In the rTg4510 mouse model, expression of the mutant human tau variant P301L leads to development of neurofibrillary tangles (NFTs), neuronal death, and memory impairment reminiscent of the pathology observed in human tauopathies. In the present study, we examined the effects of mutant tau expression on the electrophysiology and morphology of individual neurons using wholecell patch clamp recordings and biocytin filling of pyramidal cells in cortical slices prepared from rTg4510 (TG) and wild-type (WT) littermate mice. Among the TG cells, 42% contained a clear Thioflavin-S positive inclusion in the soma and were categorized as NFT positive (NFT+), while 58% had no discernable inclusion and were categorized as NFT negative (NFT−). The resting membrane potential (V r ) was significantly depolarized (+8 mV) in TG cells, and as a consequence, evoked repetitive action potential (AP) firing rates were also significantly increased. Further, single APs were significantly shorter in duration in TG cells and the depolarizing voltage deflection or "sag" evoked by hyperpolarization was significantly greater in amplitude. In addition to these functional electrophysiological changes, TG cells exhibited significant morphological alterations, including loss or significant atrophy of the apical tuft, reduced dendritic complexity and length, and reduction in spine density. Importantly, NFT− and NFT+ TG cells were indistinguishable with regard to both morphological and electrophysiological properties. Our observations show that expression of mutated tau results in significant structural and functional changes in neurons, but that these changes occur independent of mature NFT formation.

The aging rhesus macaque provides the long-sought animal model for exploring the etiology of late-onset Alzheimer's disease and for testing preventive strategies.

Whole-cell patch-clamp recordings and high resolution morphometry were used to assess functional and structural properties of layer 3 pyramidal neurons in early (< 4 months) and advanced (> 8 months) stages of tauopathy in frontal cortical slices prepared from rTg4510 tau mutant (P301L) mice. In early tauopathy, dendritic architecture is preserved. In advanced tauopathy, neurons can be categorized as either “atrophic” (58%)- exhibiting marked atrophy of the apical tuft, or “intact” (42%)- with normal apical tufts and, in some instances, proliferative sprouting of oblique branches of the apical trunk. Approximately equal numbers of atrophic and intact neurons contain neurofibrillary tangles (NFTs) or are tangle-free, lending further support to the idea that NFTs per se are not toxic. Spine density is decreased due to a specific reduction in mushroom spines, but filopodia are increased in both atrophic and intact neurons. By contrast to these morphological changes, which are robust only in the advanced stage, significant electrophysiological changes are present in the early stage and persist in the advanced stage in both atrophic and intact neurons. The most marked of these changes are: a depolarized resting membrane potential, an increased depolarizing sag potential and increased action potential firing rates- all indicative of hyperexcitability. Spontaneous excitatory postsynaptic currents are not reduced in frequency or amplitude in either stage. The difference in the time course of functionally important electrophysiological changes versus regressive morphological changes implies differences in pathogenic mechanisms underlying functional and structural changes to neurons during progressive tauopathy.

Whole-cell patch-clamp recordings and high-resolution 3D morphometric analyses of layer 3 pyramidal neurons in in vitro slices of monkey primary visual cortex (V1) and dorsolateral granular prefrontal cortex (dlPFC) revealed that neurons in these two brain areas possess highly distinctive structural and functional properties. Area V1 pyramidal neurons are much smaller than dlPFC neurons, with significantly less extensive dendritic arbors and far fewer dendritic spines. Relative to dlPFC neurons, V1 neurons have a significantly higher input resistance, depolarized resting membrane potential and higher action potential (AP) firing rates. Most V1 neurons exhibit both phasic and regular-spiking tonic AP firing patterns, while dlPFC neurons exhibit only tonic firing. Spontaneous postsynaptic currents are lower in amplitude and have faster kinetics in V1 than in dlPFC neurons, but are no different in frequency. Three-dimensional reconstructions of V1 and dlPFC neurons were incorporated into computational models containing Hodgkin-Huxley and AMPA- and GABAA-receptor gated channels. Morphology alone largely accounted for observed passive physiological properties, but led to AP firing rates that differed more than observed empirically, and to synaptic responses that opposed empirical results. Accordingly, modeling predicts that active channel conductances differ between V1 and dlPFC neurons. The unique features of V1 and dlPFC neurons are likely fundamental determinants of area-specific network behavior. The compact electrotonic arbor and increased excitability of V1 neurons support the rapid signal integration required for early processing of visual information. The greater connectivity and dendritic complexity of dlPFC neurons likely support higher level cognitive functions including working memory and planning.

The synaptic connections that form between neurons during development remain plastic and able to adapt throughout the lifespan, enabling learning and memory. However, during aging and in particular in neurodegenerative diseases, synapses become dysfunctional and degenerate, contributing to dementia. In the case of Alzheimer’s disease (AD), synapse loss is the strongest pathological correlate of cognitive decline, indicating that synaptic degeneration plays a central role in dementia. Over the past decade, strong evidence has emerged that oligomeric forms of amyloid beta, the protein that accumulates in senile plaques in the AD brain, contribute to degeneration of synaptic structure and function. More recent data indicate that pathological forms of tau protein, which accumulate in neurofibrillary tangles in the AD brain, also cause synaptic dysfunction and loss. In this review, we will present the case that soluble forms of both amyloid beta and tau protein act at the synapse to cause neural network dysfunction, and further that these two pathological proteins may act in concert to cause synaptic pathology. These data may have wide-ranging implications for the targeting of soluble pathological proteins in neurodegenerative diseases to prevent or reverse cognitive decline.