual-purpose animals. Our study highlighted the presence of several genomic regions that vary between Brown populations, in line with their different breeding histories.

The green tea polyphenol epigallocatechin-3-gallate (EGCG) restores CDKL5-dependent synaptic defects in vitro and in vivo.

CDKL5 deficiency disorder (CDD) is a rare X-linked neurodevelopmental disorder that is characterised by early-onset seizures, intellectual disability, gross motor impairment, and autistic-like features. CDD is caused by mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene that encodes a serine/threonine kinase with a predominant expression in the brain. Loss of CDKL5 causes neurodevelopmental alterations in vitro and in vivo, including defective dendritic arborisation and spine maturation, which most likely underlie the cognitive defects and autistic features present in humans and mice. Here, we show that treatment with epigallatocathechin-3-gallate (EGCG), the major polyphenol of green tea, can restore defects in dendritic and synaptic development of primary Cdkl5 knockout (KO) neurons. Furthermore, defective synaptic maturation in the hippocampi and cortices of adult Cdkl5-KO mice can be rescued through the intraperitoneal administration of EGCG, which is however not sufficient to normalise behavioural CDKL5-dependent deficits. EGCG is a pleiotropic compound with numerous cellular targets, including the dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) that is selectively inhibited by EGCG. DYRK1A controls dendritic development and spine formation and its deregulation has been implicated in neurodevelopmental and degenerative diseases. Treatment with another DYRK1A inhibitor, harmine, was capable of correcting neuronal CDKL5-dependent defects; moreover, DYRK1A levels were upregulated in primary Cdkl5-KO neurons in concomitance with increased phosphorylation of Tau, a well-accepted DYRK1A substrate. Altogether, our results indicate that DYRK1A deregulation may contribute, at least in part, to the neurodevelopmental alterations caused by CDKL5 deficiency.

Old World camels in a modern world - a balancing act between conservation and genetic improvement.

Old World camels have served humans in cross-continental caravans, transporting people and goods, connecting different cultures and providing milk, meat, wool and draught since their domestication around 3000-6000 years ago. In a world of modern transport and fast connectivity, these beasts of burden seem to be out-dated. However, a growing demand for sustainable milk and meat production, especially in countries affected by climate change and increasing desertification, brings dromedaries (Camelus dromedarius) and Bactrian camels (Camelus bactrianus) back onstage and into the focus of animal breeders and scientists. In this review on the molecular genetics of these economically important species we give an overview about the evolutionary history, domestication and dispersal of Old World camels, whereas highlighting the need for conservation of wild two-humped camels (Camelus ferus) as an evolutionarily unique and highly endangered species. We provide cutting-edge information on the current molecular resources and on-going sequencing projects. We cannot emphasise enough the importance of balancing the need for improving camel production traits with maintaining the genetic diversity in two domestic species with specific physiological adaptation to a desert environment.

Runs of homozygosity reveal genome-wide autozygosity in Italian sheep breeds.

The availability of dense single nucleotide polymorphism (SNP) assays allows for the determination of autozygous segments based on runs of consecutive homozygous genotypes (ROH). The aim of the present study was to investigate the occurrence and distribution of ROH in 21 Italian sheep breeds using medium-density SNP genotypes in order to characterize autozygosity and identify genomic regions that frequently appeared in ROH within individuals, namely ROH islands. After filtering, the final number of animals and SNPs retained for analyses were 502 and 46 277 respectively. A total of 12 302 ROH were identified. The mean number of ROH per breed ranged from 10.58 (Comisana) to 44.54 (Valle del Belice). The average length of ROH across breeds was 4.55 Mb and ranged from 3.85 Mb (Biellese) to 5.51 Mb (Leccese). Valle del Belice showed the highest value of inbreeding on the basis of ROH (FROH  = 0.099), whereas Comisana showed the lowest (FROH  = 0.016), and high standard deviation values revealed high variability in autozygosity levels within each breed. Differences also existed in the length of ROH. Analysis of the distribution of ROH according to their size showed that, for all breeds, the majority of the detected ROH were <10 Mb in length, with a few long ROH >25 Mb. The levels of ROH that we estimated here reflect the inbreeding history of the investigated sheep breeds. These results also highlight that ancient and recent inbreeding have had an impact on the genome of the Italian sheep breeds and suggest that several animals have experienced recent autozygosity events. Comisana and Bergamasca appeared as the less consanguineous breeds, whereas Barbaresca, Leccese and Valle del Belice showed ROH patterns typically produced by recent inbreeding. Moreover, within the genomic regions most commonly associated with ROH, several candidate genes were detected.

