Abstract
The plasticity of synapses underlies learning and memory. Metaplasticity is the activity-dependent regulation of future synaptic plasticity. Priming CA1 pyramidal cell basal dendrites of the rodent hippocampus with long-term potentiation (LTP)-inducing stimulation in stratum oriens (SO) inhibits subsequent LTP in the apical dendrites of stratum radiatum (SR). This metaplasticity effect is protein synthesis-dependent and aberrantly engaged in mouse models of Alzheimer’s disease, suggesting modulation of aberrant metaplastic LTP inhibition as a therapeutic target. However, more investigation into any underlying molecular mechanisms is needed. This study aimed to determine the protein involved in setting this metaplastic state. Tau was explored due to its similar effects on synaptic plasticity as priming and its quick time frame for translation.
To investigate tau involvement, electrophysiological experiments in acute hippocampal slices of wild-type and tau-knockout mice were undertaken. Theta-burst induced LTP was measured in SR 30 minutes after priming or control stimulation in SO. Immunohistochemical staining for tau protein in wild-type mouse sections followed to investigate de novo tau synthesis. Stained sections were imaged and analysed for tau-immunoreactivity separately in SO, SR and combined across both following priming or control stimulation.
Post-hoc tests following a 2-way ANOVA of electrophysiology results revealed no significant difference in SR LTP between control (147.3 ± 13.0%; n = 8) and primed (138.3 ± 9.3%; n = 9) slices from tau-knockout mice (p = 0.888), while a significant difference was seen in wild-type littermates (control, 162.7 ± 4%; n = 6) (primed, 124.3 ± 5.4%; n = 9) (P = 0.038) (mean ± SEM). However, no increase in tau-immunoreactivity was seen 30 minutes post-priming, suggesting tau is not being synthesised.
Our results revealed protein-synthesis independent tau involvement in this unusual memory mechanism. Further research will explore modulating tau function as a potential treatment for neurodegenerative disorders characterised by tau dysfunction.