Role of plasminogen in propagation of scrapie

To investigate whether plasminogen may feature in scrapie infection, we inoculated plasminogen-deficient (Plg(-/-)), heterozygous plasminogen-deficient (Plg(+/-)), and wild-type (Plg(+/+)) mice by the intracerebral or intraperitoneal (i.p.) route with the RML scrapie strain and monitored the onset of neurological signs of disease, survival time, brain, and accumulation of scrapie disease-associated forms of the prion protein (PrP(Sc)). Only after i.p. inoculation, a slight, although significant, difference in survival (P < 0.05) between Plg(-/-) and Plg(+/+) mice was observed. Neuropathological examination and Western blot analysis were carried out when the first signs of disease appeared in Plg(+/+) animals (175 days after i.p. inoculation) and when mice reached the terminal stage of illness. At the onset of symptoms, PrP(Sc) accumulation was higher in the brain and spleen of Plg(+/+) and Plg(+/-) mice than in those of Plg(-/-) mice, and these differences were paralleled by differences in the severity of spongiform changes and astrogliosis in the cerebral cortex and subcortical gray structures. Immunohistochemical analysis of the spleens before inoculation did not show any impairment of the immune system affecting follicular dendritic or lymphoid cells in Plg(-/-) mice. Once the disease progressed and mice began to die of infection, differences were no longer apparent in either brains or spleens. In conclusion, our data indicate that plasminogen has no major effect on the survival of scrapie agent-infected mice.     

Methylmercury-Induced Movement and Postural Disorders in Developing Rat: High-Affinity Uptake of Choline, Glutamate, and γ-Aminobutyric Acid in the Cerebral Cortex and Caudate-Putamen

Subcutaneous administration of methylmercuric chloride to neonatal rats resulted in movement and postural disorders during the fourth postnatal week. Sodium-dependent high-affinity uptake of radiolabeled choline, glutamate, and gamma-aminobutyric acid (GABA) was measured in homogenates of cerebral cortex and caudate-putamen. There was a significant decrease in the uptake of [3H]choline in the cerebral cortex, but not in the caudate-putamen, at the onset of neurological impairment (73-75%) and at one subclinical stage of toxicity (58-64%). No significant differences in [3H]glutamate uptake were detected in either region. The uptake of [3H]GABA in the presence of 1 mM beta-alanine, which was employed to inhibit the glial uptake process, was reduced significantly in both the cerebral cortex and caudate-putamen at the onset of neurological impairment (50-62%) and at one subclinical stage (40-51%). This decrease in [3H]GABA uptake is consistent with the results of previous studies using this animal model, which demonstrated a preferential degeneration of GABAergic neurons in the cerebral cortex and caudate-putamen of methylmercury-treated animals. Because the high-affinity uptake of choline is the rate-limiting step for acetylcholine synthesis by cholinergic neurons, the decrease in [3H]choline uptake may reflect an abnormal development of cholinergic innervation of the cerebral cortex.     

Pathogenesis of murine cytomegalovirus infection in natural killer cell-depleted mice.

The effect of natural killer (NK) cells on the course of acute and persistent murine cytomegalovirus (MCMV) infection was examined by selectively depleting NK cell activity by inoculation of mice with antibody to asialo GM1, a neutral glycosphingolipid present at high concentrations on NK cells. The dose of MCMV required to cause 50% mortality or morbidity in control C57BL/6 mice dropped 4- and greater than 11-fold, respectively, in mice first treated with anti-asialo GM1. NK cell-depleted mice had higher (up to 1,000-fold) virus titers in their lungs, spleens, and livers at days 3, 5, 7, and 9 postinfection. Spleens and livers of control mice were virus-free by day 7 postinfection, and their lungs showed no signs of active infection at any time. In contrast, MCMV had disseminated to the lungs of NK cell-depleted mice by day 5, and these mice still had moderate levels of virus in their lungs, spleens, and livers at day 9. Markedly severe pathological changes were noted in the livers and spleens of NK cell-depleted, MCMV-infected mice. These included ballooning degeneration of hepatocytes and spleen necrosis. MCMV-infected, NK cell-depleted mice had severe spleen leukopenia, and their spleen leukocytes exhibited a significantly lower (up to 13-fold) response to the T cell mitogen concanavalin A when compared with those of uninfected and MCMV-infected controls. It appeared that NK cells exerted their most potent antiviral effect early in the infection, in a pattern correlating with interferon production and NK cell activation; treatment with anti-asialo GM1 later in infection had no effect on virus titers. The relative effect of NK cell depletion on MCMV pathogenesis depended on the injection route of the virus. NK cell depletion greatly augmented MCMV synthesis and pathogenesis in mice inoculated either intravenously or intraperitoneally but had no effect on the course of disease after intranasal inoculation, at any time point examined. One month after intraperitoneal inoculation of virus, NK cell depletion resulted in a six- to eightfold increase in salivary gland virus titers in persistently infected mice, suggesting that NK cells may be important in controlling virus synthesis in the salivary gland during persistent infection. This treatment did not, however, induce dissemination of virus to other organs. These data support the hypothesis that NK cells limit the severity, extent, and duration of acute MCMV infection and that they may also be involved in regulating the persistent infection.     

