Hypoxia with inflammation and reperfusion alters membrane resistance by dynamically regulating voltage-gated potassium channels in hippocampal CA1 neurons

Hypoxia typically accompanies acute inflammatory responses in patients and animal models. However, a limited number of studies have examined the effect of hypoxia in combination with inflammation (Hypo-Inf) on neural function. We previously reported that neuronal excitability in hippocampal CA1 neurons decreased during hypoxia and greatly rebounded upon reoxygenation. We attributed this altered excitability mainly to the dynamic regulation of hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels and input resistance. However, the molecular mechanisms underlying input resistance changes by Hypo-Inf and reperfusion remained unclear. In the present study, we found that a change in the density of the delayed rectifier potassium current (IDR) can explain the input resistance variability. Furthermore, voltage-dependent inactivation of A-type potassium (IA) channels shifted in the depolarizing direction during Hypo-Inf and reverted to normal upon reperfusion without a significant alteration in the maximum current density. Our results indicate that changes in the input resistance, and consequently excitability, caused by Hypo-Inf and reperfusion are at least partially regulated by the availability and voltage dependence of KV channels. Moreover, these results suggest that selective KV channel modulators can be used as potential neuroprotective drugs to minimize hypoxia- and reperfusion-induced neuronal damage.

Hippocampal CA1 Neurons Represent Positive Feedback During the Learning Process of an Associative Memory Task

The hippocampus is crucial for forming associations between environmental stimuli. However, it is unclear how neural activities of hippocampal neurons dynamically change during the learning process. To address this question, we developed an associative memory task for rats with auditory stimuli. In this task, the rats were required to associate tone pitches (high and low) and ports (right and left) to obtain a reward. We recorded the firing activity of neurons in rats hippocampal CA1 during the learning process of the task. As a result, many hippocampal CA1 neurons increased their firing rates when the rats received a reward after choosing either the left or right port. We referred to these cells as “reward-direction cells.” Furthermore, the proportion of the reward-direction cells increased in the middle-stage of learning but decreased after the completion of learning. This result suggests that the activity of reward-direction cells might serve as “positive feedback” signal that facilitates the formation of associations between tone pitches and port choice.

Inactivation of Presenilin in inhibitory neurons results in decreased GABAergic responses and enhanced synaptic plasticity

Mutations in the Presenilin genes are the major genetic cause of Alzheimer's disease (AD). Presenilin (PS) is highly expressed in the hippocampus, which is particularly vulnerable in AD. Previous studies of PS function in the hippocampus, however, focused exclusively on excitatory neurons. Whether PS regulates inhibitory neuronal function remained unknown. In the current study, we investigate PS function in GABAergic neurons by performing whole-cell and field-potential electrophysiological recordings using acute hippocampal slices from inhibitory neuron-specific PS conditional double knockout (IN-PS cDKO) mice at 2 months of age, before the onset of age-dependent loss of interneurons. We found that the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) is reduced in hippocampal CA1 neurons of IN-PS cDKO mice, whereas the amplitude of sIPSCs is normal. Moreover, the efficacy of inhibitory neurotransmission as assessed with synaptic input/output relations for evoked mono- and di-synaptic IPSCs is markedly lowered in hippocampal CA1 neurons of IN-PS cDKO mice. Consistent with these findings, IN-PS cDKO mice display enhanced paired-pulse facilitation, frequency facilitation and long-term potentiation in the Schaffer collateral-CA1 pathway. Interestingly, depletion of intracellular Ca2+ stores by inhibition of sarcoendoplasmic reticulum Ca2+ ATPase results in a reduction of IPSC amplitude in control hippocampal neurons but not in IN-PS cDKO neurons, suggesting that impaired intracellular calcium homeostasis in the absence of PS may contribute to the deficiencies in inhibitory neurotransmission. Furthermore, the amplitude of IPSCs induced by short trains of presynaptic stimulation and paired-pulse ratio are decreased in IN-PS cDKO mice. These findings show that inactivation of PS in interneurons results in decreased GABAergic responses and enhanced synaptic plasticity in the hippocampus, providing additional evidence for the importance of PS in the regulation of synaptic plasticity and calcium homeostasis.