Astroglial gliotransmitters released via Cx43 hemichannels regulate NMDAR-dependent transmission and short-term fear memory in the basolateral amygdala.

Astrocytes release gliotransmitters via connexin 43 (Cx43) hemichannels into neighboring synapses, which can modulate synaptic activity and are necessary for fear memory consolidation. However, the gliotransmitters released, and their mechanisms of action remain elusive. Here, we report that fear conditioning training elevated Cx43 hemichannel activity in astrocytes from the basolateral amygdala (BLA). The selective blockade of Cx43 hemichannels by microinfusion of TAT-Cx43L2 peptide into the BLA induced memory deficits 1 and 24 h after training, without affecting learning. The memory impairments were prevented by the co-injection of glutamate and D-serine, but not by the injection of either alone, suggesting a role for NMDA receptors (NMDAR). The incubation with TAT-Cx43L2 decreased NMDAR-mediated currents in BLA slices, effect that was also prevented by the addition of glutamate and D-serine. NMDARs in primary neuronal cultures were unaffected by TAT-Cx43L2, ruling out direct effects of the peptide on NMDARs. Finally, we show that D-serine permeates through purified Cx43 hemichannels reconstituted in liposomes. We propose that the release of glutamate and D-serine from astrocytes through Cx43 hemichannels is necessary for the activation of post-synaptic NMDARs during training, to allow for the formation of short-term and subsequent long-term memory, but not for learning per se.

NMDA Receptor Hypofunction in the Aging-Associated Malfunction of Peripheral Tissue.

Glutamatergic transmission through NMDA receptors (NMDARs) is important for the function of peripheral tissues. In the bone, NMDARs and its co-agonist, D-serine participate in all the phases of the remodeling. In the vasculature, NMDARs exerts a tonic vasodilation decreasing blood perfusion in the corpus cavernosum and the filtration rate in the renal glomerulus. NMDARs are relevant for the skin turnover regulating the proliferation and differentiation of keratinocytes and the formation of the cornified envelope (CE). The interference with NMDAR function in the skin leads to a slow turnover and repair. As occurs with the brain and cognitive functions, the manifestations of a hypofunction of NMDARs resembles those observed during aging. This raises the question if the deterioration of the glomerular vasculature, the bone remodeling and the skin turnover associated with age could be related with a hypofunction of NMDARs. Furthermore, the interference of D-serine and the effects of its supplementation on these tissues, suggest that a decrease of D-serine could account for this hypofunction pointing out D-serine as a potential therapeutic target to reduce or even prevent the detriment of the peripheral tissue associated with aging.

Astrocytic contribution to glutamate-related central respiratory chemoreception in vertebrates.

Central respiratory chemoreceptors play a key role in the respiratory homeostasis by sensing CO2 and H+ in brain and activating the respiratory neural network. This ability of specific brain regions to respond to acidosis and hypercapnia is based on neuronal and glial mechanisms. Several decades ago, glutamatergic transmission was proposed to be involved as a main mechanism in central chemoreception. However, a complete identification of mechanism has been elusive. At the rostral medulla, chemosensitive neurons of the retrotrapezoid nucleus (RTN) are glutamatergic and they are stimulated by ATP released by RTN astrocytes in response to hypercapnia. In addition, recent findings show that caudal medullary astrocytes in brainstem can also contribute as CO2 and H+ sensors that release D-serine and glutamate, both gliotransmitters able to activate the respiratory neural network. In this review, we describe the mammalian astrocytic glutamatergic contribution to the central respiratory chemoreception trying to trace in vertebrates the emergence of several components involved in this process.

The effect of D-serine administration on cognition and mood in older adults.

BACKGROUND: D-serine is an endogenous co-agonist of the N-Methyl D-Aspartate Receptor (NMDAR) that plays a crucial role in cognition including learning processes and memory. Decreased D-serine levels have been associated with age-related decline in mechanisms of learning and memory in animal studies. Here, we asked whether D-serine administration in older adults improves cognition. RESULTS: D-serine administration improved performance in the Groton Maze learning test of spatial memory and learning and problem solving (F(3, 38)= 4.74, p = 0.03). Subjects that achieved higher increases in plasma D-serine levels after administration improved more in test performance (r2=-0.19 p = 0.009). D-serine administration was not associated with any significant changes in the other cognitive tests or in the mood of older adults (p > 0.05). METHODS: Fifty healthy older adults received D-serine and placebo in a randomized, double blind, placebo-controlled, crossover design study. We studied the effect of D-serine administration on the performance of cognitive tests and an analogue mood scale. We also collected blood samples to measure D-serine, L-serine, glutamate and glutamine levels. CONCLUSIONS: D-serine administration may be a strategy to improve spatial memory, learning and problem solving in healthy older adults. Future studies should evaluate the impact of long-term D-serine administration on cognition in older adults.

