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PubMed2005

First characterization of a large deletion of the PDHA 1 gene.

Pyruvate dehydrogenase complex (PDC) deficiency is one of the major recognized causes of congenital lactic acidosis. The most common form is due to PDHA 1 gene (Xp22.12) defects. Here, we report the case of a Polynesian girl presenting with delayed neurological development, cortical atrophy, and posterior corpus callosum agenesis. Elevated lactate and pyruvate levels in blood and cerebrospinal fluid suggested PDC deficiency. However, PDC activity was within the normal range in lymphocytes and the direct sequencing of the 11 exons and intron-exon junctions of the PDHA 1 gene did not show any changes. Long-range PCR amplification of the whole gene (16 kb) from blood DNA revealed a heterozygous deletion of approximately 4.2kb. Fine mapping of the deletion breakpoint was achieved using purified long-range PCR products for restriction enzyme analysis and direct sequencing. The deletion removed a 4,227 bp region covering part of intron 5 to part of intron 9 [g.10,145_14,371 del 4,227]. The deletion breakpoint contained a short direct repeat (GTAG), which may be derived either from the upstream or the downstream homologous sequence. The presence of a GAG triplet and inverted repeats in the vicinity of the deletion suggest replication slippage at a polymerase alpha arrest site. This is the first time that a large intragenic deletion of the PDHA 1 gene has been characterized.

Base Sequence↗
PubMed2003

Inhibition of ubiquitin ligase Siah-1A by disabled-1.

Disabled-1 (Dab1) is a cytosolic adaptor protein that plays critical roles in cortical development. However, a detailed mechanism of action has not yet been clearly defined. Through yeast two-hybrid screening, we observed that mouse Siah-1A, an E3 ubiquitin ligase containing a RING finger motif, interacts with Dab1. Co-immunoprecipitation experiments and in vitro binding experiments both indicated direct interaction between Siah and Dab1. Steady-state expression of Siah was enhanced by the presence of Dab1 or lactacystin, a representative proteasomal inhibitor. Auto-ubiquitination of Siah was inhibited by the presence of Dab1, suggesting inhibition of Siah activity and subsequent increase of Siah expression by Dab1. Both Dab1-induced increase of steady-state expression of Deleted in colorectal cancer (DCC), one of the well-known substrates of Siah, and its inhibition by Siah Delta R suggest that Dab1 increases expression of DCC through inhibiting the activity of endogenous Siah. Our results suggest that Dab1 inhibits the activity of Siah.

Animals↗
PubMed2001

Delayed onset of enhanced MK-801-induced motor hyperactivity after neonatal lesions of the rat ventral hippocampus.

BACKGROUND: Abnormalities in the glutamatergic system, glutamate/dopamine/gamma-aminobutyric acid interactions, and cortical development are implicated in schizophrenia. Moreover, patients with schizophrenia show symptom exacerbation in response to N-methyl-D-aspartate (NMDA) antagonist drugs. Using an animal model of schizophrenia, we compared the impact of neonatal and adult hippocampal lesions on behavioral responses to MK-801, a noncompetitive NMDA antagonist. METHODS: Neonatal rats were lesioned on postnatal day 7. Their motor activity in response to MK-801 was tested at a juvenile age, in adolescence, and in adulthood. We also measured binding of [(3)H]MK-801 and the expression of NR1 messenger RNA (mRNA) in the medial prefrontal cortex and nucleus accumbens. Adult rats received similar lesions and were tested 4 and 8 weeks after the lesion. RESULTS: As juveniles, neonatally lesioned rats did not differ from control rats in responsiveness to MK-801, whereas in adolescence and adulthood they showed more pronounced hyperactivity than control rats. The adult lesion did not alter behaviors elicited by MK-801. Neonatally lesioned rats showed no apparent changes in [(3)H]MK-801 binding or expression of the NR1 mRNA. CONCLUSIONS: These results suggest that an early lesion of the ventral hippocampus affects development of neural systems involved in MK-801 action without changes at the NMDA receptor level, and they show that the behavioral changes manifest first in early adulthood.

Age Factors↗
PubMed2002

Smaller frontal lobe white matter volumes in depressed adolescents.

