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1.
Br J Pharmacol ; 175(23): 4386-4397, 2018 12.
Article in English | MEDLINE | ID: mdl-30220081

ABSTRACT

BACKGROUND AND PURPOSE: NMDA receptors play a key role in both synaptic plasticity and neurodegeneration. Adenosine is an endogenous neuromodulator and through membrane receptors of the A2A subtype can influence both synaptic plasticity and neuronal death. The present work was designed to evaluate the influence of adenosine A2A receptors upon NMDA receptor activity in CA1 hippocampal neurons. We discriminated between modulation of synaptic versus extrasynaptic receptors, since extrasynaptic NMDA receptors are mostly associated with neurodegeneration while synaptic NMDA receptors are linked to plasticity phenomena. EXPERIMENTAL APPROACH: Whole-cell patch-clamp recordings were obtained to evaluate NMDA receptor actions on CA1 pyramidal neurons of young adult (5-10 weeks) male Wistar rat hippocampus. KEY RESULTS: Activation of A2A receptors with CGS 21680 (30 nM) consistently facilitated chemically-evoked NMDA receptor-currents (NMDA-PSCs) and afferent-evoked NMDA-currents (NMDA-EPSCs), an action prevented by an A2A receptor antagonist (SCH58261, 100 nM) and a PKA inhibitor, H-89 (1 µM). These actions did not reflect facilitation in glutamate release since there was no change in NMDA-EPSCs paired pulse ratio. A2A receptor actions were lost in the presence of an open-channel NMDA receptor blocker, MK-801 (10 µM), but persisted in the presence of memantine, at a concentration (10 µM) known to preferentially block extrasynaptic NMDA receptors. CONCLUSION AND IMPLICATIONS: These results show that A2A receptors exert a positive postsynaptic modulatory effect over synaptic, but not extrasynaptic, NMDA receptors in CA1 neurons and, therefore, under non-pathological conditions may contribute to shift the dual role of NMDA receptors towards enhancement of synaptic plasticity.


Subject(s)
CA1 Region, Hippocampal/metabolism , N-Methylaspartate/metabolism , Pyramidal Cells/metabolism , Receptor, Adenosine A2A/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Animals , Male , Rats , Rats, Wistar
2.
Cereb Cortex ; 28(8): 2795-2809, 2018 08 01.
Article in English | MEDLINE | ID: mdl-29053799

ABSTRACT

The cytokine erythropoietin (EPO) is the master regulator of erythropoiesis. Intriguingly, many studies have shown that the cognitive performance of patients receiving EPO for its hematopoietic effects is enhanced, which prompted the growing interest in the use of EPO-based strategies to treat neuropsychiatric disorders. EPO plays key roles in brain development and maturation, but also modulates synaptic transmission. However, the mechanisms underlying the latter have remained elusive. Here, we show that acute (40-60 min) exposure to EPO presynaptically downregulates spontaneous and afferent-evoked excitatory transmission, without affecting basal firing of action potentials. Conversely, prolonged (3 h) exposure to EPO, if followed by a recovery period (1 h), is able to elicit a homeostatic increase in excitatory spontaneous, but not in evoked, synaptic transmission. These data lend support to the emerging view that segregated pathways underlie spontaneous and evoked neurotransmitter release. Furthermore, we show that prolonged exposure to EPO facilitates a form of hippocampal long-term potentiation that requires noncanonical recruitment of calcium-permeable AMPA receptors for its maintenance. These findings provide important new insight into the mechanisms by which EPO enhances neuronal function, learning, and memory.


Subject(s)
Erythropoietin/pharmacology , Hippocampus/cytology , Hippocampus/physiology , Homeostasis/drug effects , Neuronal Plasticity/drug effects , Synapses/drug effects , Animals , Biophysics , Electric Stimulation , In Vitro Techniques , Long-Term Potentiation/drug effects , Membrane Potentials/drug effects , Nerve Net/drug effects , Nerve Net/physiology , Neurotransmitter Agents/pharmacology , Organ Culture Techniques , Patch-Clamp Techniques , Rats , Receptors, AMPA/metabolism , Receptors, Erythropoietin/metabolism , Sodium Channel Blockers/pharmacology , Synapses/physiology , Tetrodotoxin/pharmacology , Time Factors
3.
Purinergic Signal ; 12(2): 283-94, 2016 06.
Article in English | MEDLINE | ID: mdl-26897393

