The majority of presynaptic inputs originated from untransfected neurons, since virtually no GFP-fluorescent axons innervated transfected neurons due to the minute proportion (<10%) of neurons transfected with GFP-tagged htau. We thus attributed any changes in mEPSCs DAPT supplier to the modulation of postsynaptic activities by the htau in spines. Large mEPSCs (amplitude >20 pA; see arrows in Figures 4E1 and 4E2) occurred more frequently in neurons expressing GFP or WT htau than in neurons expressing P301L htau (∗∗∗p < 0.001 by Kolmogorov-Smirnov analysis for P301L versus GFP; Figures 4E3 and 4F). P301L, but not WT, htau significantly reduced the mean amplitude (∗∗∗p < 0.001 by Fisher's PLSD post hoc analysis; Figure 4G) and

frequency of mEPSCs (∗∗∗p < 0.001 by Fisher's PLSD post hoc analysis Figure 4G) compared to GFP-transfected neurons. We found similar P301L htau-mediated changes in the amplitude (∗∗∗p < 0.001 by Fisher's PLSD post hoc analysis for P301L versus rTgWT and TgNeg) and frequency (∗p < 0.05 by Fisher's PLSD post hoc analysis for P301L versus rTgWT and TgNeg) of mEPSCs in neurons cultured from rTgP301L mice, compared to those cultured from Luminespib cost rTgWT and TgNeg mice (Figures 5A–5C). Because the P301L htau-mediated electrophysiological changes in mouse

neurons mimicked the effects seen in htau-expressing rat neurons where the majority of presynaptic inputs originated from untransfected neurons, we attributed the changes in mEPSCs to the modulation of postsynaptic activities by the htau in spines, Thymidine kinase suggesting that axonal tau contributed minimally to the synaptic deficits in our in vitro experimental system and indicating that P301L htau diminished synaptic function whether its expression originated from a genomic or an extragenomic cistron. However, our results cannot exclude possible presynaptic roles of tau in the pathological

development of neurodegenerative diseases. We noted that in both rat and mouse neurons, the expression of WT htau caused a small but significant decrease (∗p < 0.05 by Kolmogorov-Smirnov analysis for WT versus GFP [Figure 4F] or WT versus TgNeg [Figure 5B]) in the probability of large mEPSC events (Figure 4F for rat and Figure 5B for mouse), suggesting that WT htau can also impair synaptic function. Presumably, this is related to the small amount of WT htau in spines (Figures 3B, 3D, 4C, and 4D). The reduced amplitude of mEPSCs caused by P301L htau suggests a reduction in the amount of functional AMPA receptors (AMPARs) on the postsynaptic membrane, which has been proposed to be a common mechanism underlying reductions in synaptic strength (Malinow and Malenka, 2002 and Newpher and Ehlers, 2008). The reduced frequency of mEPSCs, in the absence of spine loss (Figures 3E and 4C), suggests either an increase in the number of “silent synapses” or undetected weak synapses due to loss of synaptic AMPARs (Liao et al., 1995 and Isaac et al., 1995).