D-serine prevents cognitive deficits induced by acute stress.

Increasing evidence indicates that acute stress disrupts cognitive functions mediated by glutamate-NMDA receptors, although the mechanisms are not fully understood. Here we investigated whether d-serine and glycine, the endogenous co-agonists of the NMDA receptor, are regulated by acute stress. We studied the biochemical and behavioral effects of acute restraint stress in C57BL/6 mice. Acute restraint stress decreased d-serine levels in the prefrontal cortex and glycine levels in the hippocampus. Behaviorally, acute stress impaired memory consolidation in the object recognition task and prepulse inhibition of the startle response. Importantly, d-serine administration (1 g/kg, i.p.) prevented both stress-induced impairments. Taken together, our results show for the first time an interplay between stress and d-serine and warrant further research on the role of d-serine in stress-related disorders.

Deregulation of excitatory neurotransmission underlying synapse failure in Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Memory loss in AD is increasingly attributed to soluble oligomers of the amyloid-ß peptide (AßOs), toxins that accumulate in AD brains and target particular synapses. Glutamate receptors appear to be centrally involved in synaptic targeting by AßOs. Once bound to neurons, AßOs dysregulate the activity and reduce the surface expression of both N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) types of glutamate receptors, impairing signaling pathways involved in synaptic plasticity. In the extracellular milieu, AßOs promote accumulation of the excitatory amino acids, glutamate and D-serine. This leads to overactivation of glutamate receptors, triggering abnormal calcium signals with noxious impacts on neurons. Here, we review key findings linking AßOs to deregulated glutamate neurotransmission and implicating this as a primary mechanism of synapse failure in AD. We also discuss strategies to counteract the impact of AßOs on excitatory neurotransmission. In particular, we review evidence showing that inducing neuronal hyperpolarization via activation of inhibitory GABA(A) receptors prevents AßO-induced excitotoxicity, suggesting that this could comprise a possible therapeutic approach in AD.

Interacción entre gabapentina y D-serina en la prueba orofacial de la formalina / Interaction between gabapentin and D-serin in the formalin orofacial test

La gabapentina es un agente útil para el alivio de la neuralgia del trigémino y el dolor orofacial fantasma. Sin embargo, existe poca información sobre el efecto antinociceptivo de la gabapentina en los modelos de dolor orofacial. En este trabajo se investigó el efecto antinociceptivo de la gabapentina sobre el acicalado facial en la rata, provocado por la inyección de la formalina, un paradigma de dolor orofacial. La dosis de 10 mg/kg IP de la gabapentina produjo una drástica disminución del acicalado facial en la fase I y II indicando un claro efecto antinociceptivo. Sin embargo, en la dosis de 1 mg/kg IP, la gabapentina tuvo un efecto antinociceptivo sólo en la fase I. La D-serina (100 µg, ICV) no produjo efecto inyectada sola y no antagonizó el efecto antinociceptivo de la gabapentina. Por el contrario, la combinación de la gabapentina-1 mg/kg IP más D-serina redujo significativamente el acicalado facial en la fase II. Este resultado muestra una diferencia con estudios en que la gabapentina induce antinocicepción en la prueba de la formalina en la pata de la rata sólo en la fase II y la D-serina antagoniza a la gabapentina. Los resultados se discuten en relación al proceso de dolor en la pata posterior versus la estimulación dolorosa orofacial.

Gabapentin is a useful agent for the relief of trigeminal neuralgia and orofacial phantom pain. However, there is scarce information on the gabapentin analgesic effect in orofacial pain models. We tested the analgesic action of gabapentin on the formalin-induced face grooming in the rat, an orofacial pain paradigm. IP Gabapentin (10 mg/kg), induced a drastic reduction in face grooming during phase I and II, indicating a clear-cut antinociceptive effect. However, at 1 mg/kg, gabapentin had an analgesic effect only on phase I. D-serine (100 µg, ICV) was silent when given alone and did not antagonize the antinociceptive effect of gabapentin. On the contrary, gabapentin 1 mg/kg plus D-serine significantly reduced face grooming in phase II. These results show a difference between gabapentin induced orofacial analgesia and previous studies showing gabapentin-induced hind paw analgesia in the formalin test, only during phase II, as well as D-serine antagonism of gabapentin. The results are discussed in terms of different pain processing of hind paw, versus orofacial nociceptive stimulation.