Increased cortical synaptic activation of TrkB and downstream signaling markers in a mouse model of Down Syndrome

• TrkB signaling, including MAPK and PI3K, was increased in Ts65Dn cortex.
• Increased pTrkB signaling was present in synapses and signaling endosomes.
• Array tomography showed an increase in the ratio of GABAergic to glutamatergic synapses.
• TrkB signaling was dramatically increased in GABAergic synapses.
• Increased TrkB signaling in cortical circuits may contribute to cognitive deficits.

Down Syndrome (DS), trisomy 21, is characterized by synaptic abnormalities and cognitive deficits throughout the lifespan and with development of Alzheimer's disease (AD) neuropathology and progressive cognitive decline in adults. Synaptic abnormalities are also present in the Ts65Dn mouse model of DS, but which synapses are affected and the mechanisms underlying synaptic dysfunction are unknown. Here we show marked increases in the levels and activation status of TrkB and associated signaling proteins in cortical synapses in Ts65Dn mice. Proteomic analysis at the single synapse level of resolution using array tomography (AT) uncovered increased colocalization of activated TrkB with signaling endosome related proteins, and demonstrated increased TrkB signaling. The extent of increases in TrkB signaling differed in each of the cortical layers examined and with respect to the type of synapse, with the most marked increases seen in inhibitory synapses. These findings are evidence of markedly abnormal TrkB-mediated signaling in synapses. They raise the possibility that dysregulated TrkB signaling contributes to synaptic dysfunction and cognitive deficits in DS.