Biomedical subjects

J F Pasternak

Publications and source records attributed to J F Pasternak.

At least 19 recordsLinked to original sources

PubMed1999

Joubert's syndrome and prenatal hydrocephalus.

Joubert's syndrome is an autosomal-recessive condition characterized by dysgenesis of the cerebellar vermis, hypotonia, developmental delay, a respiratory pattern of alternating tachypnea and apnea, and abnormal eye movements. Radiologic findings include a midline cerebellar cleft in place of the vermis and a characteristic shape of the fourth ventricle. Prenatal hydrocephalus has been proposed as a possible etiology for the cerebellar abnormalities but has not previously been described in association with this syndrome. The authors report a patient with clinical and radiographic features consistent with Joubert's syndrome who presented with congenital hydrocephalus.

Abnormalities, Multiple↗

PubMed1998

The syndrome of acute near-total intrauterine asphyxia in the term infant.

Eleven term infants sustained an acute, near-total intrauterine asphyxia at the end of labor. Imaging studies documented a consistent pattern of injury in subcortical brain nuclei, including thalamus, basal ganglia, and brainstem; in contrast the cerebral cortex and white matter were completely or relatively spared. This pattern of injury correlated with the acute and long-term neurologic syndromes in these patients. Four patients had a severe neonatal encephalopathy that included prominent signs of brainstem dysfunction. The other seven patients had a moderate neonatal encephalopathy. Three of these patients had dystonia consistent with basal ganglia injury; all seven remained normocephalic and had good cognitive outcomes consistent with sparing of cerebral cortex and white matter. Finally, in all 11 patients, injury to organs other than the brain was usually subtle. The distribution of injury in these patients reflects the hierarchy of metabolic needs that are unmet after a severe, sudden disruption of substrate supply as occurs in an acute, severe asphyxia. Thus, the higher metabolic rate of the brain compared with other organs explains the significant neonatal encephalopathy with relative sparing of nonbrain organs. Similarly, the higher metabolic rate of subcortical nuclei compared with cerebral hemispheres explains the preponderance of subcortical damage. This clinical and imaging syndrome is in contrast with that seen in more prolonged but less severe intrauterine asphyxia, in which shunting of blood flow from nonbrain organs to the brain and from cerebral hemispheres to the thalamus and brainstem renders nonbrain organs and cerebral hemispheres most vulnerable.

Asphyxia Neonatorum↗

PubMed1998

GABAA currents in immature dentate gyrus granule cells.

We used whole cell patch clamp and gramicidin perforated patch recordings in hippocampal slices to study gamma-aminobutyric acid (GABA) currents in granule cells (GCs) from juvenile rat dentate gyrus (DG). GCs are generated postnatally and asynchronously such that they can be detected at different stages of their maturation in DG within the first month. In contrast, inhibitory interneurons are generated embryonically, and their circuitry is well developed even as their target GCs and GC excitatory connections are still being formed. In this study, two GABA currents evoked in GCs by medial perforant path stimulation are compared. The first, pharmacologically isolated by glutamate receptor blockade, is the product of direct activation of GABA interneurons with monosynaptic input to the recorded GC (monosynaptic GABAA). Monosynaptic GABAA displays slight outward rectification of its current-voltage relation, is 97% eliminated by 10 microM bicuculline and coincides temporally with the excitatory components of GC postsynaptic currents as has been described for GABAA currents in other brain regions. The second is a novel GABA response that is detectable in 10 microM bicuculline and is present on GCs only at the earliest stages of their maturation. Unlike monosynaptic GABAA, this transient GABA is eliminated by glutamate receptor blockade and hence is likely to be generated by interneurons activated via an intervening glutamatergic synapse (polysynaptically). It is predominantly chloride mediated, has a relative bicarbonate/chloride permeability ratio of 26%, and is unchanged by bath-applied saclofen and strychnine or by intracellular calcium chelation. It is 97% antagonized by 100 microM picrotoxin and 99% antagonized by 100 microM bicuculline. This current is thus a relatively bicuculline (BMI)-resistant GABAA current (BMIR-GABAA). Compared with monosynaptic GABAA, BMIR-GABAA has a later peak, slower time course of decay, and marked outward rectification. Its reversal potential is 7-8 mV depolarized to that of monosynaptic GABAA whether recorded in whole cell or with gramicidin perforated patch to preserve native internal chloride concentration. Together these data may suggest that BMIR-GABAA is evoked by an anatomically segregated population of interneurons activating a unique, developmentally regulated GABAA receptor. Further, the transient nature of this current coupled with its temporal characteristics that preclude overlap with the excitatory components of the synaptic response are consistent with a role that is trophic or signaling rather than primarily inhibitory.

