Morphological and electrophysiological changes to frontal cortical pyramidal neurons in the RTG4510 mouse model of progressive tauopathy

Abstract

The rTg4510 tau mutant (P301L) mouse recapitulates key features of human neurodegenerative tauopathies including progressive neurofibrillary tangle (NFT) formation, neuron death, and memory impairment. Whole-cell patch-clamp recordings with intracellular filling and high-resolution three-dimensional morphometric analyses were used to assess functional and structural properties of individual layer 3 pyramidal neurons at early (< 4 months) and advanced(> 8 months) stages of tauopathy in frontal cortical slices prepared from rTg4510 (TG) mice. Dendritic architecture, spine density and proportion of spine subtypes were preserved in early tauopathy. In advanced tauopathy, neurons were either 'atrophic', exhibiting marked atrophy of the apical tuft, or 'intact', with normal apical tufts. The density of spines and the proportion of mushroom spines were also reduced at this stage. Approximately equal proportions of intact and atrophic neurons contained a Thioflavin-S-positive neurofibrillary tangle (NFT+) or were tangle-free (NFT-). Significant electrophysiological changes were present in early and persisted in advanced tauopathy, but interestingly, NFT+ neurons did not differ from NFT- neurons. Key functional changes were: 1) an increased amplitude depolarizing sag potential; 2) a depolarized resting membrane potential, and; 3) increased action potential firing rates. AMPA receptor-mediated spontaneous excitatory postsynaptic currents were not reduced in frequency or amplitude at either stage. At the behavioral level, TG mice at the advanced stage were impaired on an object recognition task following a long, but not a short delay interval, providing evidence that frontal lobe function is at least partially intact. Homeostatic compensatory responses may underlie the preserved synaptic and network function of surviving frontal cortical neurons in advanced tauopathy. Consistent with this idea, a significant number of neurons at this stage exhibited: 1) increased excitability; 2) proliferation of dendrites; 3) sprouting of axonal boutons and filopodia, and; 4) formation of new, albeit smaller, asymmetric synapses seen at the ultrastructural level. In summary, functionally important electrophysiological changes precede regressive morphological changes in pyramidal neurons, both structural and functional changes occur independent of the presence or absence of a NFT, and compensatory mechanisms likely enable maintenance of frontal cortical network function for a time during pathogenesis in tauopathy.