Dendritic Mechanisms in Brain Function and Developmental Disabilities

Ralph M. Nitkin

National Center for Medical Rehabilitation Research, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA


    Introduction
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 Introduction
 
The papers assembled in this special issue of Cerebral Cortex are part of a continuing dialogue on cellular and molecular aspects of synaptic development and their impact on brain function, which was stimulated by a meeting sponsored by the National Institute of Child Health and Human Development (April 30– May 1, 1998 at the NIH). In recent years, various types of dendritic abnormalities have been described in Down syndrome, fragile-X syndrome, Rett syndrome, autism and other neurodevelopmental disorders. Subtle alterations in dendritic structure or number are precisely the types of abnormalities that would account for a brain that is largely functional, but has subtle deficits in particular cognitive and/or behavioral domains. Remarkable technical advances allow us to focus on the key cellular and molecular events in brain development, synaptic transmission and information processing. This provides us with a unique opportunity to understand the cognitive and behavioral deficits associated with these disorders, and to develop improved therapeutic strategies.

Several papers in this issue address the determinants of dendritic structure during development. Tashiro, Minden and Yuste examine the role of small signaling molecules in hippo-campal development. They use two-photon microscopy to examine the effects of GTPases of the Rho family transfected into cultured pyramidal cells, and describe the acute effects on the density and morphology of dendritic spines. Hormones and other trophic factors also shape dendritic structure, as evidenced by the profound alterations seen in thyroid hormone deficiency disorders. Thompson and Potter examine the classes of thyroid hormone-responsive genes in the brain as a basis for understanding the effect of hormonal deficiencies on neuronal development. Frotscher, Drakew and Heimrich examine the effect of afferent input on dendritic structure. Using hippo-campal neurons co-cultured with entorhinal explants, they show that the granule cell dendritic arbor develops the same laminar specificity in vitro as in vivo, but it is reduced in the absence of entorhinal co-culture. Blockade of afferent activity by tetrodotoxin affects spine morphology on granule cell dendrites but not their density.

For several decades, researchers have sought the structural basis of learning and memory. Classic debates have focused on increases in synaptic number versus increasing efficacy of specific synaptic interactions. Three papers in this issue highlight current thinking on structural changes that may provide the basis for functional alterations in neurological pathways. Geinisman reviews changes in the hippocampus associated with long-term potentiation (LTP), a simplified model of memory. Evidence from a number of researchers indicates that LTP is associated with a maturation of synaptic interactions, rather than a net increase in the number of synaptic contacts. Histological studies show a shift from less mature to more mature synaptic profiles, consistent with more efficacious transmission across existing sites and possibly even recruitment of formerly silent synapses. The structural basis of learning is less clear; some studies suggest increases in synaptic number and while others suggest maturation of existing synapses. In a related paper, McAllister reviews studies on the interplay of electrical activity and dendritic structure, which has become a dominant theme in developmental neurobiology. She examines some of the key cellular and molecular mechanisms that drive this dynamic process, and the possible role of neurotrophic factors. Lambe, Goldman-Rakic and Aghajanian examine the effects of serotonin on different regions of pyramidal dendrites within the laminate structure of the prefrontal cortex. They find evidence for layer-specific and compartment-specific effects on synaptic transmission, and discuss these finding in terms of dendritic architecture and the regulation of thalamo-cortical neurotransmission.

Cellular and molecular studies have shown that certain key aspects of neurodevelopment can be altered by abnormal intrinsic or extrinsic influences. It was only a few decades ago that Purpura and his colleagues provided the first evidence of dendritic abnormalities associated with neurodevelopmental disorders such as Down syndrome. Kaufmann and Moser provide an update on the increasing number of neurodevelopmental disorders associated with abnormal patterns of dendritic development or synaptic structure. Their paper highlights the remarkable progress we have made in identifying molecular defects and developing useful animal models. In a related paper, Kaufmann, MacDonald and Altamura report on structural proteins that regulate dendritic structure. They suggest that altered expression of cytoskeletal components may be a key to understanding the progressive pathology of certain developmental disorders, and cite improved molecular and histological techniques for evaluating these components in brain tissue.

A variety of innovative strategies are being used to understand how neurodevelopmental disorders alter synaptic function. Three papers in this volume discuss models for specific neurological disorders and potential cellular and subcellular mechanisms. Jenner, Galaburda and Sherman show how studies of aberrant cell migration (ectopias) may provide insight into the functional abnormalities associated with dyslexia. They report on mouse strains that have a high incidence of cortical ectopias, which resemble those seen in post-mortem studies of some individuals with dyslexia. The ectopias result in anomalous subcortical connections, which may have implications for understanding processing abnormalities associated with dyslexia. Benes, Taylor and Cunningham present a model for schizophrenia based on abnormal interactions between incoming dopamine fibers and GABAergic neurons in the limbic system. They discuss evidence from post-mortem studies of brains from patients with schizophrenia as well as experimental research in rodent models. Walkley, Zervas and Wiseman provide evidence for abnormal dendritic structure and ectopic sprouting associated with certain ganglioside storage disorders (e.g. Tay–Sachs, Sandhoff and Niemann–Pick disease). This has led them to more basic studies on protein trafficking to understand the role of GM2 gangliosides in dendritogenesis and in the pathogenesis of metabolic disorders.

Today we are in a better position to understand how mutant genes or altered gene expression can subtly affect early neurodevelopment and the formation of appropriate synaptic connections. One disorder that has particular relevance for dendritic mechanisms, is fragile-X syndrome. Although this is the leading heritable cause of mental retardation, the affected gene, FMR1, has only recently been identified and characterized. Irwin, Galvez and Greenough review studies on the synthesis and accumulation of the fragile-X mental retardation (FMR) protein in nerve terminals and provide evidence that it is driven by neuronal activity. This provides a potential mechanism for linking activity to the maintenance of synaptic structure, and provides a basis for understanding the behavioral and cognitive defects associated with fragile-X syndrome. Understanding of fragile-X syndrome has been greatly facilitated by the introduction of FMR-1 knockout mice, which have dendritic abnormalities similar to those seen in the human condition but more subtle cognitive and behavioral deficits. Braun and Segal have cultured hippocampal neurons from FMR-deficient mice in order to examine the cellular and molecular basis of these abnormalities. They find that even in dissociated cultures, the neurons display alterations in dendritic morphology and synaptic connectivity. They discuss these findings in the context of the functional abnormalities associated with FMR knockout mice.

As the papers in volume demonstrate, dendritic mechanisms provide the basis for fine-tuning the developing nervous system, adapting to early environmental interactions, and modifying function through learning and memory. The interdependence of neurodevelopmental events and early activity helps define ‘critical periods’ during child development and unique opportunities for educational and behavioral enrichment. Within the context of neurodevelopmental disorders, alterations in dendritic mechanisms provide the key to understanding the resulting cognitive, behavioral and social deficits. The next few decades offer special opportunities for neurobiological and behavioral researchers to strengthen the link between alterations in the brain substrate and the functional consequences, and to develop more effective therapeutic and support strategies.





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