Animals↗

PubMed1997

Metabotropic glutamate receptor mediated long-term depression in developing hippocampus.

The effects of bath application of the metabotropic glutamate receptor (mGluR) agonist 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD, 10 microM) were studied at the Schaffer collateral-CA1 synapse in hippocampal slices from rats of 8-33 days postnatal age. In immature animals (8-12 days) ACPD induced a biphasic response characterized by an acute decrease in field EPSP slope (approximately 50-60% of baseline) in the presence of the agonist, followed by long-term depression (LTD, approximately 75-80% of baseline) after washout. In animals older than 20 days, ACPD induced a slow onset potentiation or minimal change. Both the acute depression and LTD were blocked by the mGluR antagonist alpha-methyl-4-carboxyphenyl glycine (MCPG). ACPD-induced LTD was blocked by the N-methyl-D-aspartate receptor (NMDAR) antagonists D(-)-2-amino-5 phosphopentanoic acid (AP5) and dizocilpine maleate (MK-801), and by ethanol. Glutamic pyruvic transaminase, an enzyme that selectively metabolizes endogenous extracellular glutamate, also blocked LTD suggesting that the requisite NMDA currents were tonically activated by extracellular rather than synaptically released glutamate. ACPD-induced LTD was blocked by staurosporine, indicating a requirement for serinethreonine kinase activation, and was unaffected by the L-type voltage sensitive calcium channel blocker nitrendipine and the A1 adenosine receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT). Because mGluR-mediated LTD was observed only in immature CA1, mGluRs may play a role in hippocampal development, perhaps by contributing to synapse pruning in a temporally restricted fashion.

Animals↗

PubMed1996

Long-term depression at the medial perforant path-granule cell synapse in developing rat dentate gyrus.

Long-term depression (LTD) is a decrease in synaptic efficacy that may model the elimination of inappropriate synapses during brain development. LTD might therefore be expected to be prominent in the juvenile hippocampal dentate gyrus (DG), where the majority of neuronogenesis and excitatory synapse production and pruning occur in the first postnatal month. Thus far, however, LTD in immature DG remains unexplored. Low-frequency stimulus induced homosynaptic LTD was studied at the medial perforant path-granule cell synapse in rats 8-30 days of age. LTD was most consistent and was of greatest magnitude in the youngest animals, and was more robust in response to stimulation at 1 Hz than at 3 or 5 Hz. LTD was saturable by repetitive delivery of low-frequency stimulation, and reversible by tetanic stimulation that induced long-term potentiation (LTP). LTD of the field EPSP was not prevented by bath application of the NMDA receptor antagonist AP5, the mGluR antagonist MCPG, or the L-type voltage sensitive calcium channel antagonist nitrendipine. In whole cell recordings LTD induction was blocked by hyperpolarization of the postsynaptic neuron but not by calcium chelation with BAPTA. Calcium chelation blocked LTP and simultaneously unmasked tetanus induced LTD. These data demonstrate that LTD is prominent in immature DG, that LTP and LTD are complementary processes, and that LTD is likely to be induced postsynaptically because it is voltage dependent, although the mechanism of voltage dependence remains to be elucidated.