Genome-wide analysis highlights genetic dilution in Algerian sheep.

Algeria represents a reservoir of genetic diversity with local sheep breeds adapted to a large range of environments and showing specific features necessary to deal with harsh conditions. This remarkable diversity results from the traditional management of dryland by pastoralists over centuries. Most of these breeds are poorly productive, and the economic pressure leads farmers to realize anarchic cross-breeding (that is, not carried out in the framework of selection plans) with the hope to increase animal's conformation. In this study, eight of the nine local Algerian sheep breeds (D'men, Hamra, Ouled-Djellal, Rembi, Sidaoun, Tazegzawt, Berber and Barbarine) were investigated for the first time by genome-wide single-nucleotide polymorphism genotyping. At an international scale, Algerian sheep occupied an original position shaped by relations with African and European (particularly Italian) breeds. The strong genetic proximity with Caribbean and Brazilian breeds confirmed that the genetic make-up of these American breeds was largely influenced by the Atlantic slave trade. At a national scale, an alarming genetic dilution of the Berber (a primitive breed) and the Rembi was observed, as a consequence of uncontrolled mating practices with Ouled-Djellal. A similar, though less pronounced, phenomenon was also detected for the Barbarine, another ancestral breed. Genetic originality appeared to be better preserved in Tazegzawt, Hamra, D'men and Sidaoun. These breeds should be given high priority in the establishment of conservation plans to halt their progressive loss. For Berber and Barbarine that also occur in the bordering neighbor countries, urgent concerted transnational actions are needed.

Genome-wide analysis of Italian sheep diversity reveals a strong geographic pattern and cryptic relationships between breeds.

Italy counts several sheep breeds, arisen over centuries as a consequence of ancient and recent genetic and demographic events. To finely reconstruct genetic structure and relationships between Italian sheep, 496 subjects from 19 breeds were typed at 50K single nucleotide polymorphism loci. A subset of foreign breeds from the Sheep HapMap dataset was also included in the analyses. Genetic distances (as visualized either in a network or in a multidimensional scaling analysis of identical by state distances) closely reflected geographic proximity between breeds, with a clear north-south gradient, likely because of high levels of past gene flow and admixture all along the peninsula. Sardinian breeds diverged more from other breeds, a probable consequence of the combined effect of ancient sporadic introgression of feral mouflon and long-lasting genetic isolation from continental sheep populations. The study allowed the detection of previously undocumented episodes of recent introgression (Delle Langhe into the endangered Altamurana breed) as well as signatures of known, or claimed, historical introgression (Merino into Sopravissana and Gentile di Puglia; Bergamasca into Fabrianese, Appenninica and, to a lesser extent, Leccese). Arguments that would question, from a genomic point of view, the current breed classification of Bergamasca and Biellese into two separate breeds are presented. Finally, a role for traditional transhumance practices in shaping the genetic makeup of Alpine sheep breeds is proposed. The study represents the first exhaustive analysis of Italian sheep diversity in an European context, and it bridges the gap in the previous HapMap panel between Western Mediterranean and Swiss breeds.

Molecular tools and analytical approaches for the characterization of farm animal genetic diversity.

Genetic studies of livestock populations focus on questions of domestication, within- and among-breed diversity, breed history and adaptive variation. In this review, we describe the use of different molecular markers and methods for data analysis used to address these questions. There is a clear trend towards the use of single nucleotide polymorphisms and whole-genome sequence information, the application of Bayesian or Approximate Bayesian analysis and the use of adaptive next to neutral diversity to support decisions on conservation.

Genome-wide analyses reveal population structure and identify candidate genes associated with tail fatness in local sheep from a semi-arid area.

