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Miswired memory networks in developmental disorders
4 Sep, 2007 02:14 pm
Developmental disorders including Down syndrome and Fragile X syndrome share the symptom of impaired memory. Theories on the origins of these disorders focus on the points of communication between neurons in the brain, called synapses. The effectiveness of synapses in communicating information between neurons can be enhanced or weakened through a process known as ?synaptic plasticity?. Because synaptic plasticity is essential for memory storage, previous research in mouse genetic models of these syndromes has focused on synaptic plasticity. However, our recent work reveals independent alterations to the underlying pattern of the wiring of the networks wherein synaptic plasticity occurs. This new information highlights the importance of focusing on processes involved in determining network wiring when looking for therapeutic targets for developmental disorders.
Mice with genetic alterations that mirror either Down syndrome or Fragile X syndrome allow experiments that could reveal the neurological basis of impairments seen in these syndromes. Previous work, using techniques that examine large populations of synapses, has suggested synaptic plasticity is abnormal in the mouse models of these syndromes. We examined synapse function in these mice at higher resolution by using simultaneous electrical recordings from pairs of neurons that share an individual synaptic connection. We focused on a brain network known as area CA3 of the hippocampus, because this network plays key roles in memory storage.
Our goal in examining individual synapses in these mice was to reveal details of functions, like synaptic plasticity, that might not be apparent using standard techniques in which many different synapses are stimulated and measured all at once. Our work entailed recording from many individual pairs of neurons, some of which shared synaptic connections, and some of which did not, until we had a large enough sample of pairs that did share a connection to analyze.
In studying the Down syndrome mice, an important finding was that synaptic plasticity mechanisms were fully functional at the level of the individual connections in the CA3 network. However when we looked at the entire dataset, a surprising picture of a different kind emerged. We realized that the Down syndrome mice had an excessive likelihood that pairs of neurons shared synaptic connections. While about half of the pairs of neurons recorded in normal mice shared a functional connection, the connections in the CA3 network of the Down syndrome mice were significantly more abundant. This finding is intriguing because computational simulations have predicted that such exuberant connectivity within this network would lead to exactly the type of memory impairments seen in Down syndrome.
After discovering that the wiring of the CA3 network was abnormal in the Down syndrome mice, we next examined the pattern of synaptic connections in the Fragile X syndrome mice. In the Fragile X mice, we were able to discriminate whether the neurons sending out connections or the neurons receiving connections might be abnormal. This was possible because we breed mice whose brains contained a mixture of normal and Fragile X neurons. In addition, these mice were genetically altered so that neurons without the Fragile X mutation could be distinguished by the presence of green fluorescent protein. Using these mice, we found that while the Fragile X neurons received the same number of connections as the normal neurons, they did not send out as many connections as the normal neurons. This indicates that just as there are excessive synaptic connections in the Down syndrome mice, there are unbalanced synaptic connections in these Fragile X syndrome mice. Furthermore, because we studied the brains of mice with a mixture of normal and Fragile X neurons, we were able to determine that this imbalance in synaptic connectivity results from deficits in neuronal functions related to sending out, rather than receiving, synaptic connections.
Overall these two studies suggest that aside from impaired synaptic plasticity itself, abnormalities in the underlying wiring of the networks wherein synaptic plasticity occurs could contribute to memory impairments in developmental disorders. This information should encourage investigation of molecules involved in synapse formation and maintenance as potential therapeutic targets for memory impairments in Down syndrome and Fragile X syndrome. At the same time the possibility of abnormal network wiring should also be investigated in other developmental conditions. For example, the altered synaptic connectivity in the Fragile X mice is particularly interesting, as Fragile X is one cause of autism, and it could be possible that autism spectrum disorders in general involve altered network connectivity.
Hanson JE, Madison DV “Presynaptic FMR1 genotype influences the degree of synaptic connectivity in a mosaic mouse model of fragile X syndrome.” J Neurosci 2007; 27(15):4014-8.
Hanson JE, Blank M, Valenzuela RA, Garner CC, Madison DV (2007) “The functional nature of synaptic circuitry is altered in area CA3 of the hippocampus in a mouse model of Down syndrome.” J Physiol 2007; 579(1):53-67.