CD8+ T lymphocytes control murine cytomegalovirus replication in the central nervous system of newborn animals

Human CMV infection of the neonatal CNS results in long-term neurologic sequelae. To define the pathogenesis of fetal human CMV CNS infections, we investigated mechanisms of virus clearance from the CNS of neonatal BALB/c mice infected with murine CMV (MCMV). Virus titers peaked in the CNS between postnatal days 10-14 and infectious virus was undetectable by postnatal day 21. Congruent with virus clearance was the recruitment of CD8(+) T cells into the CNS. Depletion of CD8(+) T cells resulted in death by postnatal day 15 in MCMV-infected animals and increased viral loads in the liver, spleen, and the CNS, suggesting an important role for these cells in the control of MCMV replication in the newborn brain. Examination of brain mononuclear cells revealed that CD8(+) T cell infiltrates expressed high levels of CD69, CD44, and CD49d. IE1(168)-specific CD8(+) T cells accumulated in the CNS and produced IFN-gamma and TNF-alpha but not IL-2 following peptide stimulation. Moreover, adoptive transfer of brain mononuclear cells resulted in decreased virus burden in immunodepleted MCMV-infected syngeneic mice. Depletion of the CD8(+) cell population following transfer eliminated control of virus replication. In summary, these results show that functionally mature virus-specific CD8(+) T cells are recruited to the CNS in mice infected with MCMV as neonates.     

Influence of Trypanosoma evansi in adenine nucleotides and nucleoside concentration in serum and cerebral cortex of infected rats

This study aimed to evaluate the adenine nucleotides and nucleoside concentration in serum and cerebral cortex of rats infected with Trypanosma evansi. Each rat was intraperitoneally infected with 1 × 10(6) trypomastigotes suspended in cryopreserved blood (Group A; n = 18). Twelve animals were used as controls (Group B). The infected animals were monitored daily by blood smears. At days 4 and 20 post-infection (PI) it was collected serum and cerebral cortex to measure the levels of ATP, ADP, AMP and adenosine by high performance liquid chromatography (HPLC). In serum there was a significant (P < 0.05) increase in the ATP, AMP and adenosine concentrations at days 4 and 20 PI in infected rats when compared to not-infected. Furthermore, in the cerebral cortex it was observed a significant (P < 0.05) increase in the concentrations of ATP, AMP and decreased adenosine levels at day 4 PI. At day 20 PI it was only observed an increase in the AMP and adenosine concentrations in cerebral cortex of infected rats when compared to not-infected. It was not observed any difference in ADP concentration in serum and brain at days 4 and 20 PI. No change was observed histologically in the cerebral cortex of infected animals. The results allow us to conclude that infection with T. evansi in rats causes an increase in the concentrations of ATP, AMP and adenosine in serum and cerebral cortex the time periods evaluated. These alterations occurred as a result of T. evansi infection which involves neurotransmission, neuromodulation and immune response impairment confirm the importance of the purinergic system in this pathology.     

Expression of thrombospondin-1 and CD36 and CD47 receptors in the rat brain after exposure to damaging factors in the early postnatal period

The expression of thrombospondin-1 (TS-1) and its receptors CD47 and CD36 in the cerebral cortex and hippocampus of rats under damaging factors in the early postnatal period was studied. After hypoxia on the 7th day of postnatal development, an increase in the number of CD47-expressing cerebral endothelial cells (days of postnatal development: P28–P70) and reduction in the number of TS-1-expressing astrocytes in the cortex at P28 were observed. In animals subjected to early postnatal stress at the age of P2–P15, a decrease in TS-1-expressing astrocytes in the cortex and hippocampus was registered (predominantly at the age of P28). It was noted that these changes characterize the period of long-term effects (P28–P70) of early stress that is relevant to the processes of reparative angiogenesis and arresting of neurological deficits.     