Under a climate change perspective, the genetic make-up of local livestock breeds showing adaptive traits should be explored and preserved as a priority. We used genotype data from the ovine 50 k Illumina BeadChip for assessing breed autozygosity based on runs of homozygosity (ROH) and fine-scale genetic structure and for detecting genomic regions under selection in 63 Tunisian sheep samples. The average genomic inbreeding coefficients based on ROH were estimated at 0.017, 0.021, and 0.024 for Barbarine (BAR, n = 26), Noire de Thibar (NDT, n = 23), and Queue fine de l'Ouest (QFO, n = 14) breeds, respectively. The genomic relationships among individuals based on identity by state (IBS) distance matrix highlighted a recent introgression of QFO into the BAR and a genetic differentiation of NDT samples, possibly explained by past introgression of European gene pools. Genome-wide scan for ROH across breeds and within the BAR sample set identified an outstanding signal on chromosome 13 (46.58-49.61 Mbp). These results were confirmed using FST index, differentiating fat vs. thin-tailed individuals. Candidate genes under selection pressure (CDS2, PROKR1, and BMP2) were associated to lipid storage and probably preferentially selected in fat-tailed BAR animals. Our findings suggest paying more attention to preserve the genetic integrity and adaptive alleles of local sheep breeds.

The genetic resistance to gastro-intestinal strongylids in Appenninica sheep: preliminary results.

Heritability parameters of resistance to gastro-intestinal strongylids, measured as FEC (Faecal Egg Count), were evaluated in the Appenninica sheep breed. FEC heritability coefficient was 0.11 +/- 0.061 while FEC repeatability coefficients were 0.58 +/- 0.085 and 0.76 +/- 0.223 in adult females and lambs respectively. Subjects were classified, based on FEC, into three different levels of resistance to strongylids. Ewes belonging to the 'resistant class' should be conveniently exploited in mating schemes, in order to provide a method, alternative to drug administration, for a long-term parasite control; this would result particularly helpful under those production systems, such as organic farming, where the use of drugs is not allowed or limited.

Exposure to cadmium during in vitro maturation at environmental nanomolar levels impairs oocyte fertilization through oxidative damage: A large animal model study.

Cadmium is a highly toxic heavy metal with negative effects on oocyte fertilization. The aim of this study was to analyse whether cadmium-induced impairment of fertilization is caused by mitochondria dysfunction and oxidative stress in the cumulus-oocyte complex (COC). Preliminarily, 19 trace element levels were measured in ovaries from juvenile and adult ewes and age-related cadmium ovarian bioaccumulation at nanomolar concentrations was found. COCs from juvenile and adult ewes, exposed during in vitro maturation to 1nM or 100nM CdCl2, and subjected to in vitro fertilization showed significantly lower fertilization rates in exposed COCs compared with controls. In vitro matured exposed and control COCs underwent confocal microscopy analysis of mitochondria activity and reactive oxygen species (ROS) levels and lipid peroxidation (LPO) assay at cumulus cell and oocyte level. In both age groups, cadmium at nanomolar concentrations induced cumulus-oocyte mitochondria over-activity and oxidative damage which were related to impaired oocyte fertilization.

Effect of early isolation on signal transfer in the entorhinal cortex-dentate-hippocampal system.

Deprivation of socio-sensory interactions during early life impairs brain function in adulthood. In previous investigations we showed that early isolation severely affects neuron development in several structures of the hippocampal region, including the entorhinal cortex. In the present study we investigated the effects of early isolation on signal processing along the entorhinal cortex-dentate-CA3-CA1 system, a major memory circuit of the hippocampal region. Male and female guinea-pigs were assigned at 6-7 days of age to either a social or an isolated environment. At 90-100 days of age the animals were anesthetized and field potentials were recorded from the entorhinal cortex-dentate-CA3-CA1 circuit, driven by dorsal psalterium commissural volleys. Analysis of the input-output function in the different structures showed that in isolated males there was a small reduction in the input-output function of the population excitatory postsynaptic potential and population spike evoked in layer II of the entorhinal cortex. No changes occurred in isolated females. In isolated males and females there was a reduction in the input-output function of the population excitatory postsynaptic potential and population spike evoked in the dentate gyrus, CA3 and CA1, but this effect was larger in males. In isolated males, but not in females, the population spike/population excitatory postsynaptic potential ratio was reduced in all investigated structures, indicating that in males the size of the discharged neuron population was reduced more than due to the decreased input. Results show that isolation reduces the synaptic function in the whole entorhinal cortex-dentate gyrus-CA3-CA1 system. While the entorhinal cortex was moderately impaired, the dentate-hippocampal system was more severely affected. The impairment in the signal transfer along the entorhinal cortex-dentate gyrus-CA3-CA1 system was heavier in males, confirming the larger susceptibility of this sex to early experience. This work provides evidence that malfunctioning of a major hippocampal network may underlie the learning deficits induced by impoverished surroundings during early life.

