Two more key pieces underlying the puzzling genetic basis of Down syndrome have been identified. A research team led by Dr. Tarik Haydar, professor of anatomy and neurobiology at Boston University School of Medicine, has shown that two triplicate transcription factor genes, Olig1 and Olig2, may account for most of the developmental defects in a mouse model of Down syndrome (Chakrabarti et al. 2010). Therapies that normalize the expression of these two genes may restore some of the brain's normal functions in people with Down syndrome.
The mammalian forebrain consists of two main types of neurons: excitatory glutamatergic projection neurons and inhibitory GABAergic interneurons. For a brain to develop properly, the migration patterns, differentiation programs and network connectivity of these two neuron types must be precisely choreographed. Errors in this choreography may be responsible for forebrain abnormalities in people with Down syndrome and in the most widely used animal model of Down syndrome, JAX® Mice strain B6EiC3Sn a/A-Ts(1716)65Dn (001924), also known as the Ts65Dn mouse.
Recent studies have suggested that the major functional defect in the postnatal Ts65Dn forebrain is an abnormally low number of excitatory neurons and an abnormally high number of inhibitory interneurons. In addition to confirming this cell population imbalance, Haydar's team observed an increased inhibitory drive on pyramidal neurons in the Ts65Dn forebrain.
Most interneurons in the mouse forebrain are generated by precursors in brain sections called the medial and caudal ganglionic eminences (MGE and CGE). Haydar's team found that an abnormally large population of proliferative cells is generated by the MGE in TsDn65 mouse embryos. Several transcription factor genes triplicated in people with Down syndrome and the Ts65Dn mouse are known to be essential for directing the differentiation of specific cell types. Among those are the basic helix-loop-helix transcription factor genes Olig1 and Olig2. Olig2's expression pattern in the mouse MGE suggested it plays a role in generating interneurons. Not surprisingly, Haydar's team found that Olig1 and Olig2 are expressed 1.7 and 1.5 times higher than normal in the MGE of Ts65Dn embryos.
Suspecting that Olig1/Olig2 over-expression causes the interneuron over-production in the Ts65Dn brain, Haydar and his team generated Ts65Dn mice disomic for Olig1 and Olig2. They found that both the pre- and post-natal brains of these mice produce normal amounts of MGE interneurons and spontaneous inhibitory postsynaptic currents.
Taken together, the findings of the Haydar team strongly imply that the extra copies of Olig1 and Olig2 in Ts65Dn mice are largely, if not completely, responsible for the abnormally large number of interneurons and the increased inhibitory synaptic activity in the Ts65Dn mouse forebrain. These abnormalities are established prenatally, persist postnatally, and may contribute to cognitive dysfunction in Ts65Dn mice. Most importantly, these findings suggest that therapies that modulate Olig1 and Olig2 transcription may ameliorate the cognitive deficits in people with Down syndrome.
The Jackson Laboratory distributes two versions of the Ts65Dn mouse: the original B6EiC3Sn a/A-Ts(1716)65Dn (001924) and a new sighted version, B6EiC3Sn.BLiA-Ts(1716)65Dn/DnJ (005252). The sighted version is virtually identical to the original strain, but it does not produce blind offspring.