Development in vitro of cytotoxic lymphocytes against murine cytomegalovirus.

Lymphocytes cytotoxic for mouse embryo fibroblasts (MEF) infected with murine cytomegalovirus (MCMV) were produced by in vitro culture of "memory" spleen cells with UV-irradiated, MCMV-infected, MEF. Cytotoxic lymphocytes were developed from spleen cells of mice 10 to 240 days after infection with MCMV. The cytotoxic cells carried the theta and Ly 2 antigens, and were H-2 restricted in the recognition of infected target cells.     

Excess of taurine supplementation in rat: effects on GABA-related amino acids in developing nervous tissues.

The effects of taurine supplementation on GABA-related amino acid homeostasis in developing nervous tissues of suckling rats were studied. In the first two weeks of postnatal growth, cerebral cortex and cerebellum appear more accessible to taurine supplementation in comparison to retina; in addition, different changes in excitatory/inhibitory amino acids were observed. After the 5th day of life, in the retina and cerebellum of taurine-supplemented pups a decrease in GABA levels was found; in contrast, in cerebral cortex GABA content significantly increased throughout 20 days of postnatal growth. In all nervous tissues studied (except for cerebellum) glutamine concentration increased at the 5th day; then in cerebellum and in retina, but not in cerebral cortex, a significant decrease until the 20th day occurred. Furthermore, in cerebellum and retina taurine supplementation decreased glutamate levels, in comparison to controls, at the 10th and until the 20th day of postnatal life, respectively, whereas in cerebral cortex an increase in glutamate level was observed only at the 5th day. In conclusion, taurine supplementation, in excess to the usual amount from the mother's milk, affected the glutamate compartments in various cell types. The changes in GABA-related amino acid concentrations in cerebral cortex, cerebellum, and retina may depend on the different pattern of the metabolic processes at different maturative stages.     

Immunosuppression-induced defective lymphocyte proliferation to murine cytomegalovirus is prolonged following the cessation of immunosuppression

Defective murine cytomegalovirus (MCMV) antigen-specific proliferation, induced by treatment of MCMV-infected mice with either antilymphocyte globulin (ALG), prednisolone, or both agents, was eventually restored following the cessation of immunosuppression. At 100 and 278 days following the end of immunosuppressive therapy splenic lymphocytes from infected and subsequently immunosuppressed mice responded significantly in vitro to soluble MCMV antigen after having lost this response immediately upon initiation of immunosuppression. Circulating specific antibodies and mitogen-induced blast transformation were comparable between infected mice and infected mice that also were immunosuppressed. At 278 days following the cessation of immunosuppression splenocytes from infected mice that had been treated with ALG yielded greatly increased background proliferation. Nylon-wool adherence was used to obtain enriched populations of T cells, and B cells and monocytes from MCMV-infected mice. While T cells alone did not respond in vitro to MCMV antigen, recombining B cells and monocytes with the T cells reconstituted in vitro proliferation. Defective lymphocyte proliferation to MCMV for an extended period of time following the end of immunosuppressive therapy indicated a prolonged inability to respond to an active MCMV infection. Identification of the cellular basis for the proliferation defect might lead to the development of effective immunotherapy.     

DEVELOPMENT AND CHARACTERISTICS OF THE HISTAMINE-INDUCED ACCUMULATION OF CYCLIC AMP IN THE RABBIT CEREBRAL CORTEX

Abstract— In slices of adult rabbit cerebral cortex histamine at 5 μM produced a detectable rise in adenosine 3',5'-monophosphate (cyclic AMP). A maximum (20-fold) increase was observed in response to 0–5 mM histamine, with higher concentrations being less effective. The antihistaminic agent, tripelennamine, inhibited the response to 50 μM histamine in a dose-related manner. No effect on basal levels of cyclic AMP was noted with the highest dose of tripelennamine. The cyclic AMP response to 50 μM histamine was sustained for up to 1 h of incubation whether the slices and included medium were assayed together or the slices were assayed separately, although after 60 min of incubation cyclic AMP levels were higher when the medium was included in the assay. During development of the rabbit cerebral cortex, the first detectable increase of cyclic AMP in response to histamine occurred at fetal day 25, and from day 28 to birth the response was a 4-to 5-fold increase. A maximal (10-fold) response was observed at 4–8 days postpartum and by 20 days of postnatal age the response had decreased to the adult levels.     