Sex differences in the hilar mossy cells of the guinea-pig before puberty.

Numerous sex differences have been detected in the morphology of the dentate and hippocampal neurons and hippocampus-dependent memory functions. The aim of the present study was to ascertain whether the mossy cells, an interneuron population forming a recurrent excitatory circuit with the dentate granule cells, are sexually dimorphic. The brains of juvenile (15-16 days old) and peripubescent (45-46 days old) male and female guinea-pigs were Golgi-Cox stained. Mossy cells were sampled from the hilus in the septal third of the dentate gyrus and their dendritic tree and somata were analyzed. The analysis was separately conducted on mossy cells with soma located in the portions of the hilus that face the upper blade (upper hilus) and lower blade (lower hilus), respectively. The mossy cells in the upper hilus were found to be sexually dimorphic in both juvenile and peripubescent animals. At both ages females had a larger dendritic tree than males. This difference was due to a greater mean branch length and, in peripubescent animals, also to a greater number of branches. In juvenile males, the spines on the proximal dendrites (thorny excrescences) had a greater density than in females. No differences in spine density were present in peripubescent animals. Unlike the mossy cells in the upper hilus, the mossy cells in the lower hilus showed very few sex differences in juvenile animals and no differences in peripubescent animals. The few differences favored females, that had more proximal branches and a greater spine density on the distal dendrites than males. The results show that the mossy cells of the guinea-pig are sexually dimorphic prior to puberty. Extending a previous investigation, the present data provide evidence that sex differences are mainly confined to the dentate region corresponding to the upper blade and upper hilus. The observed segregation of the sexual dimorphism in the upper blade/upper hilus suggests that this region might underlie the sexual dimorphism in hippocampus-dependent memory functions.

Sex differences in the stereological parameters of the hippocampal dentate gyrus of the guinea-pig before puberty.

Studies in rats and mice have shown several sex-dependent functional and structural differences in the hippocampal region, a brain structure playing a key role in learning and memory. The aim of the present study was to establish whether sex differences exist prior to puberty in the stereological parameters of the dentate gyrus in the guinea-pig, a long-gestation rodent, whose brain is at a more advanced stage of maturation at birth than the rat and mouse. The number of granule cells and volumes of the granule cell layer, molecular layer and hilus were evaluated in Nissl-stained brains of neonatal (15-16 days old) and peripubescent (45-46 days old) guinea-pigs. Based on a pilot study, the optical disector method was preferred to the optical fractionator method to estimate cell number. For volume (Vref) estimation with the Cavalieri principle, contour tracing was preferred to the point counting method, as the latter appeared to underestimate volumes. The results showed that neonatal males had more granule cells than females in both the dorsal and ventral dentate gyrus and a larger volume in all layers. Peripubescent males had a larger volume of the granule cell layer than females in both the dorsal and ventral dentate gyrus, more granule cells in the ventral dentate gyrus, a larger volume of the hilus in both the dorsal and ventral dentate gyrus and a larger volume of the molecular layer in the ventral dentate gyrus. The results show that sex differences are present in the guinea-pig dentate gyrus prior to puberty and go in the same direction at both investigated ages, with males exhibiting more granule cells and larger volumes than females. The widespread distribution of these sex differences suggests that in the guinea-pig, similarly to other rodents, hippocampus-dependent functions may be sexually dimorphic.

Signatures of selection identify loci associated with fat tail in sheep.