ABSTRACT

Brain-derived neurotrophic factor (BDNF) and adenosine are widely recognized as neuromodulators of glutamatergic transmission in the adult brain. Most BDNF actions upon excitatory plasticity phenomena are under control of adenosine A2A receptors (A2ARs). Concerning gamma-aminobutyric acid (GABA)-mediated transmission, the available information refers to the control of GABA transporters. We now focused on the influence of BDNF and the interplay with adenosine on phasic GABAergic transmission. To assess this, we evaluated evoked and spontaneous synaptic currents recorded from CA1 pyramidal cells in acute hippocampal slices from adult rat brains (6 to 10 weeks old). BDNF (10-100 ng/mL) increased miniature inhibitory postsynaptic current (mIPSC) frequency, but not amplitude, as well as increased the amplitude of inhibitory postsynaptic currents (IPSCs) evoked by afferent stimulation. The facilitatory action of BDNF upon GABAergic transmission was lost in the presence of a Trk inhibitor (K252a, 200 nM), but not upon p75(NTR) blockade (anti-p75(NTR) IgG, 50 µg/mL). Moreover, the facilitatory action of BDNF onto GABAergic transmission was also prevented upon A2AR antagonism (SCH 58261, 50 nM). We conclude that BDNF facilitates GABAergic signaling at the adult hippocampus via a presynaptic mechanism that depends on TrkB and adenosine A2AR activation.


Subject(s)
Brain-Derived Neurotrophic Factor/metabolism , CA1 Region, Hippocampal/metabolism , Receptor, Adenosine A2A/metabolism , Receptor, trkB/metabolism , Synaptic Transmission/physiology , gamma-Aminobutyric Acid/metabolism , Animals , Inhibitory Postsynaptic Potentials/physiology , Male , Organ Culture Techniques , Patch-Clamp Techniques , Rats , Rats, Wistar
4.
Cereb Cortex ; 26(3): 1081-95, 2016 Mar.
Article in English | MEDLINE | ID: mdl-25452570

ABSTRACT

Adenosine is an endogenous neuromodulator that decreases excitability of hippocampal circuits activating membrane-bound metabotropic A1 receptor (A1R). The presynaptic inhibitory action of adenosine A1R in glutamatergic synapses is well documented, but its influence on inhibitory GABAergic transmission is poorly known. We report that GABAA receptor (GABAAR)-mediated tonic, but not phasic, transmission is suppressed by A1R in hippocampal neurons. Adenosine A1R activation strongly inhibits GABAAR agonist (muscimol)-evoked currents in Cornu Ammonis 1 (CA1) pyramidal neurons and in a specific subpopulation of interneurons expressing axonal cannabinoid receptor type 1. In addition, A1R suppresses tonic GABAAR currents measured in the presence of elevated ambient GABA as well as in naïve slices. The inhibition of GABAergic currents involves both protein kinase A (PKA) and protein kinase C (PKC) signaling pathways and decreases GABAAR δ-subunit expression. On the contrary, no A1R-mediated modulation was detected in phasic inhibitory postsynaptic currents evoked either by afferent electrical stimulation or by spontaneous quantal release. The results show that A1R modulates extrasynaptic rather than synaptic GABAAR-mediated signaling, and that this modulation selectively occurs in hippocampal pyramidal neurons and in a specific subpopulation of inhibitory interneurons. We conclude that modulation of tonic GABAAR signaling by adenosine A1R in specific neuron types may regulate neuronal gain and excitability in the hippocampus.


Subject(s)
CA1 Region, Hippocampal/physiology , Interneurons/physiology , Pyramidal Cells/physiology , Receptor, Adenosine A1/metabolism , Receptors, GABA-A/metabolism , Animals , CA1 Region, Hippocampal/cytology , CA1 Region, Hippocampal/drug effects , Cyclic AMP-Dependent Protein Kinases/metabolism , Immunoblotting , Immunohistochemistry , Inhibitory Postsynaptic Potentials/drug effects , Inhibitory Postsynaptic Potentials/physiology , Interneurons/cytology , Interneurons/drug effects , Male , Miniature Postsynaptic Potentials/drug effects , Miniature Postsynaptic Potentials/physiology , Neural Inhibition/drug effects , Neural Inhibition/physiology , Patch-Clamp Techniques , Protein Kinase C/metabolism , Pyramidal Cells/cytology , Pyramidal Cells/drug effects , Rats, Wistar , Tissue Culture Techniques
5.
Mol Neurobiol ; 51(3): 1168-83, 2015.
Article in English | MEDLINE | ID: mdl-24973144

