The neuroanatomy and neuroendocrinology of fragile X syndrome

Abstract

Fragile X syndrome (FXS), caused by a single gene mutation on the X chromosome, offers a unique opportunity for investigation of gene-brain-behavior relationships. Recent advances in molecular genetics, human brain imaging, and behavioral studies have started to unravel the complex pathways leading to the cognitive, psychiatric, and physical features that are unique to this syndrome. In this article, we summarize studies focused on the neuroanatomy and neuroendocrinology of FXS. A review of structural imaging studies of individuals with the full mutation shows that several brain regions are enlarged, including the hippocampus, amygdala, caudate nucleus, and thalamus, even after controlling for overall brain volume. These regions mediate several cognitive and behavioral functions known to be aberrant in FXS such as memory and learning, information and sensory processing, and social and emotional behavior. Two regions, the cerebellar vermis, important for a variety of cognitive tasks and regulation of motor behavior, and the superior temporal gyrus, involved in processing complex auditory stimuli, are reported to be reduced in size relative to controls. Functional imaging, typically limited to females, has emphasized that individuals with FXS do not adequately recruit brain regions that are normally utilized by unaffected individuals to carry out various cognitive tasks, such as arithmetic processing or visual memory tasks. Finally, we review a number of neuroendocrine studies implicating hypothalamic dysfunction in FXS, including abnormal activation of the hypothalamic-pituitary-adrenal (HPA) axis. These studies may help to explain the abnormal stress responses, sleep abnormalities, and physical growth patterns commonly seen in affected individuals. In the future, innovative longitudinal studies to investigate development of neurobiologic and behavioral features over time, and ultimately empirical testing of pharmacological, behavioral, and even molecular genetic interventions using MRI are likely to yield significant positive changes in the lives of persons with FXS, as well as increase our understanding of the development of psychiatric and learning problems in the general population.

Sex-specific gene–environment interactions underlying ASD-like behaviors

“…49 and references therein). The HPA axis alterations can have wide effects on behaviors and has been attributed as being one of the main correlates of social deficits in patients with fragile X syndrome (50). Prenatal LPS exposure, which activates the fetal HPA axis (47), causes structural, neurophysiological, and functional changes in the hippocampus (e.g., refs.…”

Early developmental alterations in GABAergic protein expression in fragile X knockout mice

“…The cerebellar vermis is a structure that is anatomically connected to the interpositus nucleus and hippocampus (Hessl et al, 2004), believed to play a role in motor behaviour, auditory processing, and language (Steinlin, 2008). Decreases in the cerebellar posterior vermis size has been found in patients with FXS (Mostofsky et al, 1998).…”

The cyclic AMP phenotype of fragile X and autism

“…Depending upon genetic background, behavioral and synaptic models of memory in mice are consistent with the human FX phenotype (For background, see Lombroso 2003;Hessl, Rivera et al 2004). Measures of learning and memory in a fear based paradigm were generally comparable for targeted and wild type alleles on a C57BL/6 background (Peier, McIlwain et al 2000), though these mice expressed reduced memory for avoidance in a leverpress paradigm compared to wild type (Brennan, Albeck et al 2006).…”

“…Rolipram, 4-(3-Cyclpentyloxy-4-methoxyphenyl)-2-pyrrolidinone, is a potent PDE4 inhibitor, a class that shows clinical potential in the treatment of depression. Through cAMP-mediated mechanisms, pharmacotherapy that inhibits PDE4 is prone to increase the transcription and function (Miller, Vogt et al 2002;Pace, Hu et al 2007) of reduced numbers of FX dendritic glucocorticoid receptors (Miyashiro, Beckel-Mitchener et al 2003) involved in hypothalamic-pituitaryadrenal (HPA) regulation (Hessl, Rivera et al 2004). A clinical trial of rolipram reported acceptable tolerance levels at clinically relevant doses (Fleischhacker, Hinterhuber et al 1992).…”