A converging‐methods approach to fragile X syndrome

Abstract

Converging approaches across domains of brain anatomy, cell biology, and behavior indicate that Fragile X syndrome, arising from impaired expression of a single gene and protein, appears to involve an aberration of normal developmental processes. Synapse overproduction and selective elimination, or pruning, characterize normal brain development. In autopsy tissue from Fragile X patients and in a knockout mouse model of the disease, synapse overproduction appears to occur unaccompanied by synapse pruning and maturation, leaving an excess of immature spine synapses in place. The absence of the Fragile X protein seems to impair the synthesis of important proteins at synapses. The developmental outcome in Fragile X is a nervous system that is relatively disorganized, resulting in disrupted perceptual, and cognitive social, behavior.

Premorbid Intellectual Functioning, Education, and Brain Size in Traumatic Brain Injury: An Investigation of the Cognitive Reserve Hypothesis

“…Furthermore, the relationships between brain development and structure function with measured IQ, educational attainment, and SES are not known. For example, some researchers indicate that greater use of certain cognitive functions increases the cortical volumes associated with those functions (Keenan, Thangaraj, Halpern, & Schlaug, 2001) whereas others argue that greater use results in increased synaptic pruning which enhances efficiency (Churchill et al, 2002;Irwin et al, 2001). Accordingly, education, IQ and brain size are likely highly interdependent, all contributing individually and collectively to cognitive reserve.…”

New Insights in the Biology of BDNF Synthesis and Release: Implications in CNS Function

“…In humans, spine density increases dramatically during the first few months of postnatal life, however ~40% of synapses are later selectively eliminated Huttenlocher, 1979). Maturation and pruning of dendritic spines is dependent on sensory experience and has been implicated in the activity-dependent refinement of synaptic connections (Churchill et al, 2002). The abnormal spine morphology in Bdnf klox/klox mice likely results from a deficit in spine pruning, as spine density at 3 weeks of age is normal (An et al, 2008).…”

Control of spine maturation and pruning through proBDNF synthesized and released in dendrites

“…During this pruning phase, up to 40% of spines are selectively eliminated while the remaining spines mature and change in morphology from long and thin to short and stubby (Grutzendler et al, 2002; Huttenlocher, 1979; Marin-Padilla, 1967; Rakic et al, 1986; Zuo et al, 2005). Spine maturation and spine pruning are dependent upon neuronal activity and are required for the refinement of neuronal connections in the developing brain (Churchill et al, 2002; Ethell and Pasquale, 2005; Mataga et al, 2004; Zuo et al, 2005). However, the mechanism governing spine maturation is not completely understood and very little is known about the molecular mechanism underlying spine pruning.…”