retardation, Rett syndrome, and autistic spectrum disorders. Genes that have been identified as either causing or increasing the risk for developing these disorders can be conceived as having in common the disruption of normal development and function of synapses (Chao, Zoghbi, and Rosenmund, 2007; Dierssen and Ramakers, 2006; Willemsen, Oostra, et al., 2004; Zoghbi, 2003).
Neurons and the connections between them are produced in an overabundance during fetal life relative to their levels at birth and in adulthood. The number of neurons in the human brain, for example, peaks around midgestation. Thereafter, overproduction is reduced through a process of molecularly programmed cell death, called apoptosis (de Graaf-Peters and Hadders-Algra, 2006; Levitt, 2003). For continued survival, neurons require a successful interaction with a target cell, and neurons that do not achieve this interaction will die. Neuronal survival is mediated in part by the limited availability of neurotrophic factors, a class of molecules that are derived from the target cells (Monk, Webb, and Nelson, 2001).
The process of brain development also produces an initial surplus of connections between neurons. Early in postnatal life, the density of synapses in the brain increases dramatically, reaching its peak during infancy (de Graaf-Peters and Hadders-Algra, 2006; Huttenlocher, 1984; Huttenlocher and Dabholkar, 1997; Levitt, 2003). The process of forming synapses, or synaptogenesis, is paired with the complementary process of synaptic pruning, in which some synaptic connections are eliminated. Primates are widely believed to have evolved synaptic pruning as a means for removing synaptic connections that are unused and therefore not needed in the environmental context in which the animal finds itself, while conserving and increasing the efficiency of connections that are useful in that context. Thus, survival of most of the synaptic connections that subserve human behavior is influenced by patterns of neural activity, which in turn are the product of environmental influences and experience (Kandel, Schwartz, and Jessell, 2000).
Studies in humans during childhood are limited but, in combination with data from studies in monkeys, indicate that after the peak of synaptogenesis in infancy, synapse formation and synaptic pruning plateau during childhood and then reach a regressive phase between puberty and adulthood. At that point, a massive, activity-dependent pruning eliminates more than 40 percent of synapses (de Graaf-Peters and Hadders-Algra, 2006; Huttenlocher and Dabholkar, 1997; Levitt, 2003; Rakic, 2002; Rakic, Bourgeois, and Goldman-Rakic, 1994).
Another important process in developing and refining appropriate connectivity in the brain is the wrapping of neuronal axons in an insulat-