Adenosine A2A receptor involves in neuroinflammation-mediated cognitive decline through activating microglia under acute hypobaric hypoxia.

Hypobaric hypoxia (HH) at high altitudes leads to a wide range of cognitive impairments which can handicap human normal activities and performances. However, the underlying mechanism is still unclear. Adenosine A2A receptors (A2ARs) of the brain are pivotal to synaptic plasticity and cognition. Besides, insult-induced up-regulation of A2AR regulates neuroinflammation and therefore induces brain damages in various neuropathological processes. The present study was designed to determine whether A2AR-mediate neuroinflammation involves in cognitive impairments under acute HH. A2AR knock-out and wild-type male mice were exposed to a simulated altitude of 8000 m for 7 consecutive days in a hypobaric chamber and simultaneously received behavioral tests including Morris water maze test and open filed test. A2AR expression, the activation of microglia and the production of TNF-α were evaluated in the hippocampus by immunohistochemistry and ELISA, respectively. Behavioral tests showed that acute HH exposure caused the dysfunction of spatial memory and mood, while genetic inactivation of A2AR attenuated the impairment of spatial memory but not that of mood. Double-labeled immunofluorescence showed that A2ARs were mainly expressed on microglia and up-regulated in the hippocampus of acute HH model mice. Acute HH also induced the accumulation of microglia and increased production of TNF-α in the hippocampus, which could be markedly inhibited by A2AR inactivation. These findings indicate that microglia-mediated neuroinflammation triggered by A2AR activation involves in acute HH-induced spatial memory impairment and that A2AR could be a new target for the pharmacotherapy of cognitive dysfunction at high altitudes.

Riluzole prevents soluble Aß1-42 oligomers-induced perturbation of spontaneous discharge in the hippocampal CA1 region of rats.

Abnormal accumulation of soluble amyloid beta (Aß) is believed to cause malfunction of neurons in Alzheimer's disease (AD). The hippocampus is one of the earliest affected brain regions in AD. However, little effort has been made to investigate the effects of soluble Aß1-42 oligomers on discharge properties of hippocampal neurons in vivo. This study was designed to examine the effects of soluble Aß1-42 oligomers on the discharge properties of hippocampal CA1 neurons using extracellular single-unit recordings in vivo. The protective effects of riluzole (RLZ) were also investigated for the prevention of soluble oligomers of Aß1-42-induced alterations in the spontaneous discharge of hippocampal neurons. The results showed that (1) the mean frequency of spontaneous discharge was increased by the local application of 100 µM Aß1-42 oligomers; (2) Aß1-42 oligomers also induced alterations of the neuronal firing patterns in the hippocampal CA1 region; and (3) pretreatment with 20 µM RLZ effectively inhibited the Aß1-42-induced enhancement of spontaneous discharge and alterations of neuronal firing patterns in CA1 neurons. Our study suggested that Aß1-42 oligomers induced hyperactivity and perturbed the firing patterns in hippocampal neurons. RLZ may provide neuroprotective effects on the Aß1-42-induced perturbation of neuronal activities in the hippocampal region of rats.

Gastrodin suppresses the amyloid ß-induced increase of spontaneous discharge in the entorhinal cortex of rats.

Accumulated soluble amyloid beta- (Aß-) induced aberrant neuronal network activity may directly contribute to cognitive deficits, which are the most outstanding characteristics of Alzheimer's disease (AD). The entorhinal cortex (EC) is one of the earliest affected brain regions in AD. Impairments of EC neurons are responsible for the cognitive deficits in AD. However, little effort has been made to investigate the effects of soluble Aß on the discharge properties of EC neurons in vivo. The present study was designed to examine the effects of soluble Aß(1-42) on the discharge properties of EC neurons, using in vivo extracellular single unit recordings. The protective effects of gastrodin (GAS) were also investigated against Aß(1-42)-induced alterations in EC neuronal activities. The results showed that the spontaneous discharge of EC neurons was increased by local application of soluble Aß(1-42) and that GAS can effectively reverse Aß(1-42)-induced facilitation of spontaneous discharge in a concentration-dependent manner. Moreover, whole-cell patch clamp results indicated that the protective function of GAS on abnormal hyperexcitability may be partially mediated by its inhibitory action on Aß(1-42)-elicited inward currents in EC neurons. Our study suggested that GAS may provide neuroprotective effects on Aß(1-42)-induced hyperactivity in EC neurons of rats.

Persistent sodium currents contribute to Aß1-42-induced hyperexcitation of hippocampal CA1 pyramidal neurons.

Patients with Alzheimer's disease (AD) have elevated incidence of epilepsy. Moreover, neuronal hyperexcitation occurs in transgenic mouse models overexpressing amyloid precursor protein and its pathogenic product, amyloid ß protein (Aß). However, the cellular mechanisms of how Aß causes neuronal hyperexcitation are largely unknown. We hypothesize that the persistent sodium current (INaP), a subthreshold sodium current that can increase neuronal excitability, may in part account for the Aß-induced neuronal hyperexcitation. The present study was designed to evaluate the involvement of INaP in Aß-induced hyperexcitation of hippocampal CA1 pyramidal neurons using a whole-cell patch-clamp recording technique. Our results showed that bath application of soluble Aß1-42 increased neuronal excitability in a concentration-dependent manner. Soluble Aß1-42 also increased the amplitude of INaP without significantly affecting its activation properties. In the presence of riluzole (RLZ), an antagonist of INaP, the Aß1-42-induced neuronal hyperexcitation and INaP augmentation were significantly inhibited. These findings suggest that soluble Aß1-42 may induce neuronal hyperexcitation by increasing the amplitude of INaP and that RLZ can inhibit the Aß1-42-induced abnormal neuronal activity.

Synaptic mechanisms underlying thalamic activation-induced plasticity in the rat auditory cortex.

Electrical stimulation of ventral division of medial geniculate body (MGBv) neurons evokes a shift of the frequency-tuning curves of auditory cortical (AC) neurons toward the best frequency (BF) of the stimulated MGBv neurons (frequency-specific plasticity). The shift of BF is induced by inhibition of responses at the BF of the recorded AC neuron, with coincident facilitation of responses at the BF of the stimulated MGBv neuron. However, the synaptic mechanisms are not yet understood. We hypothesize that activation of thalamocortical synaptic transmission and receptor function may contribute to MGBv stimulation-induced frequency-specific auditory plasticity and the shift of BF. To test this hypothesis, we measured changes in the excitatory postsynaptic currents in pyramidal neurons of layer III/IV in the auditory cortex following high-frequency stimulation (HFS) of the MGBv, using whole cell recordings in an auditory thalamocortical slice. Our data showed that in response to the HFS of the MGBv the excitatory postsynaptic currents of AC neurons showed long-term bidirectional synaptic plasticity and long-term potentiation and depression. Pharmacological studies indicated that the long-term synaptic plasticity was induced through the activation of different sets of N-methyl-d-aspartate-type glutamatergic receptors, γ-aminobutyric acid-type receptors, and type 5 metabotropic glutamate receptors. Our data further demonstrated that blocking of different receptors with specific antagonists significantly inhibited MGBv stimulation-induced long-term plasticity as well as the shift of BF. These data indicate that these receptors have an important role in mediating frequency-specific auditory cortical plasticity.