Laurence E. Becker

Regulation of AMPA Receptor–Mediated Synaptic Transmission by Clathrin-Dependent Receptor Internalization

Redistribution of postsynaptic AMPA- (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid-) subtype glutamate receptors may regulate synaptic strength at glutamatergic synapses, but the mediation of the redistribution is poorly understood. We show that AMPA receptors underwent clathrin-dependent endocytosis, which was accelerated by insulin in a GluR2 subunit-dependent manner. Insulin-stimulated endocytosis rapidly decreased AMPA receptor numbers in the plasma membrane, resulting in long-term depression (LTD) of AMPA receptor-mediated synaptic transmission in hippocampal CA1 neurons. Moreover, insulin-induced LTD and low-frequency stimulation-(LFS-) induced homosynaptic CA1 LTD were found to be mutually occlusive and were both blocked by inhibiting postsynaptic clathrin-mediated endocytosis. Thus, controlling postsynaptic receptor numbers through endocytosis may be an important mechanism underlying synaptic plasticity in the mammalian CNS.

Revision of the world health organization classification of brain tumors for childhood brain tumors

A classification for childhood brain tumors based upon revision of nomenclature of all brain tumors published by the World health Organization (WHO) in 1979 is proposed. Applicability of the WHO classification scheme was tested in a combined study of the clinical and pathologic features of approximately 3300 brain tumors in children. It was found to be adequate for many of the neoplasms but unsuitable for a significant proportion, including a number of complex cerebral tumors for which there was no appropriate name. Nomenclature of poorly differentiated or densely cellular neuroepithelial tumors was simplified to reflect the current state of knowledge of neuroembryology and neuro‐oncology, although the Committee members recognized that such a proposal would likely perpetuate the longstanding and continuing controversy relative to the nature and origin of these neoplasms. Cancer 56: 1869‐1886, 1985.

Abnormal neuronal development in the visual cortex of the human fetus and infant with down's syndrome. A quantitative and qualitative Golgi study.

The developmental morphology of visual cortical neurons (their numbers, dendritic arborization and numbers of spines) in 14 fetuses and infants with Downs syndrome were studied and compared with that of neurologically normal, age-matched controls. Fetuses with Trisomy 21 showed the same neuronal morphology and spine counts as control fetuses. However, the newborns and older infants with Downs syndrome showed shorter basilar dendrites and decreased numbers of spines with altered morphology and defective cortical layering.

A specific histochemical marker (lectin Ricinus communis agglutinin-1) for normal human microglia, and application to routine histopathology

SummaryMicroglia were demonstrated in paraffinembedded human nervous tissues with an avidinbiotin peroxidase method andRicinus communis agglutinin-1 (RCA-1). Specific staining was observed in cell bodies and processes of microglia. Although endothelial cells and blood cells reacted with RCA-1, they were easily distinguished morphologically from microglia. Astrocytes, oligodendrocytes, and neurons did not react with RCA-1. These results suggest that RCA-1 can be used as a new histochemical marker for microglia in normal human brain.

Marked disparity between age-related changes in dopamine and other presynaptic dopaminergic markers in human striatum.

Because age‐related changes in brain dopaminergic innervation are assumed to influence human disorders involving dopamine (DA), we measured the levels of several presynpatic DAergic markers [DA, homovanillic acid, tyrosine hydroxylase (TH), aromatic l‐amino acid decarboxylase (AADC), vesicular monoamine transporter 2 (VMAT2), and dopamine transporter (DAT)] in post‐mortem human striatum (caudate and putamen) from 56 neurologically normal subjects aged 1 day to 103 years. Striatal DA levels exhibited pronounced (2‐ to 3‐fold) post‐natal increases through adolescence and then decreases during aging. Similarly, TH and AADC increased almost 100% during the first 2 post‐natal years; however, the levels of TH and, to a lesser extent, AADC then declined to adult levels by approximately 30 years of age. Although VMAT2 and DAT levels closely paralleled those of TH, resulting in relatively constant TH to transporter ratios during development and aging, a modest but significant decline (13%) in DAT levels was observed in only caudate during aging. This biphasic post‐natal pattern of the presynaptic markers suggests that striatal DAergic innervation/neuropil appears to continue to develop well past birth but appears to become overelaborated and undergo regressive remodeling during adolescence. However, during adulthood, a striking discrepancy was observed between the loss of DA and the relative preservation of proteins involved in its biosynthesis and compartmentation. This suggests that declines in DA‐related function during adulthood and senescence may be explained by losses in DA per se as opposed to DAergic neuropil.