2-Amino-5-phosphonovalerate↗

PubMed1996

Developmental changes in membrane properties and postsynaptic currents of granule cells in rat dentate gyrus.

1. Whole cell patch-clamp recordings were used to study dentate gyrus granule cells in hippocampal slices from juvenile rats (postnatal days 8-32). Membrane properties were measured with the use of current-clamp recordings and were correlated with the morphology of a subgroup of neurons filled with biocytin. The components of the postsynaptic currents (PSCs) induced by medial perforant path stimulation were characterized with the use of specific receptor antagonists in voltage-clamp recordings. 2. Granule cells located in the middle third of the superior blade of stratum granulosum from the rostral third of hippocampus were divided into three groups according to their input resistance (IR). Neurons with low IR (206 +/- 182 M omega, mean +/- SD) had hyperpolarized resting membrane potentials (-82 +/- 7 mV) and high-amplitude action potentials (108 +/- 23 mV). Neurons were high IR (1,259 +/- 204 M omega) had more depolarized resting membrane potentials (-54 +/- 6 mV) and lower-amplitude action potentials (71 +/- 10 mV). Neurons with intermediate IR (619 +/- 166 M omega) also had intermediate resting membrane potentials (-63 +/- 7 mV) and action potential amplitudes (86 +/- 14 mV). Low-IR neurons became increasingly prevalent with advancing postnatal age, but neurons from each group could be found throughout the entire period under study. 3. Morphological studies of low-IR neurons revealed an extensive dendritic arborization that traversed the entire molecular layer and was characteristic of mature granule cells. High-IR cells had smaller somata and short, simple dendritic arborization that incompletely penetrated the molecular layer and were classified as immature. Intermediate-IR cells had morphological features of intermediate maturity. 4. The initial phase of the PSC evoked at -80 mV was a fast inward current that was comparable with respect to latency to peak, latency to onset, and 10-90% rise time in neurons of all maturities held at -80 mV. This current was 6-cyano-7-nitroquinoxaline-2,3-dione sensitive. 5. The decay phases of PSCs at -80 mV varied with neuronal maturity. Mature neurons had monoexponential decays (tau = 8.9 +/- 3.6). Intermediate and immature neurons had prominent later inward currents that resulted in slower decays. In the case of the immature neurons, the inward current during the decay phase could be separated from the initial fast inward peak. The later inward currents in intermediate and immature neurons were bicuculline sensitive. 6. With the use of uniform ionic conditions of the extracellular and patch solutions, current-voltage relations and reversal potentials for pharmacologically isolated alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA), and gamma-aminobutyric acid-A (GABAA) currents were comparable across all cell maturities. Calculated ratios for peak GABAA/NMDA/AMPA currents decreased significantly with maturation as follows: 9.4 +/- 2.9/1.4 +/- 0.5/1.0 for immature cells, 7.2 +/- 2.5/1.5 +/- 0.7O/1.0 for intermediate cells, and 2.0 +/- 1.2/0.9 +/- 0.4/1.0 for mature cells. 7. GABA current was mediated both by polysynaptic activation of interneurons and by direct activation of interneurons with monosynaptic input onto granule cells. The proportional contributions of mono- and polysynaptic GABA to total GABA were comparable across all cell maturities; latency to peak GABA current decreased with increasing cell maturity for both mono- and polysynaptic components. 8. We conclude that PSCs evoked in granule cells by medial perforant path activation in neurons of all maturities consist of both glutamatergic and GABAergic components. PSCS are dominated by GABAergic neurotransmission in immature granule cells, and the contribution of glutamatergic neurotransmission increases with neuronal maturation. The greater ratio of peak GABAA to glutamate currents and the longer time interval between their respective peaks combine to produce a distinctive PSC shape

Animals↗

PubMed1995

AP5 blocks LTP in developing rat dentate gyrus and unmasks LTD.

