Changes In Brain Anatomy And The Synapse

Dorn Spinal Therapy

Spine Healing Therapy

Get Instant Access

Humans with FXS do not show gross cortical abnormalities and have normal brain weights. In some patients there is ventricular enlargement and an increase in hippocampal volumes. MRI studies indicate that the posterior vermis of the cerebellum is decreased and that the size of the caudate nucleus and hippocampus is increased. A diminished white-to-gray matter ratio was also observed in the same study27. The volumes of the cerebellum, caudate nucleus, and the size of the ventricles correlates positively with cognitive functioning28,29. Looking at these anatomical differences, it might seem easy to suggest that the anatomical differences are the cause of the cognitive deficits seen. Since the caudate volume correlates with the methylation status of the FMR1 gene29, there is a possibility that gene expression is somehow linked to the size of these structures.

The first hints of changes in the synapse were seen in humans in 1985. Adult FXS males were shown to have longer thin spines, and less short mature spines30. Post mortem examination of FXS patient brain tissue revealed their cells to have fewer spines with mushroom or stubby (mature) morphologies. Paradoxically, there was also an increase in overall spine density in these FXS patients30. Although these results are indicative of dendritic changes in FXS, it should be noted that the dendritic spines of only six FXS patients of various ages have been examined, many of whom have been on medication for a significant part of their lives. Thus it is not clear if synaptic changes are central to the disorder, and turning to an animal model of FXS was an important step in validating any dendritic abnormalities.

Thin Stubby Mushroom Dendrite Spine
Figure 30.1. Abnormal Spine Numbers in FMR1 Knockout Mice. The photomicrograph depicts cortical dendrites in normal wild-type animals (top picture) and FMR1 knockout animals (bottom picture). Note the increase in spine numbers apparent in the dendrite from the FMR1 knockout animal.

The FMR1 knockout mouse on an FVB background did not give a clear indication of any changes in spine density. This appears to be due to to complications specific to this mouse strain, however overall their dendrites do appear similar to those reported in humans31. Recently, the C57 mouse background strain has shown that the FMR1 knockout mouse has an increased spine density, like humans (see Figure 30.1). In both background strains, the dendrites were characterized by long spines with a predominantly immature phenotype. In this study spine maturity was assessed independent of length31-33. It is important to note that some studies have pointed to a more transient expression of the spine phenotype in FMR1 knockout mice at different ages. Younger slice culture neurons (7-10 days) show immature spine morphologies, but these differences are less apparent at 2 or 4 weeks of age34. In cultured neurons at 3 weeks of age, short, low density spines are predominant35. Conversely, in FMR1 knockout mice, no changes in spine morphology are apparent at around 28 days of age, but there are changes later on (73-76 days of age)36. Interestingly, in human FXS patients, cognitive deficits seem to increase with age.

The work in slice culture neurons34 has led to the hypothesis that a lack of FMRP leads to improper synapse pruning and maturation. FMRP appears to have an involvement in synapse formation, as evidenced by the paradoxically shorter dendrites, and reduced spine numbers observed in cultures. These cells also have fewer functional connections, with weaker excitatory currents that develop slower35. Another study in the Drosophila model showed that dFMRP is a negative regulator of neuronal elaboration and synaptic differentiation. This research group focused on the learning and memory center of the drosophila brain, the mushroom bodies 37. It still remains to be shown whether or not these spine abnormalities are responsible for a limited capacity to process information.

Was this article helpful?

0 0
Defeat Drugs Death

Defeat Drugs Death

This Book Is One Of The Most Valuable Resources In The World When It Comes To Helpful Info On Avoiding And Beating A Fatal Drug Addiction!

Get My Free Ebook

Post a comment