In a new study published today in the open-access journal PLOS Biology, researchers from the University of Michigan, led by Bing Ye, have discovered that an additional copy of a gene responsible for regulating synapse formation in the cortex leads to heightened inhibitory signaling in the brain of a Down syndrome mouse.
This new insight may shed light on some of the neurological impacts of Down syndrome and could have significant implications for understanding and treating other related conditions, such as autism and epilepsy.
According to recent scientific research, Down syndrome results from the presence of an extra copy of chromosome 21, leading to a condition known as trisomy 21. This genetic abnormality causes affected individuals to have three copies of this particular chromosome instead of the typical two copies. The additional genetic material from the extra chromosome affects the expression of 200-300 genes, leading to a range of symptoms and health issues.
The neurological effects of Down syndrome are among the most significant and widely studied. While the specific genes responsible for these neurological symptoms remain uncertain, previous research has suggested that the Down syndrome cell adhesion molecule (DSCAM) may play a role. Studies on animal models have demonstrated that increased levels of this gene can impact the size of presynaptic terminals, which are regions of neurons that release neurotransmitters to downstream neuronal receptors.
Researchers led by Ye investigated the impact of triplication of the Down syndrome cell adhesion molecule (DSCAM) gene on GABAergic neurons in the neocortex, the outer layer of the brain. GABAergic synapses in the brain release the neurotransmitter GABA, which acts as an inhibitor, dampening the activity of downstream neurons. To study this effect, the team bred female mice carrying a mouse equivalent of trisomy 21 with a male mouse carrying one normal DSCAM gene and one mutant gene. This breeding strategy generated offspring with varying genetic profiles, including euploid mice with two functional copies of DSCAM, trisomic mice with three functional copies of DSCAM (modeling Down syndrome), and trisomic mice with two functional copies of DSCAM but an extra copy of chromosome 21 (effectively normal for DSCAM but not for the rest of chromosome 21).
The researchers observed that mice with three functional copies of the DSCAM gene had an increase in the number of GABAergic terminals forming synapses on target neurons in the neocortex. In contrast, mice with two functional copies of the DSCAM gene had normal numbers of terminals, even though they had elevated levels of amyloid precursor protein (APP) in the brain, which is another biochemical effect of trisomy 21 due to triplication of the APP gene.
The impact of gene triplication on GABAergic synaptic transmission was also evident functionally. Mice with three copies of the gene showed more inhibitory signaling in the target areas of the neocortex, suggesting that the excessive amount of DSCAM was responsible for the higher number of GABAergic nerve terminals and increased synaptic transmission. The researchers also discovered that they could reduce the number of nerve terminals and inhibit GABAergic signaling by preventing the production of normal levels of DSCAM.
Ye explained that changes in DSCAM expression have been associated with various brain disorders, such as Down syndrome, autism spectrum disorder, intractable epilepsy, and bipolar disorder. The research findings indicate that irregular DSCAM levels could be a shared causative factor in GABAergic dysfunction among these conditions.
Ye adds, “This study shows excessive inhibitory connections in the cerebral cortex of mouse models of Down syndrome, and demonstrates that the extra copy of the DSCAM gene is the cause.”
Source: 10.1371/journal.pbio.3002078
Image Credit: Bing Ye (CC-BY 4.0, https://creativecommons.org/licenses/by/4.0/)