The hippocampal dentate gyrus undergoes active neuronogenesis as well as growth and regression of neuronal elements and connections during the early postnatal period. In some brain regions, most notably in the visual system, both activity-dependent synaptic plasticity and NMDA receptor activation are candidate mechanisms by which neuronal architecture may be refined during brain maturation. To investigate whether similar mechanisms might obtain in developing dentate, we studied the effects of tetanic stimulation before and after NMDA receptor blockade in hippocampal slices from rats at 7-33 days. Field potentials were recorded in the suprapyramidal granule cell layer in response to stimulation of the medial perforant path. Robust long-term potentiation (LTP) of population spike amplitude (approximately 200% of baseline) was produced by a single tetanus (100 Hz, 2 s, 200 microseconds) at all ages studied. Application of 10 microM AP5 depressed population spike amplitude only in the younger slices (approximately 81% of baseline at 8-15 days; approximately 86% of baseline at 16-24 days), suggesting that the NMDA receptor-mediated component of normal synaptic transmission is higher in early development and decreases with maturation. AP5 prevented or significantly diminished LTP at all ages, establishing the NMDA dependence of LTP induction in the medial perforant path throughout development. AP5 also unmasked tetanus-induced homosynaptic long-term depression (62-75% of baseline) in the younger slices (8-24 days). Thus, prominent NMDA receptor-mediated activity and the capacity for bidirectional synaptic plasticity are characteristic of immature dentate. These processes may influence dentate morphogenesis by contributing to the growth, regression, and stabilization of neuronal elements.

2-Amino-5-phosphonovalerate↗

PubMed1994

Perforant path kindling alters dentate gyrus field potentials and paired pulse depression in an age-dependent manner.

The effects of rapid perforant path kindling on field potentials and paired pulse depression were studied in the dentate gyrus of rats at four developmental stages: 14-16 days, 20-22 days, 27-29 days and 40-60 days (adult). In rats 14-29 days kindling was associated with sustained potentiation of population spike amplitude and population EPSP slope; in adults a progressive decline was seen in both measures. Inhibitory circuitry as assessed by paired pulse depression was intact at all ages studied. Kindling produced no lasting changes in this measure at 14-22 days; in the older age groups a significant increase in paired pulse depression was seen. Thus immature animals differed from adults in that they manifested persistent facilitation of excitatory transmission as a result of kindling and failed to mount a compensatory inhibitory response. These results suggest that the balance between excitation and inhibition is more readily shifted toward excitation in immature animals in a manner that may contribute to their unique vulnerability to epileptogenesis.

Aging↗

PubMed1993

Hypoxic-ischemic brain damage in the term infant. Lessons from the laboratory.

Term infants who have sustained brain damage from intrauterine asphyxia can often be classified into one of two distinct clinical and radiologic syndromes. The first consists of damage to the cerebral hemispheres. The second consists of damage predominantly involving the basal ganglia and thalamus. Results of studies of asphyxia in experimental animals are presented.

Animals↗

PubMed1992

Fetal stroke associated with elevated maternal anticardiolipin antibodies.

Middle cerebral artery infarction explains some cases of congenital hemiparesis with or without neonatal stroke. The etiology of the stroke is often obscure. We describe two infants with imaging evidence of middle cerebral artery infarction whose mothers had elevated anticardiolipin antibody levels after delivery. We speculate that these antibodies may have been responsible for intrauterine thromboembolic stroke.

Adult↗

PubMed1990

NMDA receptor antagonists inhibit kindling epileptogenesis and seizure expression in developing rats.