Identification of genomic regions that have been targets of selection for phenotypic traits is one of the most challenging applications of dense marker panels in animal genetics. In this study, a genomewide scan using approximately 50,000 SNP was performed in an attempt to identify genomic regions associated with fat deposition in sheep, the importance of this not only being limited to livestock facing future climate changes but also for elucidating the physiology of lipid metabolism. The genotyping results obtained with the Ovine SNP50K BeadChip in 2 fat tail breeds were compared with those obtained in 13 thin tail breeds. Direct sequencing of the annotated genes located in proximity to the markers with opposite allele frequency in thin tail vs. fat tail sheep gave additional SNP of interest. To further confirm the results of the genomewide scan, we genotyped the SNP within these genes in the 2 groups of sheep. A missense mutation in the gene, with different allele frequency in the 2 groups, was detected. The results indicated and as the most probable genes involved in the fat tail phenotype.

Inhibition of Zac1, a new gene differentially expressed in the anterior pituitary, increases cell proliferation.

Zac1 is a new zinc finger protein that concomitantly controls apoptosis and cell cycle arrest through separate pathways. The mouse Zac1 gene is mainly expressed in the pituitary gland and in different brain areas. In this study regional and cellular expression of Zac1 in the pituitary gland was determined by in situ hybridization. Zac1 messenger RNA was abundantly expressed in the anterior pituitary lobe compared with that in the intermediate and posterior lobes. Zac1 transcripts were found in all hormone-secreting cell types, with the highest levels in GH- and PRL-producing cells. To investigate the impact of Zac1 in pituitary cell proliferation, we ablated the endogenous Zac1 gene by antisense treatment in two murine cell types, AtT-20 and TtT/GF, that are representative of granular and agranular cell lineages, respectively. The decline in Zac1 protein levels under antisense treatment was accompanied by increased DNA synthesis in clonal corticotroph and folliculo-stellate cells, as demonstrated by enhanced [3H]thymidine incorporation (36% and 50%, respectively). Antisense oligonucleotides against Zac1 controlled cell proliferation in a dose-dependent way, and mutagenized antisense oligonucleotides were inert. Conclusively, our data provide the first evidence of a role for Zac1 in pituitary growth control.

Sex differences in the hippocampal dentate gyrus of the guinea-pig before puberty.

The aim of the present research was to ascertain the presence of sex differences in the hippocampal dentate gyrus of the guinea-pig, a long-gestation rodent which gives birth to mature young and whose brain is at a more advanced stage of maturation at birth than that of the rat and mouse. The brains of neonatal (15-16 days old) and prepubescent (45-46 days old) male and female guinea pigs were Golgi-Cox stained. Granule cells were sampled from the upper (suprapyramidal) and lower (infrapyramidal) blade of the septal dentate gyrus and their dendritic tree and soma were measured. The analysis was conducted separately on granule cells with soma in the superficial (superficial granule cells) and deep (deep granule cells) half of the granule cell layer. Numerous sex differences were found in the upper blade of the dentate gyrus. Neonatal males had more dendritic branches than females in the innermost dendritic tree of both superficial and deep granule cells, but females had more branches over the middle/outer dendritic tree and a longer dendritic length. In prepubescent animals, the sex difference in the middle dendritic tree of the superficial granule cells changed direction, with males having more branches than females. In the deep granule cells, the sex differences were similar to those in neonatal animals. In both granule cell types, the dendritic length was similar in the two sexes. While no sex differences were found in dendritic spine density in neonatal animals, in prepubescent animals spine density was greater in females. In the lower blade the granule cells showed very few sex differences in both neonatal and prepubescent animals. This study shows wide dynamically changing sex differences in the granule cells located in the upper blade of the septal dentate gyrus, but almost no differences in the lower blade. These results demonstrate that sex differences are not ubiquitous in the dentate gyrus and suggest that the lower blade, unlike the upper blade, might be involved in non-sexually dimorphic behaviors.

Long-lasting effects of chronic neonatal blockade of N-methyl-D-aspartate receptor through the competitive antagonist CGP 39551 in rats.