ABSTRACT

We have previously demonstrated the involvement of specific apoptosis-associated microRNAs (miRNAs), including miR-34a, in mouse neural stem cell (NSC) differentiation. In addition, a growing body of evidence points to a critical role for autophagy during neuronal differentiation, as a response-survival mechanism to limit oxidative stress and regulate synaptogenesis associated with this process. The aim of this study was to further investigate the precise role of miR-34a during NSC differentiation. Our results showed that miR-34a expression was markedly downregulated during neurogenesis. Neuronal differentiation and cell morphology, synapse function, and electrophysiological maturation were significantly impaired in miR-34a-overexpressing NSCs. In addition, synaptotagmin 1 (Syt1) and autophagy-related 9a (Atg9a) significantly increased during neurogenesis. Pharmacological inhibition of autophagy impaired both neuronal differentiation and cell morphology. Notably, we showed that Syt1 and Atg9a are miR-34a targets in neural differentiation context, markedly decreasing after miR-34a overexpression. Syt1 overexpression and rapamycin-induced autophagy partially rescued the impairment of neuronal differentiation by miR-34a. In conclusion, our results demonstrate a novel role for miR-34a regulation of NSC differentiation, where miR-34a downregulation and subsequent increase of Syt1 and Atg9a appear to be crucial for neurogenesis progression.


Subject(s)
Cell Differentiation/physiology , Membrane Proteins/biosynthesis , MicroRNAs/physiology , Neural Stem Cells/metabolism , Synapses/metabolism , Synaptotagmin I/biosynthesis , Vesicular Transport Proteins/biosynthesis , Animals , Autophagy/physiology , Autophagy-Related Proteins , Gene Expression Regulation , Mice , Prosencephalon/cytology , Prosencephalon/metabolism
6.
Trends Neurosci ; 36(4): 248-57, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23332692

ABSTRACT

It is widely accepted that Hebbian forms of plasticity mediate selective modifications in synaptic strength underlying information encoding in response to experience and circuit formation or refinement throughout development. Several complementary forms of homeostatic plasticity coordinate to keep Hebbian plasticity in check, frequently through the actions of conserved regulatory molecules. Recent evidence suggests that this may be the case for adenosine, which is ubiquitous in the brain and is released by both neurons and glial cells via constitutive and activity-dependent mechanisms. Through A1 and A2A receptor activation, adenosine modulates neuronal homeostasis and tunes the ability of synapses to undergo and/or sustain plasticity. Here, we review how adenosine equilibrates neuronal activity and sets the stage for synaptic plasticity.


Subject(s)
Adenosine/metabolism , Neuronal Plasticity/physiology , Neurons/cytology , Synapses/physiology , Animals , Brain/cytology , Humans , Neurons/physiology , Receptors, Purinergic P1/metabolism
7.
Neurobiol Aging ; 34(2): 551-61, 2013 Feb.
Article in English | MEDLINE | ID: mdl-22621777

ABSTRACT

Synapses are considered the earliest site of Alzheimer's disease (AD) pathology, where synapse density is reduced, and synaptic loss is highly correlated with cognitive impairment. Tauroursodeoxycholic acid (TUDCA) has been shown to be neuroprotective in several models of AD, including neuronal exposure to amyloid ß (Aß) and amyloid precursor protein (APP)/presenilin 1 (PS1) double-transgenic mice. Here, we show that TUDCA modulates synaptic deficits induced by Aß in vitro. Specifically, TUDCA reduced the downregulation of the postsynaptic marker postsynaptic density-95 (PSD-95) and the decrease in spontaneous miniature excitatory postsynaptic currents (mEPSCs) frequency, while increasing the number of dendritic spines. This contributed to the induction of more robust and synaptically efficient neurons, reflected in inhibition of neuronal death. In vivo, TUDCA treatment of APP/PS1 mice abrogated the decrease in PSD-95 reactivity in the hippocampus. Taken together, these results expand the neuroprotective role of TUDCA to a synaptic level, further supporting the use of this molecule as a potential therapeutic strategy for the prevention and treatment of AD.


Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/pharmacology , Neuroprotective Agents/pharmacology , Synapses/drug effects , Taurochenodeoxycholic Acid/pharmacology , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Cell Death/drug effects , Cell Death/physiology , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Disease Models, Animal , Down-Regulation , Hippocampus/drug effects , Hippocampus/metabolism , Mice , Mice, Transgenic , Neurons/drug effects , Neurons/metabolism , Presenilin-1/genetics , Presenilin-1/metabolism , Rats , Rats, Wistar , Synapses/metabolism
8.
Neuropharmacology ; 65: 114-22, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23041538

ABSTRACT

Long lasting enhancement of synaptic transmission can be triggered by brief bursts of afferent stimulation, underlying long-term potentiation (LTP), and also by brief ischemia in a process known as i-LTP. The extent to which LTP and i-LTP rely on comparable cellular mechanisms remains unclear. Under physiological conditions, LTP induction drives transient expression of calcium-permeable AMPARs (CP-AMPARs) at synapses, whose ability to undergo plasticity is primed by endogenous activation of adenosine A(2A) receptors (A(2A)Rs). The present work thus addressed the contribution of CP-AMPARs and A(2A)Rs to i-LTP, which was induced in rat hippocampal slices by brief (10 min) oxygen/glucose deprivation (OGD). The amplitude of afferent-evoked excitatory postsynaptic currents (EPSCs) recorded from CA1 pyramidal neurons was decreased during OGD but gradually recovered toward values significantly above (157 ± 17%) the baseline (100%) 40-50 min after re-oxygenation. This i-LTP was precluded by CP-AMPAR blockade (internal spermine (500 µM) or extracellular NASPM (20 µM) application) as well as by A(2A)R blockade with a selective antagonist (SCH 58261, 100 nM). OGD prompted sustained (>70 min) facilitation of mEPSC amplitude and frequency, and decreased mEPSC decay time, all of which were prevented by SCH 58261 (100 nM). The ability of NASPM (20 µM) to acutely inhibit EPSCs 1 h after OGD, but not in control conditions nor in OGD-challenged slices when in the presence of SCH 58261 (100 nM), further supports sustained CP-AMPAR recruitment by i-LTP in an A(2A)R-dependent way. We propose that although i-LTP may initially mimic LTP, failure of auto-regulated CP-AMPAR removal from synapses could constitute an early divergent event between these forms of plasticity.


Subject(s)
Calcium/metabolism , Hippocampus/blood supply , Hippocampus/metabolism , Neuronal Plasticity/physiology , Receptors, AMPA/biosynthesis , Synapses/metabolism , Animals , Cell Hypoxia/drug effects , Cell Hypoxia/physiology , Excitatory Postsynaptic Potentials/drug effects , Excitatory Postsynaptic Potentials/physiology , Gene Expression Regulation , Hippocampus/drug effects , Male , Neuronal Plasticity/drug effects , Organ Culture Techniques , Pyrimidines/pharmacology , Rats , Rats, Wistar , Receptors, AMPA/agonists , Receptors, AMPA/antagonists & inhibitors , Spermine/pharmacology , Synapses/drug effects , Triazoles/pharmacology
9.
Neuropharmacology ; 64: 97-107, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22820274

ABSTRACT

The synapse is a crowded area. In the last years, the concept that proteins can be organized in different membrane domains according to their structure has emerged. Cholesterol-rich membrane domains, or lipid rafts, form an organized portion of the membrane that is thought to concentrate signaling molecules. Accumulating evidence has shown that both the pre-synaptic and post-synaptic sites are highly enriched in lipid rafts, which are likely to organize and maintain synaptic proteins in their precise localization. Here we review recent studies highlighting the importance of lipid rafts for synaptic function and plasticity, as well as their relevance for age or disease-related cognitive impairment. This article is part of a Special Issue entitled 'Cognitive Enhancers'.


