The amygdala NT3-TrkC pathway underlies inter-individual differences in fear extinction and related synaptic plasticity.

Fear-related pathologies are among the most prevalent psychiatric conditions, having inappropriate learned fear and resistance to extinction as cardinal features. Exposure therapy represents a promising therapeutic approach, the efficiency of which depends on inter-individual variation in fear extinction learning, which neurobiological basis is unknown. We characterized a model of extinction learning, whereby fear-conditioned mice were categorized as extinction (EXT)-success or EXT-failure, according to their inherent ability to extinguish fear.

Adenosine A Receptors Shut Down Adenosine A Receptor-Mediated Presynaptic Inhibition to Promote Implementation of Hippocampal Long-Term Potentiation.

Adenosine operates a modulation system fine-tuning the efficiency of synaptic transmission and plasticity through A and A receptors (AR, AR), respectively. Supramaximal activation of AR can block hippocampal synaptic transmission, and the tonic engagement of AR-mediated inhibition is increased with increased frequency of nerve stimulation. This is compatible with an activity-dependent increase in extracellular adenosine in hippocampal excitatory synapses, which can reach levels sufficient to block synaptic transmission.

Caffeic acid recovers ischemia-induced synaptic dysfunction without direct effects on excitatory synaptic transmission and plasticity in mouse hippocampal slices.

Caffeic acid is a polyphenolic compound present in a vast array of dietary components. We previously showed that caffeic acid reduces the burden of brain ischemia joining evidence by others that it can attenuate different brain diseases. However, it is unknown if caffeic acid affects information processing in neuronal networks.

Downregulation of Sirtuin 1 Does Not Account for the Impaired Long-Term Potentiation in the Prefrontal Cortex of Female APPswe/PS1dE9 Mice Modelling Alzheimer's Disease.

Alzheimer's disease (AD), which predominantly affects women, involves at its onset a metabolic deregulation associated with a synaptic failure. Here, we performed a behavioral, neurophysiological and neurochemical characterization of 9-month-old female APPswe/PS1dE9 (APP/PS1) mice as a model of early AD. These animals showed learning and memory deficits in the Morris water maze, increased thigmotaxis and anxiety-like behavior and showed signs of fear generalization.

Feedback facilitation by adenosine A receptors of ATP release from mouse hippocampal nerve terminals.

The adenosine modulation system is mostly composed by inhibitory A receptors (AR) and the less abundant facilitatory A receptors (AR), the latter selectively engaged at high frequency stimulation associated with synaptic plasticity processes in the hippocampus. AR are activated by adenosine originated from extracellular ATP through ecto-5'-nucleotidase or CD73-mediated catabolism. Using hippocampal synaptosomes, we now investigated how adenosine receptors modulate the synaptic release of ATP.

Increased Synaptic ATP Release and CD73-Mediated Formation of Extracellular Adenosine in the Control of Behavioral and Electrophysiological Modifications Caused by Chronic Stress.

Increased ATP release and its extracellular catabolism through CD73 (ecto-5'-nucleotidase) lead to the overactivation of adenosine A receptors (AR), which occurs in different brain disorders. AR blockade blunts mood and memory dysfunction caused by repeated stress, but it is unknown if increased ATP release coupled to CD73-mediated formation of extracellular adenosine is responsible for AR overactivation upon repeated stress. This was now investigated in adult rats subject to repeated stress for 14 consecutive days.

The striatum drives the ergogenic effects of caffeine.

Caffeine is one of the main ergogenic resources used in exercise and sports. Previously, we reported the ergogenic mechanism of caffeine through neuronal AR antagonism in the central nervous system [1]. We now demonstrate that the striatum rules the ergogenic effects of caffeine through neuroplasticity changes.

Increased ATP Release and Higher Impact of Adenosine A Receptors on Corticostriatal Plasticity in a Rat Model of Presymptomatic Parkinson's Disease.

