Joseph F. Pasternak

Soluble oligomers of β amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus

The dementia in Alzheimer disease (AD) is usually attributed to widespread neuronal loss in conjunction with the pathologic hallmarks of intracellular neurofibrillary tangles and extracellular plaques containing amyloid (Aβ) in fibrillar form. Recently it has been demonstrated that non-fibrillar assemblies of Aβ possess electrophysiologic activity, with the corollary that they may produce dementia by disrupting neuronal signaling prior to cell death. We therefore examined the effects of soluble oligomers of Aβ1-42 on long-term potentiation (LTP) and long-term depression (LTD), two cellular models of memory, in the dentate gyrus of rat hippocampal slices. Compared with vehicle controls, slices pre-incubated 60 min in the presence of Aβ-derived diffusible ligands (ADDLs) showed no differences in threshold intensity to evoke a synaptic response, slope of field excitatory post-synaptic potentials (EPSPs), or the input/output function. Tetanus-induced LTP and reversal of LTD were strongly inhibited in ADDLs-treated slices whereas LTD was unaffected. These data suggest that soluble non-fibrillar amyloid may contribute to the pathogenesis of AD both by impairing LTP/memory formation at the cellular level and by creating ‘neuroplasticity imbalance’ manifested by unopposed LTD in the setting of impaired capacity for neural repair via reversal of LTD or LTP.

Stimulant therapy and seizure risk in children with ADHD

Stimulants are an effective treatment frequently prescribed for attention-deficit-hyperactivity disorder (ADHD), but they commonly are believed to lower the threshold for seizures. Although several studies have revealed that stimulants do not exacerbate well-controlled epilepsy, there is a paucity of data about seizure risk in nonepileptic children treated with stimulants. Two hundred thirty-four children (179 males, 9.1 +/- 3.6 years of age; 55 females, 9.6 +/- 3.9 years of age) with uncomplicated ADHD received electroencephalograms (EEGs) performed in our institution. Thirty-six patients (15.4%) demonstrated epileptiform abnormalities, and 198 (84.6%) demonstrated normal or nonepileptiform EEGs. Rolandic spikes accounted for 40% of the abnormal EEGs and 60% of those with focal abnormalities. Stimulant therapy was elected by 205 of 234 patients (87.6%). Seizures occurred only in the treated group, in one of 175 patients with a normal EEG (incidence 0.6%, 95% confidence intervals 0%-1.7%) and three of 30 treated patients with epileptiform EEGs (incidence 10%, 95% confidence interval 0%-20.7%). Seizures occurred in two of 12 children (16.7%) with rolandic spikes. These data suggest that a normal EEG can be used to assign children with ADHD to a category of minimal risk for seizure. In contrast, an epileptiform EEG in neurologically normal children with ADHD predicts considerable risk for the eventual occurrence of seizure. The risk, however, is not necessarily attributable to stimulant use.

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.

ApoE isoform affects LTP in human targeted replacement mice.

Inheritance of the &egr;4 allele for apolipoprotein E (apoE) increases the risk of Alzheimer disease and memory impairment, whereas &egr;2 decreases these risks compared with the most common &egr;3 allele, but the mechanism for these effects is unknown. Long-term potentiation (LTP) is an experimentally induced increase in synaptic efficacy that models memory. Using hippocampal slices from wild type (WT), apoE knockout (apoE-KO), and targeted replacement mice expressing human apoE2, E3, or E4 (apoE-TR) we found that although all strains had comparable basal synaptic transmission, LTP was significantly greater in WT and apoE3-TR than in apoE-KO, apoE2-TR or apoE4-TR. This novel system may be used to investigate the mechanisms of apoE isoform dependent modulation of susceptibility to memory impairment.

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.