Epidermal growth factor receptor ontogeny in mice with congenital hypothyroidism

To assess the effect of endogenous thyroid hormone on hepatic EGF receptors in developing mice we measured EGF binding to plasma membrane receptors in liver and brain of mice with congenital hypothyroidism and in euthyroid controls at 20, 30 and 40 days of age. At 20 days hepatic EGF receptor binding was low in both hypothyroid and control animals. Between 20 and 30 days the hepatic binding increased dramatically in the euthyroid animals, an increase that was greater in males than females. The increase in binding was due to an increase in the high affinity receptor population. Among hypothyroid animals there were no changes in hepatic EGF receptor binding with increasing age. In cerebral cortex EGF binding was similar in euthyroid and hypothyroid animals at all ages. These results suggest that thyroxine has regulatory effects on the postnatal ontogeny of hepatic EGF receptors.     

巨细胞病毒感染对新生豚鼠胸腺的影响

新生豚鼠皮下接种豚鼠巨细胞病毒(GPCMV)后,导致动物胸腺急性感染。感染豚鼠胸腺在接种后第五天开始出现病毒,第十天达高峰。此外,感染动物胸腺的发育受到抑制,细胞总数和T淋巴细胞数随朐腺中病毒滴度的增高而进行性下降,至接种GPCMV后第十天最显著。由于病毒对T细胞的作用,细胞表面红细胞受体的丧失导致胸腺Null细胞百分比高于对照动物。     

Neurochemical profile of the developing mouse cortex determined by in vivo 1H NMR spectroscopy at 14.1 T and the effect of recurrent anaesthesia

The neurochemical profile of the cortex develops in a region and time specific manner, which can be distorted by psychiatric and other neurological pathologies. Pre-clinical studies often involve experimental mouse models. In this study, we determined the neurochemical profile of C57BL/6 mice in a longitudinal study design to provide a reference frame for the normal developing mouse cortex. Using in vivo proton NMR spectroscopy at 14 T, we measured the concentrations of 18 metabolites in the anterior and posterior cortex on postnatal days (P) 10, 20, 30, 60 and 90. Cortical development was marked by alterations of highly concentrated metabolites, such as N-acetylaspartate, glutamate, taurine and creatine. Regional specificity was represented by early variations in the concentration of glutamine, aspartate and choline. In adult animals, regional concentration differences were found for N-acetylaspartate, creatine and myo-inositol. In this study, animals were exposed to recurrent isoflurane anaesthesia. Additional experiments showed that the latter was devoid of major effects on behaviour or cortical neurochemical profile. In conclusion, the high sensitivity and reproducibility of the measurements achieved at 14 T allowed us to identify developmental variations of cortical areas within the mouse cortex.     

Ellagic acid protects from myelin-associated sphingolipid loss in experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE), the most common model for multiple sclerosis, is characterized by inflammatory cell infiltration into the central nervous system and demyelination. Previous studies have demonstrated that administration of some polyphenols may reduce the neurological alterations of EAE. In this work, we show that ellagic acid, a polyphenolic compound, is beneficial in EAE, most likely through stimulation of ceramide biosynthesis within the brain. EAE was induced in Lewis rats by injection of guinea-pig spinal cord tissue along with Freund's complete adjuvant containing Mycobacterium tuberculosis. Clinical signs first appeared at day 8 post-immunization and reached a peak within 3?days, coincident with reduction of myelin basic protein (MBP) in the cortex. Sphingolipids, the other major components of myelin, also decreased at the acute phase of EAE, both in the cerebral cortex and in the spinal cord. In rats receiving ellagic acid in the drinking water from 2?days before immunization, the onset of the disease was delayed and clinical signs were reduced. This amelioration of clinical signs was accompanied by sustained levels of both MBP and sphingolipid in the cortex, without apparent changes in infiltration of inflammatory CD3+ T-cells, microglial activation, or weight loss, which together suggest a neuroprotective effect of ellagic acid. Finally, in glioma and oligodendroglioma cells we demonstrate that urolithins, the ellagic acid metabolites that circulate in plasma, stimulate the synthesis of ceramide. Together these data suggest that ellagic acid consumption protects against demyelination in rats with induced EAE, likely by a mechanism involving sphingolipid synthesis.     