Extracellular ATP can be a danger signal, but its role in striatal circuits afflicted in Parkinson's disease (PD) is unclear and was now investigated. ATP was particularly released at high stimulation intensities from purified striatal nerve terminals of mice, which were endowed with different ATP-P2 receptors (P2R), although P2R antagonists did not alter corticostriatal transmission or plasticity. Instead, ATP was extracellularly catabolized into adenosine through CD73 to activate adenosine A receptors (AR) modulating corticostriatal long-term potentiation (LTP) in mice.

Aβ peptides blunt the adenosine A receptor-mediated control of the interplay between PX and PY receptors mediated calcium responses in astrocytes.

The contribution of astrocytes to Alzheimer's disease (AD) is still ill defined. AD involves an abnormal accumulation of amyloid-β peptides (Aβ) and increased production of danger signals such as ATP. ATP can direct or indirectly, through its metabolism into adenosine, trigger adaptive astrocytic responses resulting from intracellular Ca oscillations.

Simultaneous Alteration of the Circadian Variation of Memory, Hippocampal Synaptic Plasticity, and Metabolism in a Triple Transgenic Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by progressive memory deficits accompanied by synaptic and metabolic deficits, namely of mitochondrial function. AD patients also display a disrupted circadian pattern. Thus, we now compared memory performance, synaptic plasticity, and mitochondria function in 24-week-old non-transgenic (non-Tg) and triple transgenic male mice modeling AD (3xTg-AD) at Zeitgeber 04 (ZT-4, inactive phase) and ZT-16 (active phase).

Increased ATP release and CD73-mediated adenosine A receptor activation mediate convulsion-associated neuronal damage and hippocampal dysfunction.

Extracellular ATP is a danger signal to the brain and contributes to neurodegeneration in animal models of Alzheimer's disease through its extracellular catabolism by CD73 to generate adenosine, bolstering the activation of adenosine A receptors (AR). Convulsive activity leads to increased ATP release, with the resulting morphological alterations being eliminated by AR blockade. However, it is not known if upon convulsions there is a CD73-mediated coupling between ATP release and AR overactivation, causing neurodegeneration.

Neuromodulation and neuroprotective effects of chlorogenic acids in excitatory synapses of mouse hippocampal slices.

The increased healthspan afforded by coffee intake provides novel opportunities to identify new therapeutic strategies. Caffeine has been proposed to afford benefits through adenosine A receptors, which can control synaptic dysfunction underlying some brain disease. However, decaffeinated coffee and other main components of coffee such as chlorogenic acids, also attenuate brain dysfunction, although it is unknown if they control synaptic function.

Crosstalk Between ATP-P and Adenosine A Receptors Controlling Neuroinflammation in Rats Subject to Repeated Restraint Stress.

Depressive conditions precipitated by repeated stress are a major socio-economical burden in Western countries. Previous studies showed that ATP-P receptors (PR) and adenosine A receptors (AR) antagonists attenuate behavioral modifications upon exposure to repeated stress. Since it is unknown if these two purinergic modulation systems work independently, we now investigated a putative interplay between PR and AR.

Exercise decreases aberrant corticostriatal plasticity in an animal model of l-DOPA-induced dyskinesia.

Physical exercise attenuates the development of l-3,4-dihydroxyphenylalanine (l-DOPA)-induced dyskinesia (LID) in 6-hydroxydopamine-induced hemiparkinsonian mice through unknown mechanisms. We now tested if exercise normalizes the aberrant corticostriatal neuroplasticity associated with experimental murine models of LID. C57BL/6 mice received two unilateral intrastriatal injections of 6-hydroxydopamine (12 μg) and were treated after 3 wk with l-DOPA/benserazide (25/12.

Motor Deficits Coupled to Cerebellar and Striatal Alterations in Ube3a Mice Modelling Angelman Syndrome Are Attenuated by Adenosine A Receptor Blockade.

Angelman syndrome (AS) is a neurogenetic disorder involving ataxia and motor dysfunction, resulting from the absence of the maternally inherited functional Ube3a protein in neurons. Since adenosine A receptor (AR) blockade relieves synaptic and motor impairments in Parkinson's or Machado-Joseph's diseases, we now tested if AR blockade was also effective in attenuating motor deficits in an AS (Ube3a) mouse model and if this involved correction of synaptic alterations in striatum and cerebellum. Chronic administration of the AR antagonist SCH58261 (0.