Morphologic and electrophysiologic maturation in developing dentate gyrus granule cells

Dentate gyrus granule cells from immature (7-28 days) Sprague-Dawley rats were examined with whole cell patch clamp recordings and biocytin filling in in vitro hippocampal slice preparations. Although recordings were confined to the middle third of the suprapyramidal limb of the dentate, the granule cells exhibited marked variability in their physiologic properties: input resistance (IR) ranged from 250 MOmega to 3 GOmega, and resting membrane potential (RMP) from -82 to -41 mV. Both IR and RMP were inversely correlated with dendritic length, a morphometric indicator of cell maturity. Thus the highest IR cells were the youngest, and maturation was characterized by a progressive decrease in IR, hyperpolarization of RMP, and elongation of the dendritic arbor. When cells were grouped by IR, significant intergroup differences were found in RMP, dendritic length, and number of dendritic terminal branches. Although cells of all IR categories were examined throughout the age spectrum under study, none of the inter-IR group differences was age-dependent. These data suggest that IR provides a reasonable estimate of granule cell maturity and that maturation entails predictable changes in cell properties and morphology. These aspects of maturation correlate with each other, are independent of animal age, and most likely proceed according to a program related to cell birth.

Failure of daily lumbar punctures to prevent the development of hydrocephalus following intraventricular hemorrhage

A prospective study of 48 infants with periventricular-intraventricular hemorrhage was carried out to evaluate the role of daily lumbar punctures, instituted from the time of diagnosis of the hemorrhage, in prevention of posthemorrhagic hydrocephalus and improvement in immediate outcome. The data lead to the following conclusions: (1) minor hemorrhage (Grade I) is associated with minimal risk of death or hydrocephalus; (2) moderate hemorrhage (Grade II) is associated with low risk of death and intermediate risk of hydrocephalus, and serial lumbar punctures do not reduce these risks; and (3) severe hemorrhage (Grade III) is associated with high risks of death or hydrocephalus or both, and serial lumbar punctures also do not reduce these risks.

Regional cerebral blood flow in the beagle puppy model of neonatal intraventricular hemorrhage Studies during systemic hypertension

The newborn beagle puppy serves as an animal model for intraventricular hemorrhage (IVH) of the premature infant. Since increased systemic blood pressure has been implicated in the genesis of IVH in both babies and puppies, we studied regional cerebral blood flow in control and hypertensive puppies. Hypertension significantly increased blood flow to all structures. The largest increases occurred in gray matter, especially deep cerebral and brainstem nuclei. Blood flow also increased to deep hemispheric white matter, but the magnitude of the increase was smaller. Hypertension also increased blood flow to the subependymal germinal matrix (GM). The magnitude of the increase to most of the GM was small and similar to deep hemispheric white matter. The increase to the most rostral GM was higher and equal to the mean increase seen in gray matter. This rostralcaudal gradient of hypertension-induced hyperperfusion may explain the tendency for IVH to occur in rostral GM in premature babies. However, the failure to find a disproportionate increase in blood flow to GM during hypertension implies that additional factors besides hypertension-induced GM hyperperfusion may be involved in the pathogenesis of IVH.

Neonatal asphyxia: Vulnerability of basal ganglia, thalamus, and brainstem

Two infants who suffered acute intrapartum asphyxia resulting in severe neonatal encephalopathy are described. Although computed tomography revealed no abnormalities, magnetic resonance imaging documented unequivocal lesions in the thalamus, basal ganglia, parasagittal cortex, brainstem tectum, and midline cerebellum in one patient and in the basal ganglia and parasagittal cortex in the other. Thus, magnetic resonance imaging was more sensitive than computed tomography in detecting acute brain damage after neonatal asphyxia and may become an important tool in improving our understanding of the relationship between adverse perinatal events, neonatal encephalopathy, and neurologic morbidity.

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

ABSTRACT: Intracerebral hemorrhage in premature infants commonly originates in the germinal matrix (GM). We performed a quantitative analysis of cerebral micro-vasculature 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 μ) than cortex (6.9 μ), caudate (7.9 μ), and white matter (8.9 μ). 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 μ. 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.