Glucocortiocoid Treatment of MCMV Infected Newborn Mice Attenuates CNS Inflammation and Limits Deficits in Cerebellar Development

Infection of the developing fetus with human cytomegalovirus (HCMV) is a major cause of central nervous system disease in infants and children; however, mechanism(s) of disease associated with this intrauterine infection remain poorly understood. Utilizing a mouse model of HCMV infection of the developing CNS, we have shown that peripheral inoculation of newborn mice with murine CMV (MCMV) results in CNS infection and developmental abnormalities that recapitulate key features of the human infection. In this model, animals exhibit decreased granule neuron precursor cell (GNPC) proliferation and altered morphogenesis of the cerebellar cortex. Deficits in cerebellar cortical development are symmetric and global even though infection of the CNS results in a non-necrotizing encephalitis characterized by widely scattered foci of virus-infected cells with mononuclear cell infiltrates. These findings suggested that inflammation induced by MCMV infection could underlie deficits in CNS development. We investigated the contribution of host inflammatory responses to abnormal cerebellar development by modulating inflammatory responses in infected mice with glucocorticoids. Treatment of infected animals with glucocorticoids decreased activation of CNS mononuclear cells and expression of inflammatory cytokines (TNF-α, IFN-β and IFNγ) in the CNS while minimally impacting CNS virus replication. Glucocorticoid treatment also limited morphogenic abnormalities and normalized the expression of developmentally regulated genes within the cerebellum. Importantly, GNPC proliferation deficits were normalized in MCMV infected mice following glucocorticoid treatment. Our findings argue that host inflammatory responses to MCMV infection contribute to deficits in CNS development in MCMV infected mice and suggest that similar mechanisms of disease could be responsible for the abnormal CNS development in human infants infected in-utero with HCMV.     

Diagnosis of encephalitozoonosis in experimentally infected rabbits by intradermal and immunofluorescence tests.

The indirect immunofluorescence antibody test was performed on serial blood samples from eight young New Zealand White rabbits with experimental encephalitozoonosis. The test showed seroconversion in six of the eight infected rabbits by the 8th day after inoculation and in all rabbits by the 15th day. Antibody titers reached a peak by about the 36th day after inoculation and remained significantly elevated until the termination of the experiment at 84 days after inoculation. None of four sham-inoculated rabbits showed an immunofluorescence response by the 60th day after inoculation. Immunofluorescence and intradermal test responses were compared before infection and at the 60th day after inoculation in a total of 32 experimentally infected rabbits. Both tests were equally effective (100%) in detecting infected animals. Six of eight (first group) and 22 of 24 (second group) experimentally infected rabbits were confirmed histologically to have lesions compatible with encephalitozoonosis. No cross reactions were observed between Encephalitozoon cuniculi and Toxoplasma gondii, Eimeria perforans, or Eimeria stiedai by intradermal test or immunofluorescence test.     

Neospora caninum (Protozoa: apicomplexa) infections in mice

Groups of mice were given 0 mg, 4 mg, or 2 mg of methylprednisolone acetate (MPA) 7 days prior to, the day of, and 7 days after subcutaneous inoculation with 0 or 2 x 10(5) tachyzoites of Neospora caninum. Clinical signs of disease were seen only in mice given both MPA and N. caninum tachyzoites. Mice given 4 mg MPA and N. caninum tachyzoites developed severe disseminated neosporosis and most died or were killed when comatose 11-13 days postinoculation (PI). Acute pneumonia, polymyositis, encephalitis, hepatitis, and pancreatitis were the main lesions in these mice. Mice given 2 mg MPA and N. caninum developed mild pneumonia and many mice began showing neurological signs 14 days PI. Neurological signs consisted mainly of pronounced head-tilting and associated impairment of movement. Grossly visible 1-2-mm single or multiple, white areas of discoloration were seen in the brains of many of these mice. Encephalitis, ganglioradiculoneuritis, pneumonia, and polymyositis were the main changes seen in these mice. Tissue cysts of N. caninum were only seen in mice given 2 mg MPA and were first seen 21 days PI. Tissue cysts were 16-34 by 13-29 microns and had a 1.5-3.0-microns-thick cyst wall. Tissue cysts were seen only in the brain. Mice given 4 mg MPA and tachyzoites and host cells that had been frozen for 1 wk did not develop clinical signs of infection, indicating that freezing kills tachyzoites and that viruses or other agents were not involved in the genesis of disease seen in mice given MPA and viable tachyzoites.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cell-mediated immune responses in mice infected with fonsecaea pedrosoi

