Autism is one of the leading causes of human intellectual disability (ID).
More than 1% of the human population has autism spectrum disorders (ASDs), and it
has been estimated that over 50% of those with ASDs also have ID. Fragile X
syndrome (FXS) is the most common inherited form of mental retardation and is the
leading known genetic cause of autism, affecting approximately 1 in 4000 males and
1 in 8000 females. Approximately 30% of boys with FXS will be diagnosed with
autism in their later lives.
The cause of FXS is through an over-expansion of the CGG trinucleotide
repeat located at the 5’ untranslated region of the FMR1 gene, leading to
hypermethylation of the surrounding sequence and eventually partially or fully
silencing of the gene. Therefore, the protein product of the gene, fragile X mental
retardation protein (FMRP), is reduced or missing.
As a single-gene disorder, FXS offers a scientifically tractable way to
examine the underlying mechanism of the disease and also shed some light on
understanding ASD and ID. The mouse model of FXS (Fmr1−/y mice) is widely
accepted and used as a good model, offering good structural and face validity. Since
a primary deficit of FXS is believed to be altered neuronal communication, in this
thesis I examined white matter tract and dendritic spine abnormalities in the mouse
model of FXS. Loss of FMRP does not alter the gross morphology of the white
matter. However, recent brain imaging studies indicated that loss of FMRP could
lead to some minute abnormalities in different major white matter tracts in the human
brain. The gross white matter morphology and myelination was unaltered in the
Fmr1−/y mice, however, a small but significant increase of axon diameter in the
corpus callosum (CC) was found compared to wild-type (WT) controls. Our
computation model suggested that the increase of axon diameter in the Fmr1−/y mice
could lead to an increase of conduction velocity in these animals.
One of the key phenotypes reported previously in the loss of FMRP is the
increase of “immature” dendritic spines. The increase of long and thin spines was
reported in several brain regions including the somatosensory cortex and visual
cortex in both FXS patients and the mouse model of FXS. Although recent studies
which employed state-of-the-art microscopy techniques suggested that only minute
differences were noticed between the WT and Fmr1−/y mice. In agreement with
previous findings, I found an increase of dendritic spine density in the visual cortex
in the Fmr1−/y mice, and spine morphology was also different between the two
genotypes. We found that the spine head diameter is significantly increased in the
CA1 area of the apical dendrites of the Fmr1−/y mice compared to WT controls.
Dendritic spine length is also significantly increased in the same region of the
Fmr1−/y mice. However, apical spine head size does not alter between the two
genotypes in the V1 region of the visual cortex, and spine length is significantly
decreased in the Fmr1−/y mice compared to WT animals in this region.
Lovastatin, a drug known as one of the 3-hydroxy-3-methyl-glutaryl-CoA
(HMG-CoA) reductase inhibitors, functions as a modulator of the mitogen-activated
protein kinases (MAPK) pathway through inhibiting Ras farnesylation, was used in
an attempt to rescue the dendritic spine abnormalities in the Fmr1−/y mice. Mice
lacking FMRP are susceptible to audiogenic seizure (AGS). Previous work has
shown that 48 hr of lovastatin treatment reduced the incidence of AGS in the Fmr1−/y
mice. However, chronic lovastatin treatment failed to rescue the spine density and
morphology abnormalities in the Fmr1−/y mice.
Mouse models are invaluable tools for modelling human diseases. However
inter-strain differences have often confounded results between laboratories. In my
final Chapter of this thesis, I compared two commonly used C57BL/6 substrains of
mice by recording their electrophysiological responses to visual stimuli in vivo. I
found a significant increase of high-frequency gamma power in adult C57BL/6JOla
mice, and this phenomenon was reduced during the critical period. My results
suggested that the C57BL/6JOla substrain has a significant stronger overall
inhibitory network activity in the visual cortex than the C57BL/6J substrain. This is
in good agreement with previous findings showing a lack of open-eye potentiation to
monocular deprivation in the C57BL/6JOla substrain, and highlights the need for
appropriate choice of mouse strain when studying neurodevelopmental models.
They also give valuable insights into the genetic mechanisms that permit experience-dependent
developmental plasticity.
In summary, these findings give us a better understanding of the fine structure
abnormalities of the Fmr1−/y mice, which in turn can benefit future discoveries of the
underlying mechanisms of neurodevelopmental disorders such as ID and ASDs