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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 A 2A receptors (A 2A Rs) of the brain are pivotal to synaptic plasticity and cognition. Besides, insult-induced up-regulation of A 2A R regulates neuroinflammation and therefore induces brain damages in various neuropathological processes. The present study was designed to determine whether A 2A R-mediate neuroinflammation involves in cognitive impairments under acute HH. A 2A R 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. A 2A R 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 A 2A R attenuated the impairment of spatial memory but not that of mood. Double-labeled immunofluorescence showed that A 2A Rs 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 A 2A R inactivation. These findings indicate that microglia-mediated neuroinflammation triggered by A 2A R activation involves in acute HH-induced spatial memory impairment and that A 2A R could be a new target for the pharmacotherapy of cognitive dysfunction at high altitudes. [ABSTRACT FROM AUTHOR]

Abnormal accumulation of soluble amyloid beta (Aβ) 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 Aβ1-42 oligomers on discharge properties of hippocampal neurons in vivo. This study was designed to examine the effects of soluble Aβ1-42 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 Aβ1-42-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 Aβ1-42 oligomers; (2) Aβ1-42 oligomers also induced alterations of the neuronal firing patterns in the hippocampal CA1 region; and (3) pretreatment with 20 μM RLZ effectively inhibited the Aβ1-42-induced enhancement of spontaneous discharge and alterations of neuronal firing patterns in CA1 neurons. Our study suggested that Aβ1-42 oligomers induced hyperactivity and perturbed the firing patterns in hippocampal neurons. RLZ may provide neuroprotective effects on the Aβ1-42-induced perturbation of neuronal activities in the hippocampal region of rats. [ABSTRACT FROM AUTHOR]

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 β protein (Aβ). However, the cellular mechanisms of how Aβ causes neuronal hyperexcitation are largely unknown. We hypothesize that the persistent sodium current ( I NaP ), a subthreshold sodium current that can increase neuronal excitability, may in part account for the Aβ-induced neuronal hyperexcitation. The present study was designed to evaluate the involvement of I NaP in Aβ-induced hyperexcitation of hippocampal CA1 pyramidal neurons using a whole-cell patch-clamp recording technique. Our results showed that bath application of soluble Aβ 1-42 increased neuronal excitability in a concentration-dependent manner. Soluble Aβ 1-42 also increased the amplitude of I NaP without significantly affecting its activation properties. In the presence of riluzole (RLZ), an antagonist of I NaP , the Aβ 1-42 -induced neuronal hyperexcitation and I NaP augmentation were significantly inhibited. These findings suggest that soluble Aβ 1-42 may induce neuronal hyperexcitation by increasing the amplitude of I NaP and that RLZ can inhibit the Aβ 1-42 -induced abnormal neuronal activity. [ABSTRACT FROM AUTHOR]

Abnormal accumulation of soluble amyloid beta (Aβ) 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 Aβ1-42 oligomers on discharge properties of hippocampal neurons in vivo. This study was designed to examine the effects of soluble Aβ1-42 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 Aβ1-42-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 Aβ1-42 oligomers; (2) Aβ1-42 oligomers also induced alterations of the neuronal firing patterns in the hippocampal CA1 region; and (3) pretreatment with 20 μM RLZ effectively inhibited the Aβ1-42-induced enhancement of spontaneous discharge and alterations of neuronal firing patterns in CA1 neurons. Our study suggested that Aβ1-42 oligomers induced hyperactivity and perturbed the firing patterns in hippocampal neurons. RLZ may provide neuroprotective effects on the Aβ1-42-induced perturbation of neuronal activities in the hippocampal region of rats.

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.