Time course of cellular and humoral immune responses in mice infected with Fonsecaea pedrosoi was investigated by using an antigen prepared from culture filtrate of this fungus. Mice were infected by intravenous injection with yeast-like cells of the fungus. Viable fungus was recovered from the brain of the infected mice until the 36th day after inoculation, and from the other organs examined until 14th to 16th day. Inflammatory lesions were observed in the brain, lung, heart, liver, spleen, kidney and intestine during the first 30 days after inoculation. Macrophage migration inhibition factor response in these mice was insignificant until 8 days after inoculation. A significant response was developed at day 10 and persisted until day 63. This response returned negative by 95 days after inoculation. Lymphocyte transformation response of these mice was negative until 4 days after inoculation. At day 6 blastogenic index increased to 1.5, and at day 10, 14 and 16 the indices were 1.8, 2.4 and 1.7 respectively. Precipitin response to this fungus could not be detected in these mice until 16 days after inoculation. Positive results were obtained at day 21 and lasted until 51 days after inoculation. The precipitin titers, however, did not exceed one fold in any of these mice.     

Folic Acid Prevents Behavioral Impairment and Na+,K+-ATPase Inhibition Caused by Neonatal Hypoxia–Ischemia

Folic acid plays an important role in neuroplasticity and acts as a neuroprotective agent, as observed in experimental brain ischemia studies. The aim of this study was to investigate the effects of folic acid on locomotor activity, aversive memory and Na(+),K(+)-ATPase activity in the frontal cortex and striatum in animals subjected to neonatal hypoxia-ischemia (HI). Wistar rats of both sexes at postnatal day 7 underwent HI procedure and were treated with intraperitoneal injections of folic acid (0.011 μmol/g body weight) once a day, until the 30th postnatal day. Starting on the day after, behavioral assessment was run in the open field and in the inhibitory avoidance task. Animals were sacrificed by decapitation 24 h after testing and striatum and frontal cortex were dissected out for Na(+),K(+)-ATPase activity analysis. Results show anxiogenic effect in the open field and an impairment of aversive memory in the inhibitory avoidance test in HI rats; folic acid treatment prevented both behavioral effects. A decreased Na(+),K(+)-ATPase activity in striatum, both ipsilateral and contralateral to ischemia, was identified after HI; a total recovery was observed in animals treated with folic acid. A partial recovery of Na(+),K(+)-ATPase activity was yet seen in frontal cortex of HI animals receiving folic acid supplementation. Presented results support that folic acid treatment prevents memory deficit and anxiety-like behavior, as well as prevents Na(+),K(+)-ATPase inhibition in the striatum and frontal cortex caused by neonatal hypoxia-ischemia.     

Ablation of TNAP function compromises myelination and synaptogenesis in the mouse brain

Mutations in the tissue-nonspecific alkaline phosphatase (TNAP) gene can result in skeletal and dental hypomineralization and severe neurological symptoms. TNAP is expressed in the synaptic cleft and the node of Ranvier in normal adults. Using TNAP knockout (KO) mice (Akp2(-/-)), we studied synaptogenesis and myelination with light- and electron microscopy during the early postnatal days. Ablation of TNAP function resulted in a significant decrease of the white matter of the spinal cord accompanied by ultrastructural evidence of cellular degradation around the paranodal regions and a decreased ratio and diameter of the myelinated axons. In the cerebral cortex, myelinated axons, while present in wild-type, were absent in the Akp2 ( -/- ) mice and these animals also displayed a significantly increased proportion of immature cortical synapses. The results suggest that TNAP deficiency could contribute to neurological symptoms related to myelin abnormalities and synaptic dysfunction, among which epilepsy, consistently present in the Akp2 (-/-) mice and observed in severe cases of hypophosphatasia.