Altered maturation of the primary somatosensory cortex in a mouse model of fragile X syndrome.
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and results from the loss of the fragile X mental retardation protein (FMRP). Many fragile X-related cognitive and behavioral features emerge during childhood and are associated with abnormal synaptic and cellular organization of the cerebral cortex. Identifying the roles of FMRP in cortical development will provide a basis for understanding the pathogenesis of the syndrome. However, how the loss of FMRP influences the developmental trajectory of cortical maturation remains unclear. We took advantage of the stereotyped and well-characterized development of the murine primary somatosensory cortex to examine cortical maturation during a time-window that corresponds to late embryonic and early postnatal development in the human. In the Fmr1 knockout mouse, we find a delay in somatosensory map formation, alterations in the morphology profile of dendrites and spines of layer 4 neurons and a decrease in the synaptic levels of proteins involved in glutamate receptor signaling at times corresponding to the highest levels of FMRP expression. In contrast, cortical arealization, synaptic density in layer 4 and early postnatal regulation of mRNAs encoding synaptic proteins are not altered in Fmr1 knockout mice. The specificity of the developmental delay in Fmr1 knockout mice indicates that the loss of FMRP does not result in a general stalling of cerebral cortex maturation. Instead, our results suggest that inaccurate timing of developmental processes caused by the loss of FMRP may lead to alterations in neural circuitry that underlie behavioral and cognitive dysfunctions associated with FXS.
Centre for Integrative Physiology, The University of Edinburgh, Edinburgh, UK. s.till@ed.ac.uk
Sally M
SM
Till
Lasani S
LS
Wijetunge
Viktoria G
VG
Seidel
Emily
E
Harlow
Ann K
AK
Wright
Claudia
C
Bagni
Anis
A
Contractor
Thomas H
TH
Gillingwater
Peter C
PC
Kind
D000818:Animals; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D012333:RNA, Messenger / Q000378:metabolism; D013003:Somatosensory Cortex / Q000378:metabolism*
D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger; C497684:Fmr1 protein, mouse