A competitive antagonist of the N-methyl-D-aspartate receptor, CGP 39551, was administered daily to neonatal rats with increasing doses from postnatal day 1 to 22. These animals displayed approximately 50% decrease of body weight at the end of treatment and, therefore, both normal and neonatally undernourished rats were used as controls. At a young adult stage (55-75 days of age) CGP 39551-treated rats showed a much higher spontaneous locomotor activity as compared to control groups. This hypermotility was counteracted by D1 and D2 dopamine antagonists while administration of methamphetamine increased, to the same extent, the differential basal locomotor activity of treated and control groups. The locomotor activity response to the N-methyl-D-aspartate channel blocker, dizocilpine maleate, was significantly shifted to the right for treated rats so that an equivalent increase of motility was obtained by doubling the dose effective for control animals. In in vivo microdialysis experiments, similar amounts of dopamine were collected from the striatum of treated and control rats after high K+ or methamphetamine stimulation, the only difference being a greater Ca2+ dependency of the depolarization-induced dopamine release in treated rats. Assays for different neurochemical parameters, carried out at 80-90 days of age, suggested some alteration of the balance between excitatory and inhibitory circuits in the basal ganglia of CGP 39551-treated rats. Tyrosine hydroxylase and calbindin immunostaining, as well as acetylcholinesterase histochemistry, revealed a similar picture in the striatum of treated and control rats. However, 5'-nucleotidase histochemistry showed a stronger and evenly distributed reactivity in the striatum of treated rats, opposite to the weaker and patchy localization of normal or undernourished controls. From the present results it is possible to conclude that chronic blockade of the N-methyl-D-aspartate receptor during neonatal brain maturation results in long-lasting alteration of locomotor activity which appears related to functional changes of the dopamine receptors as well as to an altered balance between various excitatory and inhibitory neurotransmitter and neuromodulatory systems.

Activation of a reporter gene responsive to NGFI-B in cultured neurons and astrocytes.

NGFI-B is an immediate early gene and orphan member of the nuclear receptor superfamily. It is induced in several tissues, including brain, and in cultured cerebellar granule cells in response to different stimuli. Since both the induction of its mRNA as well as the level and function of its gene product are under the control of the inducing stimulus, we wanted to study the final outcome of the stimulus, i.e., transcriptional activity, by means of a specific, artificial reporter gene in cultured CNS cells. Cultured cerebellar granule cells and astrocytes were transfected with an NGFI-B responsive reporter gene to study the role of NGFI-B as a transcriptional activator after stimulation of the protein kinase A and C pathways. In both cell types, stimulation of either protein kinase A or C with forskolin (10 microM) or phorbol 12-myristate 13-acetate (0.1 microM), respectively, gave up to fivefold induction of the reporter gene. In the granule cells a combined treatment gave a strong synergistic induction of the reporter gene. The astrocytes showed only weak synergy, indicating cell-specific regulation of the target gene by the two kinases.

Induction of the PAC1-R (PACAP-type I receptor) gene by p53 and Zac.

Pituitary adenylate cyclase-activating polypeptides and PAC1-R are expressed during early embryogenesis and PACAP's neurotrophic action supports a role in neuronal development. In the adult brain PACAP functions as a neuroprotective factor that attenuates the neuronal damage resulting from various insults. The tumor suppressor gene p53 and the new zinc finger protein Zac regulate apoptosis and cell cycle arrest through unrelated pathways and both genes are up-regulated under cerebral ischemia. We report here that p53 and Zac induce expression of the PAC1-R gene. By this mechanism p53 and Zac could fine-tune the balance between death promoting and protective signals and may thus fulfil a dual role in ischemia.

Chronic neonatal blockade of NMDA receptor does not affect developmental polyamine metabolism but results in altered response to the excitotoxic induction of ornithine decarboxylase.

Neonatal rats were subjected to chronic blockade of the N-methyl-D-aspartate (NMDA) receptor through daily systemic administration of increasing doses of the competitive antagonist CGP 39551 from postnatal days 1-22. Treatment did not result in any significant alteration of the levels of putrescine, spermidine and spermine or in the constitutively expressed activity of the key enzyme for polyamine biosynthesis, ornithine decarboxylase (ODC), as evaluated at 10 and 20 days of age. However, in 30-day-old rats significant differences were observed in the process of excitotoxic ODC induction in the olfactory cortex and the hippocampus of chronically-treated rats: the increase of ODC activity caused by systemic administration of kainic acid took place more rapidly but it was shorter and apparently reached a smaller peak in treated animals as compared to controls. This result, in conjunction with previous data on neurochemistry and locomotor activity of similarly treated rats, strengthens the suggestion that functional alterations of some brain circuits may be the consequence of the blockade of NMDA receptor during the critical neonatal period of brain maturation.