Development of Anaplastic Changes in Low-Grade Astrocytomas of Childhood

The authors present their experience with six children who developed anaplastic astrocytomas after receiving treatment for low-grade astrocytomas. Five children were from a series of 55 children with optic chiasmatic-hypothalamic gliomas who have been studied since 1976. The sixth child initially had a low-grade astrocytoma of the thalamus. The mean age of the children at initial presentation was 5.3 years. Five children were treated with surgery and radiation therapy; one child with a chiasmatic-hypothalamic glioma received radiation therapy alone. The amount of external radiation therapy used in all children was 50-52.5 Gy delivered in standard fractionations over approximately 6 weeks to include the volume of the original tumor plus a margin of 2 cm. The time to anaplastic transformation varied between 2 and 10 years (mean, 6.4 years). At tumor recurrence, the children had seizures or symptoms and signs of raised intracranial pressure. The location of the second tumor in all patients was either at the primary site or within the field of radiation therapy. Five of the six children underwent a second craniotomy and subtotal resection of their malignant gliomas. One child had positive cerebrospinal fluid cytology and multiple intraspinal metastatic tumor nodules detected by magnetic resonance imaging. On histopathological examination, four children had anaplastic astrocytoma, and two had glioblastoma multiforme. Four of the six children have died of their anaplastic astrocytomas (mean time from diagnosis of anaplastic astrocytoma to death, 10 months). Two children underwent chemotherapy and spinal irradiation for their anaplastic astrocytomas, and are currently alive and undergoing treatment. The possible mechanisms by which anaplastic tumors have developed in children treated previously for low-grade astrocytomas is discussed. The data suggest that radiation therapy may have played an integral role in the genesis of anaplastic astrocytomas in these children.

Surgical Management of Children with Temporal Lobe Epilepsy and Mass Lesions

In a review of 48 children who underwent temporal lobectomy for temporal lobe epilepsy, 16 patients had mass lesions in the temporal lobe. These mass lesions consisted of 12 tumors, 3 vascular malformations, and 1 arachnoid cyst. In 9 of 10 patients where the hippocampus was present in the pathological specimen and was not involved by tumor, there was concomitant mesial temporal sclerosis. All 16 patients have been followed for more than 1 year. Nine are free of seizures, with 4 of these 9 still on medication. Seven patients have had a greater than 50% reduction in seizures.

Dendrites, dementia and the down syndrome

Findings from a Golgi study of the visual cortex in patients with the Down syndrome were compared with those from neurologically normal, age-matched control subjects. The dendritic atrophy seen in childhood continued into adulthood, with a marked decrease in dendritic branching, dendritic length, and spine frequency in elderly adults with the Down syndrome. Subject more than 30 years old occasionally had degenerating pyramidal neurons in the cerebral cortex and degenerated pyramidal neurons and aspiny stellate cells, particularly in the temporal cortex. These dendritic abnormalities may be related to mental retardation in children and early dementia in older adults who have the Down syndrome. The genetic and extrinsic factors may be important determinants of Alzheimer type dementia in the Down syndrome.

Optic pathway/hypothalamic gliomas : A dilemma in management

Optic pathway gliomas follow an unpredictable course. Some remain static for years; others increase rapidly in size and often lead to death. This unpredictability, along with the histological similarity of these tumors, has resulted in controversy about their management. We have reviewed the results of management of all 62 patients with a diagnosis of optic pathway/hypothalamic glioma treated at The Hospital for Sick Children during the years 1976-1990. Twelve patients received no direct treatment, and 3 only a biopsy. Six patients were treated with radiotherapy alone. Eight patients received radiotherapy following a biopsy. Seventeen patients were treated by resection alone and 16 had a resection followed by radiotherapy. Eight patients received chemotherapy in addition to other therapy, and in 5 of them the chemotherapy was given as an initial therapy. Forty-eight patients are well with their visual deficits but 7 of them are receiving hormone replacement therapy. Six patients have significant neurologic deficits and 8 have died.

Dendritic development in human occipital cortical neurons.

Using quantitative techniques on rapid Golgi impregnations, the dendrites from neurons of visual cortex from 14 infants ranging in age from 20 weeks gestation to 7 years were assessed. Neurons in layers 3 and 5 were separately evaluated. The total dendritic length for all dendritic branches reached a maximum of 2800 microns for layer 3 neurons and 3400 microns for layer 5 neurons. At or before 40 weeks gestation, the dendritic tree of layer 3 neurons had reached 35% of the maximum compared with 55% of the maximum for layer 5 neurons. Dendritic branching occurred earlier in layer 5 and growth continued to be more advanced than in layer 3. After 40 weeks gestation in these layers no new branch orders were added to basal dendrites but 3 branch orders were added to apical dendrites. The determination of normal values for dendritic length, number of orders, and number of branches during early development provides a foundation for comparison of dendritic maturation in children with a variety of neurologic disorders.