Altered Intrinsic Pyramidal Neuron Properties and Pathway-Specific Synaptic Dysfunction Underlie Aberrant Hippocampal Network Function in a Mouse Model of Tauopathy.

The formation and deposition of tau protein aggregates is proposed to contribute to cognitive impairments in dementia by disrupting neuronal function in brain regions, including the hippocampus. We used a battery of in vivo and in vitro electrophysiological recordings in the rTg4510 transgenic mouse model, which overexpresses a mutant form of human tau protein, to investigate the effects of tau pathology on hippocampal neuronal function in area CA1 of 7- to 8-month-old mice, an age point at which rTg4510 animals exhibit advanced tau pathology and progressive neurodegeneration. In vitro recordings revealed shifted theta-frequency resonance properties of CA1 pyramidal neurons, deficits in synaptic transmission at Schaffer collateral synapses, and blunted plasticity and imbalanced inhibition at temporoammonic synapses. These changes were associated with aberrant CA1 network oscillations, pyramidal neuron bursting, and spatial information coding in vivo. Our findings relate tauopathy-associated changes in cellular neurophysiology to altered behavior-dependent network function. SIGNIFICANCE STATEMENT: Dementia is characterized by the loss of learning and memory ability. The deposition of tau protein aggregates in the brain is a pathological hallmark of dementia; and the hippocampus, a brain structure known to be critical in processing learning and memory, is one of the first and most heavily affected regions. Our results show that, in area CA1 of hippocampus, a region involved in spatial learning and memory, tau pathology is associated with specific disturbances in synaptic, cellular, and network-level function, culminating in the aberrant encoding of spatial information and spatial memory impairment. These studies identify several novel ways in which hippocampal information processing may be disrupted in dementia, which may provide targets for future therapeutic intervention.

Continuation-based numerical detection of after-depolarization and spike-adding thresholds.

The changes in neuronal firing pattern are signatures of brain function, and it is of interest to understand how such changes evolve as a function of neuronal biophysical properties. We address this important problem by the analysis and numerical investigation of a class of mechanistic mathematical models. We focus on a hippocampal pyramidal neuron model and study the occurrence of bursting related to the after-depolarization (ADP) that follows a brief current injection. This type of burst is a transient phenomenon that is not amenable to the classical bifurcation analysis done, for example, for periodic bursting oscillators. In this letter, we show how to formulate such transient behavior as a two-point boundary value problem (2PBVP), which can be solved using well-known continuation methods. The 2PBVP is formulated such that the transient response is represented by a finite orbit segment for which onsets of ADP and additional spikes in a burst can be detected as bifurcations during a one-parameter continuation. This in turn provides us with a direct method to approximate the boundaries of regions in a two-parameter plane where certain model behavior of interest occurs. More precisely, we use two-parameter continuation of the detected onset points to identify the boundaries between regions with and without ADP and bursts with different numbers of spikes. Our 2PBVP formulation is a novel approach to parameter sensitivity analysis that can be applied to a wide range of problems.

Dynamical systems analysis of spike-adding mechanisms in transient bursts.

Transient bursting behaviour of excitable cells, such as neurons, is a common feature observed experimentally, but theoretically, it is not well understood. We analyse a five-dimensional simplified model of after-depolarisation that exhibits transient bursting behaviour when perturbed with a short current injection. Using one-parameter continuation of the perturbed orbit segment formulated as a well-posed boundary value problem, we show that the spike-adding mechanism is a canard-like transition that has a different character from known mechanisms for periodic burst solutions. The biophysical basis of the model gives a natural time-scale separation, which allows us to explain the spike-adding mechanism using geometric singular perturbation theory, but it does not involve actual bifurcations as for periodic bursts. We show that unstable sheets of the critical manifold, formed by saddle equilibria of the system that only exist in a singular limit, are responsible for the spike-adding transition; the transition is organised by the slow flow on the critical manifold near folds of this manifold. Our analysis shows that the orbit segment during the spike-adding transition includes a fast transition between two unstable sheets of the slow manifold that are of saddle type. We also discuss a different parameter regime where the presence of additional saddle equilibria of the full system alters the spike-adding mechanism.

Inhibition of post-synaptic Kv7/KCNQ/M channels facilitates long-term potentiation in the hippocampus.

Activation of muscarinic acetylcholine receptors (mAChR) facilitates the induction of synaptic plasticity and enhances cognitive function. In the hippocampus, M(1) mAChR on CA1 pyramidal cells inhibit both small conductance Ca(2+)-activated KCa2 potassium channels and voltage-activated Kv7 potassium channels. Inhibition of KCa2 channels facilitates long-term potentiation (LTP) by enhancing Ca(2+)calcium influx through postsynaptic NMDA receptors (NMDAR). Inhibition of Kv7 channels is also reported to facilitate LTP but the mechanism of action is unclear. Here, we show that inhibition of Kv7 channels with XE-991 facilitated LTP induced by theta burst pairing at Schaffer collateral commissural synapses in rat hippocampal slices. Similarly, negating Kv7 channel conductance using dynamic clamp methodologies also facilitated LTP. Negation of Kv7 channels by XE-991 or dynamic clamp did not enhance synaptic NMDAR activation in response to theta burst synaptic stimulation. Instead, Kv7 channel inhibition increased the amplitude and duration of the after-depolarisation following a burst of action potentials. Furthermore, the effects of XE-991 were reversed by re-introducing a Kv7-like conductance with dynamic clamp. These data reveal that Kv7 channel inhibition promotes NMDAR opening during LTP induction by enhancing depolarisation during and after bursts of postsynaptic action potentials. Thus, during the induction of LTP M(1) mAChRs enhance NMDAR opening by two distinct mechanisms namely inhibition of KCa2 and Kv7 channels.

A unified model of CA1/3 pyramidal cells: an investigation into excitability.

After-depolarisation is a hallmark of excitability in hippocampal pyramidal cells of CA1 and CA3 regions, because it constitutes the subthreshold relation between inward and outward ionic currents. This relationship determines the nominal response to stimuli and provides the necessary conditions for firing a spike or a burst of action potentials. Nevertheless, after-depolarisation is an inherently transient phenomenon that is not very well understood. We study after-depolarisation using a single-compartment pyramidal-cell model based on recent voltage- and current-clamp experimental data. We systematically investigate CA1 and CA3 behaviour and show that changes to maximal conductances of T-type Ca(2+)-current and muscarinic-sensitive and delayed rectifier K(+)-currents are sufficient to switch the behaviour of the model from a CA3 to a CA1 neuron. We use model analysis to define after-depolarisation and bursting threshold. We also explain the influence of particular ionic currents on this phenomenon. This study ends with a sensitivity analysis that demonstrates the influence of specific currents on excitability. Counter-intuitively, we find that a decrease of Na(+)-current could cause an increase in excitability. Our analysis suggests that a change of high-voltage activated Ca(2+)-current can have a similar effect.