Background for non-scientists

FMR1 Gene
Fragile X gene that normally produces a protein called FMRP, which is necessary for normal development and functioning of the brain. In individuals with Fragile X syndrome, the FMR 1 gene is mutated so it cannot produce FMRP.

DNA
Master template for genetic information in cells. Your genetic code determines who you are. Each of the 40,000 or so genes in each cell consists of a sequence of DNA.

Phenotype
The total characteristics displayed by an organism as the result of the expression of its genes.

Messenger RNA (mRNA)
Working copy of the genetic code transcribed from DNA. It is carried from the nucleus of a cell (where the DNA resides) to the rest of the cell, where it is translated into the actual proteins that perform most of the functions of the cell. The purpose of each gene is to produce a protein.

Knockout mice
Fragile X mice that lack the protein FMRP because they have been bred to delete the FMR1 gene.

How Nerve Signals Travel

Neurons
The human brain is made up of 10 billion nerve cells called “neurons” which form a complex interconnected network of neural circuits. The neurons carry all the signals through the brain and are the basis of our thoughts and actions, our learning and memory, our consciousness and our personality. Each individual neuron looks like an uprooted tree, with long spidery roots on one end (called dendrites) and a main trunk on the other (called an axon). Signals pass from the axons of one cell and are received by the dendrites of the next cell across a gap called a synapse.

Neurotransmitters
When an electrical impulse is transmitted from the dendrites of a neuron, it travels one way, along the axon, until it reaches any of the axon terminals. This triggers the release of a chemical called a neurotransmitter from this presynaptic neuron. The neurotransmitter then floats across this microscopic gap, or synapse, until it lodges in specific receptor sites of the post-synaptic neuron. The interaction of neurotransmitters with their corresponding receptors causes electrical and chemical changes in the receiving neurons as well as altered gene activity.

Glutamate
There are many different types of neurotransmitters in various parts of the brain, but Glutamate is the major excitatory neurotransmitter, accounting for a vast majority of brain activity.

GABA
GABA, the major inhibitory neurotransmitter, keeps this process in check so that runaway electrical activity does not lead to seizures.

Synapse’s strengthen or weaken
As a result of neural activity, synapses and their connections can change constantly. Certain patterns of synaptic activity cause the synaptic connection to:

• strengthen — this is called Long Term Potentiation (LTP)
• weaken — this is called Long Term Depression (LTD)

Some people refer to this as a “use it or lose it” effect. Synapses that are heavily used get built up or stronger, while those that are not used wither away.

A synapse’s strength depends on the number of receptors it has. Neurons change the density of receptors on their postsynaptic membranes as a mechanism for changing their own excitability in response to stimuli.

Synaptic plasticity
In a dynamic process that is maintained in equilibrium, two particular receptors called NMDA and AMPA receptors are added or removed to the membrane by specific processes. These processes, and the number of receptors on the membrane, can be altered by synaptic activity. Experiments have shown that AMPA receptors are delivered to the membrane due to repetitive NMDA receptor activation. This is what neuroscientists mean when they speak of the synaptic plasticity of synapses and it is generally thought to be the basis for most of our learning and memory.

Many researchers are now referring to Fragile X as a disorder of synaptic plasticity and there is much excitement surrounding this mechanism since it has the potential to be corrected.

Researchers have achieved a breakthrough by identifying a brain pathway (mGluR) that is defective in Fragile X syndrome (FXS) and also implicated in autism. Drugs are now being developed to target this pathway and researchers have shown that these compounds can correct abnormalities in FXS animal models.