BACKGROUND: Prior studies have demonstrated reduced frontal lobe volumes in depressed adolescents. In this study, frontal lobe gray and white matter volumes in adolescents with major depressive disorder were evaluated. METHODS: Nineteen depressed and thirty-eight healthy comparison adolescents were recruited for a magnetic resonance imaging study. Images were segmented into gray matter, white matter, and cerebrospinal fluid. Morphometric measurements of the whole brain and frontal lobe region were completed. RESULTS: Whole brain volumes were significantly smaller in depressed subjects compared with the healthy comparison subjects. Significantly smaller frontal white matter volumes and significantly larger frontal gray matter volumes were found in the depressed subjects, after controlling for age and whole brain volume. CONCLUSIONS: These results are consistent with the hypothesis that a deficit in frontal volume exists during cortical development in adolescents with depression. Further studies are needed to assess whether volume differences resolve over time and the extent to which these differences influence response to treatment.

Adolescent↗
PubMed2003

Bilateral frontal polymicrogyria and epilepsy in a patient with Turner mosaicism: a case report.

Turner's syndrome (TS) is rarely associated with serious abnormalities of brain structure or malformations of cortical development. We report a 17-year-old girl with TS and 45,XO/46,XX mosaicism presenting bilateral frontal polymicrogyria (BFP) and epilepsy. To our knowledge, the association between TS and BFP has never been reported to date. Our observation confirms that in humans the X-chromosome plays an important role in the development and specialization of brain structure and function. We hypothesize that the absence or abnormalities of developmental genes localized on the X-chromosome could be involved in the pathogenesis of BFP observed in our patient.

Adolescent↗
PubMed1997

Contrast sensitivity in infants and children with Down syndrome.

A new contrast sensitivity (CS) card test was used to estimate contrast sensitivity in 18 infants and children with Down syndrome (DS). The results showed that although the overall shape of the contrast sensitivity functions (CSFs) of the subjects with DS was the typical inverted-U, their CSFs were depressed in comparison to control subjects and this relative loss became larger with increasing spatial frequency. In addition, there was little improvement in CS with age and the mean CSF among children with DS (mean age = 7.3 years) was equivalent statistically to a group of 12-month-olds without DS. The Teller Acuity Cards (TAC) were also used to assess visual acuity in 17 of the 18 children in our sample. The results of these tests showed that their visual acuity (VA) was significantly lower than normal, but was consistent with that extrapolated from each subject's CSF. Taken together with previous anatomical and developmental findings, our results suggest that the deficits in spatial vision among children with DS is due primarily to restricted cortical development, and secondarily, to the additional accommodative and ocular conditions that are prevalent in this population.

Adolescent↗
PubMed2000

REM sleep - by default?

Elements of three old, overlapping theories of REM sleep (REM) function, the Ontogenetic, Homeostatic and Phylogenetic hypotheses, together still provide a plausible framework - that REM (i) is directed towards early cortical development, (ii) "tones up" the sleeping cortex, (iii) can substitute for wakefulness, (iv) has a calming effect. This framework is developed in the light of recent findings. It is argued that the "primitiveness" of REM and its similarity to wakefulness liken it to a default state of "non-wakefulness" or a waking antagonist, anteceding "true" (non-REM) sleep. The "toning up" is reflected by inhibition of motor, sensory and (importantly) emotional systems, together pointing to integrated "flight or fight" activity, that preoccupies/distracts the organism when non-REM is absent and wakefulness unnecessary. Dreaming facilitates this distraction. In rodents, REM can provide stress coping and calming, but REM deprivation procedures incorporating immobility may further enhance stress and confound outcomes. REM "pressure" (e.g. REM rebounds) may be a default from a loss of inhibition of REM by non-REM. REM can be reduced and/or replaced by wakefulness, without adverse effects. REM has little advantage over wakefulness in providing positive cerebral recovery or memory consolidation.

Animals↗
PubMed1997

Behavioral changes in rats with early ventral hippocampal damage vary with age at damage.