N-Methyl-D-aspartate (NMDA) receptor antagonists inhibit both the kindling process and the expression of seizures in previously kindled adult rats. Experimental seizures are more readily produced in infant than adult rats, possibly related to a developmental predominance of NMDA receptor-mediated effects. If so, reduction of seizure susceptibility by NMDA receptor antagonists should be more dramatic in infant rats than in adults. We studied the effect of ketamine and MK-801 on kindling epileptogenesis and seizure expression in 15-day-old rats. Ketamine (5, 10, and 20 mg/kg) and MK-801 (0.033 and 0.1 mg/kg) both significantly increased the latency to stage 3 or 4 seizures in dose-dependent fashion. These results were similar to those found in adults but occurred at slightly lower doses. Ketamine 20 mg/kg and MK-801 0.33 mg/kg totally eliminated clinical seizure activity and nearly abolished afterdischarge in previously kindled infant rats, effects exceeding those reported in adults using doses up to 6 times as great. These results support the hypotheses that NMDA receptor-mediated neurotransmission plays an important role in seizure production and the increased seizure susceptibility in immature brain and raise the possibility that NMDA receptor antagonists could be useful antiepilepsy agents in young children.

Animals↗

PubMed1989

Proconvulsant effects of aminophylline during amygdala kindling in developing rats.

Aminophylline (A) is a proconvulsant in adult rats. We studied the effect of A on amygdala kindling in 15-day-old rat pups. Production of generalized seizures was significantly promoted by A at doses ranging from 10 to 100 mg/kg. Terminal status epilepticus (TSE) was produced in 33% of pups receiving 25 mg/kg A, 75% of pups receiving 50 mg/kg A, and 100% of pups receiving 100 mg/kg A. The number of stimuli needed to produce a stage 4-5 generalized seizure was significantly smaller in animals receiving 10 mg/kg A (5.7 +/- 3.4), 25 mg/kg A (3.4 +/- 2.4), 50 mg/kg A (1.9 +/- 1.4), or 100 mg/kg A (1.9 +/- 1.6) than in saline-treated controls (12.3 +/- 3.7) (P less than 0.001). In addition, 16% of pups receiving 50 mg/kg and 33% of pups receiving 100 mg/kg A and never stimulated developed TSE. These seizure-promoting effects of A in rat pups undergoing amygdala kindling are far more dramatic and occur at far lower doses than those previously reported in adults.

Age Factors↗

PubMed1987

Parasagittal infarction in neonatal asphyxia.

A patient is described who suffered a bilateral hemorrhagic infarction in the parasagittal cerebrum following neonatal asphyxia. This case confirms experimental results that show the parasagittal cerebrum is especially vulnerable to ischemic damage in newborns.

Asphyxia Neonatorum↗

PubMed1987

The effect of systemic arterial hypertension on blood-to-tissue transport in experimental gliomas.

Systemic arterial hypertension was induced with epinephrine in 15 rats with 39 transplanted RG-2 brain tumors in an attempt to increase blood-to-tissue transport of a water-soluble compound. In 4 rats, hypertension was induced acutely (less than 5 sec), and in 11 hypertension was induced more slowly (over 5 min). Regional values of the unidirectional blood-to-tissue transfer constant (K) of alpha aminoisobutyric acid were measured with quantitative autoradiography. Mean arterial blood pressure (BP) over the experimental period increased from 117 +/- 17 mmHg (SD) to 168 +/- 18 mmHg in the rats with slowly induced hypertension, and from 124 +/- 4 to 142 +/- 5 mmHg in the acute hypertension group. Peak BP was 208 +/- 16 in the first group and 216 +/- 13 mmHg in the second. Intracerebral hemorrhage occurred in 10/15 animals, and there was disruption of BBB in tumor-free brain in 10/15 animals. Averaged mean whole tumor K of AIB in all hypertensive rats was 0.052 +/- 0.022 ml/g/min, compared to 0.037 +/- 0.015 ml/g/min in normotensive controls; there was no difference in mean tumor K between the two hypertensive groups. However, in intraparenchymal tumors without hemorrhage, K was only 0.039 +/- 0.013 ml/g/min. Although the mean K of AIB was higher in brain tumors of the hypertensive rats, the increase is unlikely to be meaningful in terms of augmented delivery of water-soluble drugs to brain tumors, and the high incidence of intracerebral hemorrhage countermands any clinical use of this approach.

