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Wednesday, 10 October 2012

Investigating Fragile X syndrome

Our research focuses on the neurons in networks in the brain and aims to understand the mechanisms that underlie the workings of our minds.

Our approach is to study how networks of nerve cells in the brain communicate together, how they connect with each other and how a change in a single gene in the brain can alter a brain network. The Human Genome Project has shown that humans have 20-25,000 different genes. We're still working on the exact number, but current estimates put it at 23,2291. Around 20,000 (86%) of these genes are thought to express in our brains2, but again, the exact count is unknown. Given these vast numbers, it may seem surprising that one gene can have a strong effect. But a single gene really can cause the difference between say a normal IQ and having learning difficulties & cognitive impairments. For example, take the intellectual disability and autism disorder, Fragile X syndrome: people with this monogenic disorder have an impairment of one specific gene3. This results in cognitive impairments, anxiety, higher levels of autism & epilepsy along with other non-cognitive symptoms. Within the brain itself, we find the structural connections made between nerve cells, the synapses, look different to those in an unaffected brain. The synapses are more immature in their development, on average, and are more abundant in the brain.

Diagram of synapses in typical and Fragile X brain networks
Synapses in a typical brain network, and those in a Fragile X network.
Image credit: Meredith lab, VU University Amsterdam

But how do we study the effects of a single gene on brain cell networks in a cognitive disorder? And is the increased number of structural connections between nerve cells in Fragile X syndrome reflected in brain function? To directly test our ideas that there are changes occurring in brain networks due to a single gene, we use brain tissue from  genetically-engineered mice to measure functional connections between nerve cells. We test if a nerve cell is connected to its immediate neighbours ('short-range') or to more distant nerve cells ('long-range' partners) using a combination of electrodes to measure neural activity and fluorescent dyes that monitor changes in brain network activity4.

Lab mouse at Meredith lab
Mice are more similar to us than you might expect.
Image credit: Meredith lab, VU University Amsterdam
Perhaps surprisingly, mice not only have a very similar but slightly higher number of genes to humans (estimated to be 24,9481), and between 70-90% similarity exists between mouse and human genomes. Of all genes identified in mice, 99% of them have a corresponding (homolog) gene in humans. To study the activity patterns of neurons in a brain, our research needs brain tissue that is still alive. Live human brain tissue, usually donated by patients undergoing brain surgery for epilepsy or tumours, is extremely rare to acquire and only a handful of labs worldwide have access to this tissue for experiments. Given the genetic similarities between mice and men, mouse brain is a suitable alternative from which we can record neuronal activity and test our ideas. In general, cells in mouse brain use similar chemical and electrical signals to human neurons. However, what differentiates a human neuron from that of a mouse is still largely a mystery: from testing both human and mouse neurons, we believe a key difference lies in the speed of information processing that the neuron can operate at.

From measuring the nerve cells of mice without the Fragile X gene, we recently found that the nerve cells have more connections with each other in a frontal part of the brain5. Frontal brain regions are important for attention and forward-planning and are thought to be strongly affected in autism and intellectual disability disorders. These differences we found occurred in young mice at stages of brain development equivalent to early postnatal development (up to six months after birth) or even before birth in humans. Thus a change in a single gene can affect our brain networks even before we start to develop and mature cognitively.

When thinking about how to study the underlying mechanisms of how our human mind works, it may seem counter-intuitive to investigate brain function via its dysfunction. But the occurrence of monogenic disorders such as Fragile X syndrome gives us insight into the role that single genes can play upon brain networks underlying our cognition. By working at the interface between molecule and mind, we hope our research can take a step further to understanding the nerve cells and the networks within our thoughtful brains.

This guest article is by Rhiannon Meredith - a junior group leader at the VU University in Amsterdam, The Netherlands. Rhiannon is working with a research team to investigate the neurobiology of brain function in neurodevelopmental disorders such as autism and intellectual disability.

why don't all these papers have links?
1 Genome sequence of the Brown Norway rat yields insights into mammalian evolution (2004) Rat Genome Sequencing Project Consortium. Nature 428, 493-521
2 Spatio-temporal transcriptome of the human brain (2011) Kang et al. Nature 428, 493-521
3 Fragile X syndrome Fragile X syndrome
4 How we measure nerve cell activity in a piece of brain tissue:
5 Hyperconnectivity and slow synapses during early development of medial prefrontal cortex in a mouse model for mental retardation and autism (2012) Testa-Silva G, Loebel A, Giugliano M, de Kock CP, Mansvelder HD, Meredith RM. Cereb Cortex. 22(6):1333-42.