Our previous work demonstrated that neonatal (on postnatal day 7, PD7) excitotoxic damage of the ventral hippocampus (VH) results in delayed emergence of behaviors related to dopaminergic (DA) transmission. In this study, the developmental effects of VH lesions induced at two other ages were investigated in the rat. Ibotenic acid or artificial cerebrospinal fluid was infused into the VH of 3- (PD3) or 14- (PD14)-day-old rat pups. Amphetamine-induced (1.5 mg/kg, i.p.) locomotor activity was assessed in the sham and lesioned rats prior to (PD35) and after puberty (PD56 and PD86). Apomorphine-induced (0.75 mg/kg s.c.) stereotypic behaviors were measured on PD56. Similar VH lesions resulted in different profiles of behavioral abnormalities depending upon the age at which they were induced. The PD3 lesioned rats displayed hyperlocomotion to amphetamine only after puberty, while the PD14 lesioned rats manifest hyperlocomotion as early as 3 weeks after surgery (at PD35). Moreover, the PD3 lesioned rats tended to show more stereotypic behaviors in response to apomorphine than the sham-operated controls, while the PD14 rats had a profoundly diminished stereotypic response. The behavioral changes in the PD3 lesioned rats are reminiscent of those previously described in animals lesioned at PD7. In contrast, the deficits in the PD14 lesioned animals resemble those seen before in rats lesioned in adulthood. These results indicate that the pattern of impairments associated with the excitotoxic VH lesion varies with age at lesion, i.e. a similar pattern seems to be associated with lesions up to PD7, but not by PD14. To the extent that the neonatal VH lesion in the rat models certain phenomenological aspects of schizophrenia, including the temporal pattern of symptom onset, these results provide evidence that the model requires an early defect in limbic cortical development.

Aging↗
PubMed1998

Chronic exposure to either somatostatin (SS) or octreotide, a long-lasting SS analogue, affects SS expression in the postnatal visual cortex of the rat.

The peptide somatostatin (SS) is widely distributed in the mammalian brain where it modulates neuronal activity through interactions with specific membrane-bound receptor subtypes (ssts). Five different ssts were characterized so far (sst1-5) and their selective agonists were developed on the basis of their binding specificity. SS and ssts are transiently expressed in the developing brain, suggesting a functional role of somatostatinergic systems in neuronal maturation. In the present study, we investigated the effects of chronic exposure to either the SS synthetic analogue, SS-14 or octreotide (a long-acting sst2-preferring analogue) on the maturation of SS-immunoreactivity (-ir) in the primary visual cortex of the rat. SS-ir maturation was investigated both by an evaluation of the number of SS-immunoreactive cells and by radioimmunoassay (RIA) to measure the levels of SS in the postnatal visual cortex. In the visual cortex of normal rats, the number of SS-positive cells markedly increased during the second postnatal week and then significantly decreased until the adult value was reached at the third week. Early and repeated intracerebroventricular (i.c.v.) injections of either SS-14 or octreotide prevented the increase in the number of SS-positive cells, with adult values reached at the end of the first postnatal week. Similarly, administration of either SS-14 or octreotide significantly decreased the SS content of the visual cortex, measured at the end of the second postnatal week. These results show that high local concentrations of either SS-14 or octreotide interfere with SS expression in developing cortical neurons in a restricted postnatal period.

Aging↗
PubMed2001

LIS1: from cortical malformation to essential protein of cellular dynamics.

The LIS1 gene was cloned following the study of children with lissencephaly and cytogenetic abnormalities involving chromosome 17p, however, the role of the LIS1 protein in normal cortical development is not precisely defined. LIS1 is a component of evolutionarily conserved intracellular multiprotein complexes and recent literature shows that these complexes are essential, not only for neuronal migration, but they might also be fundamental components of the machinery for cell proliferation and intracellular transport.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2003

Growth factors: can they promote neurogenesis?

Cortical development is a complex process in which extrinsic and intrinsic factors modulate the sequential generation of neurons and glia. Following successive rounds of division, precursors become determined along a neuronal or glial lineage prior to cell cycle exit and differentiation. Although the influence of growth factors in cell fate specification is not new, until recently little was known about the signaling pathways by which they regulate neuronal differentiation. Menard and colleagues have examined this issue and have demonstrated a role for the MEK-C/EBP (mitogen-activated-protein-kinase kinase and CCAAT/enhancer-binding protein) pathway in the promotion of growth factor-mediated neurogenesis.

Animals↗
PubMed1999

Persistent neuronal density changes related to the establishment of a motor memory.

