Dendritic Mechanisms in Brain Function and Developmental Disabilities

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 hippocampal 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 hippocampal 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 neuro