Download 2006 natl fx fnd abstract - University of Illinois Archives

Architecture of spines and dendrites in fragile X syndrome: An overview.
William T. Greenough, Ph.D., Roberto Galvez, Ph.D., Aaron W. Grossman, B.A., Scott
A. Irwin, M.D. Ph.D., Brandon C. McKinney, M.S., Im Joo Rhyu M.D. Ph.D., Georgina
M. Aldridge, B.S., Julie A. Markham, Ph.D.
Bill, you’ve got 1 word to spare. I pasted your old version below so if I dropped any
important ideas you can try to put them back. Good luck! Also, do you mind if my name
goes before Robert’s?
350 word / 3500 character limit
In studies of Fragile X syndrome (FXS) and Fmr1 knockout mice, a model for FXS, a
consistent finding has been pathology of dendritic spines, the post-synaptic target of
excitatory inputs. Increasing evidence indicates that the "wiring diagram" of the Fragile
X brain is profoundly disordered, and understanding how such disorder arises may be
important for developing treatments. The neocortex of patients with FXS is characterized
by an excess of dendritic spines, many of which tend to be longer and thinner than those
in unaffected individuals. Spines in the Fmr1 knockout mouse neocortex have a similar
phenotype that appears to arise through abnormalities in spine maturation and in the
developmental "pruning" process that eliminates inappropriate connections. Fmr1
knockout mice also exhibit abnormal pruning of dendrites in neurons of the
somatosensory cortex and olfactory bulb. Thus the “wiring diagram” of these brain
regions may be generated by a combination of impaired pruning and impaired
modification of synapses. We subsequently examined the hippocampal formation, where
the pattern of development is somewhat different from that of the cerebral cortex. In area
CA1, the profile of spine shapes in Fmr1 knockouts is abnormal compared with the spine
shape profile of wildtype mice, and seems to reflect the profile seen in area CA1 of
younger animals. In addition, spines of each shape are longer in knockout CA1 than in
controls. Spines in the dentate gyrus also appear to develop abnormally. For example,
the density of spines along these dendrites appears elevated across development,
suggesting that no pruning deficit exists in this brain region. As a clearer picture of
Fragile X neuropathology emerges, we find that some measures differ by brain region
(presence or absence of pruning) whereas other measures are observed across several
brain regions (increased spine length and density). Spine maturation and plasticity may
therefore be regulated in each brain region by different mechanisms, some of which
require FMRP (absent in Fragile X syndrome) and its mRNA cargos, and others for
which FMRP is less important. Brain organization in FXS likely involves the
convergence of these mechanisms, providing a context in which development unfolds.
1. To illustrate progress in understanding the mechanisms behind the
changes in brain structure that occur in fragile X syndrome
2. To illustrate that common principles underlie brain development
in fragile X and unaffected individuals
3. To present this work at a level that will speak to scientists and
yet be understood by parents and family members
4. To illustrate the value of basic research using animal models of
fragile X syndrome in developing criteria that can be used to
evaluate the potential effects of treatments.
Old version
Increasing evidence indicates that the "wiring diagram" of the nervous system in Fragile
X syndrome is seriously disordered, beyond the level of mere differential strength of
synapses (e.g., Kogan et al., Neurology 2004, 63:1634-39). Understanding how such
disorder arises may be important to developing treatments. The cerebral cortex in FXS is
characterized by an excess of spines, the post-synaptic target of most excitatory inputs,
onto principal neurons. The FXS spines also tend to be longer and thinner than those in
unaffected individuals. The knockout (KO) mouse model for FXS similarly has an excess
of spines overall and an excess of long, thin spines on cerebral cortical neurons. These
differences may arise through abnormalities in the developmental "pruning" process that
eliminates unused or inappropriate connections. Evidence for this includes abnormal
dendritic pruning in "barrel" neurons of the somatosensory cortex, and in mitral cells of
the olfactory bulb in the KO mouse. In addition, the pruning of spines seen in
development of the somatosensory cortex in normal mice is not evident in the KO mouse.
Thus for cerebral cortex (and olfactory bulb) the neural phenotype seems to be generated
by a combination of pruning and of modification of synapses. We have subsequently
examined the hippoccampal formation in which the pattern of development is somewhat
different from that of the cerebral cortex but appears to follow a broad set of common
rules of development. Thus subfield CA1 (or hippocampus proper) [Aaron, could you fill
in a relatively simple statement here?] Our preliminary results for hippocampal dentate
gyrus indicateŠ. This pattern of different patterns in some measures across brain regions
(e.g., presence or absence of pruning) and similarities in other measures (increased spine
density; increased spine length) suggests that brain organization in FXS may involve a
combination of Fmr1-independent local determinants that provide a context in which
development unfolds and Fmr1-dependent global determinants that may reflect specific
influences of the fragile X gene or of its mRNA cargoes that are disrupted in common
across brain regions]