Rats were trained in a lateralized reaching motor task during either an 'early' (22-31 days old) or a 'late' (62-71 days old) postnatal period. The 'late' group showed significant neuronal density reduction in cortical layers II-III of the contralateral motor forelimb representation. The 'early' group evidenced a similar localized contralateral effect that persisted after a subsequent period without training. Furthermore, in this group, a bilateral overall decrease in neuronal density was found throughout the motor cortex. This bilateral experience and age-dependent effect is conceivably related to a critical period of motor cortical development. The localized reduction of neuronal density strongly indicates a morphological expression of the motor engram. Our present study supports the concept that the acquisition and retention of motor learning involves the persistence of structural changes in the brain.

Animals↗
PubMed2001

Unilateral induced neocortical malformation and the formation of ipsilateral and contralateral barrel fields.

Freezing lesions to the developing cortical plate of rodents results in a focal malformation resembling human 4-layered microgyria, and this malformation has been shown to result in local and widespread disruptions of neuronal architecture, connectivity, and physiology. Because we had previously demonstrated that microgyria caused disruptions in callosal connections, we hypothesized that freeze lesions to the postero-medial barrel sub-field (PMBSF) in one hemisphere would affect the organization of this barrel field contralaterally. We placed freeze lesions in the presumptive PMBSF of neonatal rats and, in adulthood, assessed the architecture of the ipsilateral and contralateral barrel fields. Malformations in the PMBSF resulted in a substantial decrease in the number of barrels as identified by cytochrome oxidase activity. More importantly, we found an increase in the total area of the contralateral PMBSF, although there was no difference in individual barrel cross-sectional areas, indicating an increase in the area of inter-barrel septae. This increase in the septal area of the contralateral PMBSF is consistent with changes in callosal and/or thalamic connectivity in the contralateral hemisphere. These results are another example of both local and widespread disruption of connectional architecture following induction of focal microgyria.

Animals↗
PubMedDate not supplied

Reelin immunoreactivity in the adult neocortex: a comparative study in rodents, carnivores, and non-human primates.

Recent evidence indicates that, in addition to playing a crucial role in early cortical development, intercellular signaling mediated by the protein Reelin may be widely active in the adult neocortex. The extent of Reelin distribution and its functional role in the adult are not clear yet. Here, we have examined Reelin immunoreactivity in the neocortex of an adult rodent (rat, Rattus norvegicus), a carnivore (ferret, Mustela putorius), and a primate (macaque monkeys Macaca nemestrina, Macaca mulatta) at the optic microscope level. Our data show that the neocortex of all three species contains several morphologically distinct populations of interneurons whose perikaryon and proximal dendritic processes are heavily immunoreactive for Reelin. The laminar distribution of these cells is species-specific. In addition, discrete reelin-immunoreactive pericellular structures are present in virtually all neocortical neurons of macaques.

Animals↗
PubMed2003

Cellular physiology of the neonatal rat cerebral cortex.

The early development of the cerebral cortex is characterized by neurogenesis, neuronal migration, cellular differentiation and programmed cell death. Cajal-Retzius cells, developing cortical plate neurons and subplate cells form a transient synaptic circuit which may serve as a template for the formation of cortical layers and columns. These three neuronal cell types show distinct electrophysiological properties and synaptic inputs. Endogenous or exogenous harmful disturbances during this developmental period may lead to the preservation of early cortical circuits, which may act as trigger zones for the initiation of pathophysiological activity.

Action Potentials↗
PubMed2001

National survey on West syndrome in Korea.

