Compromised synaptic signal from prefrontal cortex to mediodorsal thalamus in Alzheimer's disease models and its rescue by kinase inhibitors.

One of the most important neural circuits controlling cognitive processes is the projection from prefrontal cortex (PFC) to thalamus. To determine the strength of PFC projections to different thalamic nuclei, we performed optogenetic experiments by injecting channelrhodopsin-2 (ChR2) to medial PFC and recording synaptic responses evoked by light stimulation of ChR2-expressing terminals in thalamic neurons. The mediodorsal thalamus (MD) had markedly larger synaptic currents than neighbouring areas, suggesting that PFC sends prominent signals to MD. To determine whether the PFC to MD pathway is altered at early stages of Alzheimer's disease (AD), we used two mouse models (∼4 months old), transgenic mice carrying the human P301S mutation of microtubule-associated protein tau (Tau), and familial AD mice carrying five mutations on APP and PS1 (5xFAD). Both AD mouse models exhibited a more significant decline in short-term depression (STD) of synaptic responses in response to repeated light stimulation of MD ChR2 signals. Optogenetic imaging showed that Tau mice had significantly reduced ChR2 expression in MD axon terminals innervated by PFC. Next, we inhibited two kinases, serum and glucocorticoid-regulated kinase 1 (SGK1) and glycogen synthase kinase-3 beta (GSK3β), both of which can induce tau hyperphosphorylation and the ensuing disruption of microtubule-based transport in AD. Treatment with SGK1 or GSK3β inhibitor normalized STD of PFC to MD synaptic responses in Tau mice, but not in 5xFAD mice. These results suggest that the synaptic connectivity in the PFC-to-MD pathway is compromised in AD, which may be due to tau kinase-induced disruption of axonal transport. KEY POINTS: Optogenetic recordings reveal the strong connection from prefrontal cortex (PFC) to mediodorsal thalamus (MD). Short-term depression (STD) of PFC to MD synaptic responses is altered in P301S Tau and 5xFAD mouse models of Alzheimer's disease (AD). Optogenetic imaging uncovers the significantly reduced PFC to MD projection in Tau mice. Inhibition of tau kinase SGK1 or GSK3β normalizes STD of PFC to MD synaptic responses in Tau mice, but not 5xFAD mice. These results suggest that the synaptic information transfer from PFC to MD pathway is compromised in AD, probably via tau kinase-induced disruption of axonal transport.