Consequences of hyperphosphorylated tau on the morphology and excitability of hippocampal neurons in aged tau transgenic mice.

ABSTRACT

The intracellular accumulation of hyperphosphorylated tau characterizes many neurodegenerative diseases such as Alzheimer's disease and frontotemporal dementia. A critical role for tau is supported by studies in transgenic mouse models expressing the P301L mutation with accumulation of hyperphosphorylated human tau in hippocampal pyramidal neurons of aged mice. Especially, the somatodendritic mislocalization of hyperphosphorylated tau seems to affect the neuronal network of the hippocampus. To show the consequences of aggregation of hyperphosphorylated tau within hippocampal neurons of aged mice, the CA1 pyramidal cells were analyzed morphologically and electrophysiologically. Here we demonstrate in the P301L pR5 mouse model that hyperphosphorylated tau leads to an increase in stubby spines and filopodia, as well as a decrease in total dendritic length of hippocampal pyramidal neurons due to a decrease in apical dendritic length and nodes. This atrophy is in line with the significant reduction in CA1 long-term potentiation. Furthermore, mutant tau induced a depolarized threshold for action potential initiation and an increased current of inward rectifying potassium channels, which should lead, together with the long-term potentiation decrease, to a decreased excitability of CA1 neurons.