Affiliations: Neuroscience Drug Discovery DK, H. Lundbeck A/S, Valby, Denmark
Correspondence:
[*]
Correspondence to: Nils Ole Dalby, Department of Pharmacology and Pharmacotherapy, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark. Tel.: +45 2285 9920; Fax: +45 3533 6020; E-mail: [email protected].
Note: [1] Department of Pharmacology and Pharmacotherapy, University of Copenhagen, Copenhagen, Denmark.
Abstract: The formation of neurofibrillary tangles from the assembly of hyperphosphorylated tau leads to dendritic and axonal instability, synaptic degeneration, and neuronal loss. To understand the early physiological consequences of aberrant tau expression, we characterized the physiology of CA1 pyramidal neurons in rTg4510 female mice and non-transgenic (wt) littermate controls. We studied mice at the age of 10–12 weeks where only minimal hyperphosphorylated pretangle tau was present, and 22–24 weeks old mice with significant neurofibrillary tangle pathology. Our electrophysiological analysis included input–output relation, paired-pulse facilitation, and whole cell patch-clamp recordings of neurons to measure action potential threshold and action potential properties, chord-conductance, and characterization of AMPA receptor mediated synaptic transmission. We found that the input–output relation in field (excitatory postsynaptic potentials, EPSP) and whole cell recordings (excitatory postsynaptic currents, EPSC) were impaired in rTg4510 mice compared to wt controls at both ages. We measured a diminished tail current charge after depolarizing voltage input in rTg4510 mice compared to wt in both young and aged mice. Additionally, mini-EPSC properties (peak and decay time) were essentially similar between genotypes and age groups investigated. Surprisingly, in the 22–24 week old group, the mini-EPSC frequency was significantly increased (interevent interval 0.8 ± 0.1 in wt compared to 0.3 ± 0.1 in rTg4510 mice). These data indicate that the developmentally regulated expression of human P301L tau in CA1 pyramidal neurons coincide with changes in neuronal excitability but also that significant presynaptic changes occur late during the progression of tau pathology in this mouse model.