Aminoisobutyric Acids↗

PubMed1987

Revascularization for moyamoya disease: five-year follow-up.

We present a case of severe moyamoya disease in a 4-year-old child involving the anterior and posterior circulations. Encephaloduroarteriosynangiosis was performed and the child was followed for 5 years with serial angiography. Early clinical stabilization was attained and the child has normal or superior intellectual development despite her early fixed deficits. Follow-up angiography revealed the development of several large direct anastomotic channels.

Arterial Occlusive Diseases↗

PubMed1987

Quantitative analysis of cerebral vessels in the newborn puppy: the structure of germinal matrix vessels may predispose to hemorrhage.

Intracerebral hemorrhage in premature infants commonly originates in the germinal matrix (GM). We performed a quantitative analysis of cerebral microvasculature from newborn puppies, a model for neonatal periventricular and intraventricular hemorrhage, at the light and electron microscopic level. GM vessels were compared with those of other brain regions in an effort to delineate pathogenetically significant structural features that might predispose to hemorrhage. Light microscopic examination revealed that GM vessel density (103.0 vessels/mm2) was similar to that in white matter (98.3 vessels/mm2), but lower than that of cortex (155.6 vessels/mm2) or caudate (259.9 vessels/mm2). Mean blood vessel diameter was slightly larger in GM (9.0 mu) than cortex (6.9 mu), caudate (7.9 mu), and white matter (8.9 mu). Ultrastructurally, GM vessels were thinner along greater portions of their circumferences than vessels from other brain regions, as shown by their smaller ratio of vessel wall area/vessel lumen area and their greater fraction of vessel wall with thickness less than 0.25 mu. In addition, a significantly larger fraction of GM capillary wall lacked direct contact with perivascular structures. We postulate that the larger size, thinner walls, and diminished support from surrounding neuropil, which characterize GM vessels, may render them more susceptible to both physical (e.g. hypertension) and metabolic (e.g. hypoxia) insults than vessels from other brain regions.

Animals↗

PubMed1985

Autoregulation of cerebral blood flow in the newborn beagle puppy.

Regional cerebral blood flow (RCBF) was measured in 17 newborn beagle puppies under conditions of moderate hypotension, normotension, and moderate hypertension. RCBF demonstrated autoregulation over the blood pressure range 35-70 mm Hg. When arterial pressure exceeded 75 mm Hg, RCBF increased significantly for all grey matter structures, 2 of 4 white matter structures, and 2 of 3 germinal matrix structures. The magnitude of the hypertension-induced increase in RCBF was highest for thalamic and mesencephalic nuclei, intermediate in cerebral cortex and other subcortical nuclei, and lowest in white matter. The hypertension-induced increase in CBF was low (similar to white matter) in some areas of germinal matrix but higher (similar to midline cerebral cortex) to rostral germinal matrix. The differences in RCBF during hypertension between rostral germinal matrix and cerebral white matter may partially explain the vulnerability of the germinal matrix to hemorrhage.

Animals↗

PubMed1985

Isolated ventricles following intraventricular hemorrhage.

Panventricular enlargement often follows intraventricular hemorrhage in the premature neonate. During a recent 12-month period, the authors identified five infants who required shunting because of symptomatic post-hemorrhagic hydrocephalus, which was progressive despite serial lumbar punctures and the use of indwelling subcutaneous ventricular reservoirs. In the first 6 months following placement of the initial shunt, four of the infants required an additional shunt for isolated ventricles. Two children had isolation of the lateral ventricles and required bilateral shunts. Two other children had isolation of the fourth ventricle from the lateral ventricular system and required posterior fossa shunts. All of the children were treated successfully using multiple shunts. In all cases, progressive dilation of the isolated ventricle was unaccompanied by the usual clinical signs of shunt malfunction. It appears that isolated ventricular systems are common following post-hemorrhagic hydrocephalus and these children must be followed closely with ultrasound and computerized tomography scanning.

Cerebral Hemorrhage↗