AIM: To investigate and analyze the current epidemiological and clinical data for West syndrome (WS) in Korea, including treatments and outcome. METHODS: Prepared survey forms were sent to hospitals located all over Korea to collect data on cases of WS treated between January 1997 and June 2000. Data from 21 institutes were returned. RESULTS: Data were collected for 358 children (219 boys and 139 girls) who were diagnosed and treated for WS. The incidences of WS were 112 cases in 1997, 104 cases in 1998, 108 cases in 1999, and 34 cases in the first half of 2000. Based on these figures, the presumed annual incidence of WS in Korea was derived to be one in 4000 live births, although there was a great inter-district variability. Regarding the etiology, 138 cases (38.5%) were cryptogenic. For the 220 symptomatic cases, hypoxic-ischemic encephalopathy (HIE) was the most common etiologic factor (50.8%), followed by central nervous system anomaly including malformation of cortical development (21.4%), and neurocutaneous syndrome (8.6%). Clinically flexor type spasms were most common (59.2%) and 199 cases (55.6%) revealed typical hypsarrhythmia, electroencephalographically. During 1997 and 1998, vigabatrin (VGB) was used most frequently for the treatment of WS, followed by valproic acid and adrenocorticotropic hormone (ACTH). In 1999 and 2000, the use of ACTH diminished and topiramate was used more frequently than ACTH. Spasms were controlled in 230 cases (64.2%) and evolution to other seizure types was observed in 44 cases (11.2%). Developmental and/or mental retardation were noticed in 270 cases (75.4%). CONCLUSIONS: The yearly incidence of WS did not show significant change in Korea between 1997 and 2000. Among symptomatic WS, HIE was the most common cause. During the period of this study, VGB was the most popular therapeutic regimen possibly because of shortage of ACTH. Recently, topiramate has showed promising signs as a therapy for WS.

Adrenocorticotropic Hormone↗
PubMed2003

Bilateral posterior agyria-pachygyria and epilepsy.

We analyzed the electroclinical findings in two patients with bilateral posterior agyria-pachygyria. Both patients presented with mental retardation, mild motor deficit and epilepsy. The electroclinical findings were characterized by frequent tonic or atonic generalized seizures with occasionally simple or complex partial seizures. Interictal electroencephalography (EEG) showed occipital spikes and diffuse polyspike-wave paroxysms predominantly in the posterior region. Ictal EEG showed diffuse 10-11 Hz activity. Cerebral magnetic resonance imagings (MRIs) showed thickened cortex in the parieto-occipital lobes, bilaterally and symmetrically. The volume of underlying white matter appeared reduced, and the overlying subarachnoid spaces were enlarged. The occipital horns were dilated. These findings were compatible with agyria-pachygyria of the posterior portions of the brain. In conclusion, in patients with mental retardation, mild motor deficit and epilepsy characterized by tonic or atonic generalized seizures, interictal EEG with diffuse polyspike-wave paroxysms predominantly in posterior region, posterior focal epileptilorm abnormalities and ictal diffuse 10-11 Hz activity, bilateral parieto-occipital agyria-pachygyria should be considered as a possible etiology. Magnetic resonance image is the best neuroradiological study to identify this disorder of cortical development.

Adolescent↗
PubMed2002

Differential effects of prenatal cocaine exposure on selected subunit mRNAs of the GABA(A) receptor in rabbit anterior cingulate cortex.

We have previously shown that in the dopamine-rich anterior cingulate cortex (ACC), significant changes in gamma-aminobutyric acid (GABA) immunoreactivity occur in the offspring of rabbits given intravenous injections of cocaine (3 mg/kg) twice daily during pregnancy. In the present study, the effects of prenatal cocaine exposure on the developmental expression of specific GABA(A) receptor subunit mRNAs were investigated. We compared the distribution of the alpha1, beta2, and gamma2 subunit mRNAs in cocaine- and saline-treated offspring aged postnatal days 20 and 60 (P20, P60). At P20, prenatal cocaine exposure resulted in a significant increase in alpha1 subunit mRNA in ACC lamina III and a significant reduction in the amounts of the beta2 subunit mRNA in ACC lamina II. No differences between cocaine- and saline-treated controls were detected for gamma2 subunit mRNA levels in ACC. Although the pattern of labeling was altered in cocaine-exposed animals, Nissl sections revealed no differences in lamination, indicating that the changes in GABA(A) subunit mRNAs could not be attributed to abnormal cytoarchitectonics. In P60 brains, no significant differences were observed between cocaine- and saline-treated material, indicating that the observed differences were transient. Collectively, our data show that prenatal cocaine exposure elicits differential, lamina-specific changes in mRNA levels encoding selected subunits of the GABA(A) receptor. Since these changes occur during a critical period when fine tuning of synaptic organization is achieved by processes of selective elimination or stabilization of synapses, we suggest that specific subunit mRNAs of the GABA(A) receptor play a role in cortical development.

Amino Acid Sequence↗