Use of knockout mice to explore CNS effects of adenosine.

The initial exploration using pharmacological tools of the role of adenosine receptors in the brain, concluded that adenosine released as such acted on AR to inhibit excitability and glutamate release from principal neurons throughout the brain and that adenosine A receptors (AR) were striatal-'specific' receptors controlling dopamine DR. This indicted AR as potential controllers of neurodegeneration and AR of psychiatric conditions. Global knockout of these two receptors questioned the key role of AR and instead identified extra-striatal AR as robust controllers of neurodegeneration.

Adenosine A receptors format long-term depression and memory strategies in a mouse model of Angelman syndrome.

Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of function of the maternally inherited Ube3a neuronal protein, whose main features comprise severe intellectual disabilities and motor impairments. Previous studies with the Ube3a mouse model of AS revealed deficits in synaptic plasticity and memory. Since adenosine A receptors (AR) are powerful modulators of aberrant synaptic plasticity and AR blockade prevents memory dysfunction in various brain diseases, we tested if AR could control deficits of memory and hippocampal synaptic plasticity in AS.

Role of Adenosine in Epilepsy and Seizures.

Adenosine is an endogenous anticonvulsant and neuroprotectant of the brain. Seizure activity produces large quantities of adenosine, and it is this seizure-induced adenosine surge that normally stops a seizure. However, within the context of epilepsy, adenosine plays a wide spectrum of different roles.

Validation of an LC-MS/MS Method for the Quantification of Caffeine and Theobromine Using Non-Matched Matrix Calibration Curve.

Caffeine is one of the most widely consumed psycho-stimulants. The study of the beneficial effects of caffeine consumption to decrease the risk of developing several neuropsychiatric pathologies is receiving increasing attention. Thus, accurate and sensitive methods have been developed, mainly by LC-MS/MS, in order to quantify caffeine and its metabolites.

Synaptic and memory dysfunction in a β-amyloid model of early Alzheimer's disease depends on increased formation of ATP-derived extracellular adenosine.

Adenosine A receptors (AR) overfunction causes synaptic and memory dysfunction in early Alzheimer's disease (AD). In a β-amyloid (Aβ)-based model of early AD, we now unraveled that this involves an increased synaptic release of ATP coupled to an increased density and activity of ecto-5'-nucleotidase (CD73)-mediated formation of adenosine selectively activating AR. Thus, CD73 inhibition with α,β-methylene-ADP impaired long-term potentiation (LTP) in mouse hippocampal slices, which is occluded upon previous superfusion with the AR antagonist SCH58261.

Enhanced ATP release and CD73-mediated adenosine formation sustain adenosine A receptor over-activation in a rat model of Parkinson's disease.

Background And Purpose: Parkinson's disease (PD) involves an initial loss of striatal dopamine terminals evolving into degeneration of dopamine neurons in substantia nigra (SN), which can be modelled by 6-hydroxydopamine (6-OHDA) administration. Adenosine A receptor blockade attenuates PD features in animal models, but the source of the adenosine causing A receptor over-activation is unknown. As ATP is a stress signal, we have tested if extracellular catabolism of adenine nucleotides into adenosine (through ecto-5'-nucleotidase or CD73) leads to A receptor over-activation in PD.

Treatment with A receptor antagonist KW6002 and caffeine intake regulate microglia reactivity and protect retina against transient ischemic damage.

Transient retinal ischemia is a major complication of retinal degenerative diseases and contributes to visual impairment and blindness. Evidences indicate that microglia-mediated neuroinflammation has a key role in the neurodegenerative process, prompting the hypothesis that the control of microglia reactivity may afford neuroprotection to the retina against the damage induced by ischemia-reperfusion (I-R). The available therapeutic strategies for retinal degenerative diseases have limited potential, but the blockade of adenosine A receptor (AR) emerges as candidate strategy.