Subject(s)
Aging , Membrane Microdomains/metabolism , Neurodegenerative Diseases/metabolism , Neuronal Plasticity , Synapses/metabolism , Synaptic Transmission , Animals , Central Nervous System/drug effects , Central Nervous System/metabolism , Humans , Membrane Microdomains/drug effects , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/prevention & control , Neuronal Plasticity/drug effects , Neurons/drug effects , Neurons/metabolism , Nootropic Agents/pharmacology , Nootropic Agents/therapeutic use , Synapses/drug effects , Synaptic Transmission/drug effects
10.
J Neurosci ; 32(34): 11750-62, 2012 Aug 22.
Article in English | MEDLINE | ID: mdl-22915117

ABSTRACT

Parkinson's disease (PD) is the most common representative of a group of disorders known as synucleinopathies, in which misfolding and aggregation of α-synuclein (a-syn) in various brain regions is the major pathological hallmark. Indeed, the motor symptoms in PD are caused by a heterogeneous degeneration of brain neurons not only in substantia nigra pars compacta but also in other extrastriatal areas of the brain. In addition to the well known motor dysfunction in PD patients, cognitive deficits and memory impairment are also an important part of the disorder, probably due to disruption of synaptic transmission and plasticity in extrastriatal areas, including the hippocampus. Here, we investigated the impact of a-syn aggregation on AMPA and NMDA receptor-mediated rat hippocampal (CA3-CA1) synaptic transmission and long-term potentiation (LTP), the neurophysiological basis for learning and memory. Our data show that prolonged exposure to a-syn oligomers, but not monomers or fibrils, increases basal synaptic transmission through NMDA receptor activation, triggering enhanced contribution of calcium-permeable AMPA receptors. Slices treated with a-syn oligomers were unable to respond with further potentiation to theta-burst stimulation, leading to impaired LTP. Prior delivery of a low-frequency train reinstated the ability to express LTP, implying that exposure to a-syn oligomers drives the increase of glutamatergic synaptic transmission, preventing further potentiation by physiological stimuli. Our novel findings provide mechanistic insight on how a-syn oligomers may trigger neuronal dysfunction and toxicity in PD and other synucleinopathies.


Subject(s)
Long-Term Potentiation/drug effects , Synapses/drug effects , Synaptic Transmission/drug effects , Synaptic Transmission/physiology , alpha-Synuclein/pharmacology , 6-Cyano-7-nitroquinoxaline-2,3-dione/pharmacology , Animals , Biophysics , Biotinylation , Cell Line, Tumor , Excitatory Amino Acid Antagonists/pharmacology , Excitatory Postsynaptic Potentials/drug effects , Extracellular Fluid/metabolism , Hippocampus/cytology , Humans , Insulin/pharmacology , L-Lactate Dehydrogenase/metabolism , Long-Term Potentiation/physiology , Male , Neuroblastoma/pathology , Organ Culture Techniques , Patch-Clamp Techniques , Rats , Rats, Wistar , Receptors, N-Methyl-D-Aspartate/metabolism , Valine/analogs & derivatives , Valine/pharmacology , alpha-Synuclein/biosynthesis , alpha-Synuclein/chemistry
11.
Hippocampus ; 22(2): 276-91, 2012 Feb.
Article in English | MEDLINE | ID: mdl-21080412

ABSTRACT

Phosphorylation of glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors by Protein Kinase A (PKA) is known to regulate AMPA receptor (AMPAR) trafficking and stabilization at the postsynaptic membrane, which in turn is one of the key mechanisms by which synaptic transmission and plasticity are tuned. However, not much is known as to how Gs-coupled receptors contribute to endogenous PKA-mediated regulation of AMPA receptor function. Here we report that activation of the excitatory A(2A) adenosine receptor by 2-[4-(2-p-carboxyethyl)phenylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680, 1-30 nM) facilitates AMPA-evoked currents in CA1 pyramidal neurons, by a mechanism dependent on PKA activation, but not on protein synthesis. This modulation of AMPA currents was mimicked by forskolin (1 µM) and did not occur in stratum radiatum interneurons. Superfusion of the A(2A) receptor agonist also caused an increase in the amplitude of miniature excitatory postsynaptic currents (mEPSCs), as well as in the membrane levels of GluR1 subunits phosphorylated at the PKA site (Ser845). The impact of this increase on GluR1-containing AMPA receptor expression was evidenced by the potentiation of LTP at the CA3-CA1 synapse that followed brief activation of A(2A) receptors. We thus propose that in conditions of increased adenosine availability, A(2A) receptor activation is responsible for setting part of the endogenous GluR1 Ser-845 phosphorylation tonus and hence, the availability of the GluR1-containing AMPA receptor extrasynaptic pool for synaptic insertion and reinforcement of synaptic strength.


Subject(s)
Neuronal Plasticity/physiology , Pyramidal Cells/physiology , Receptor, Adenosine A2A/metabolism , Receptors, AMPA/biosynthesis , Synaptic Transmission/physiology , alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/metabolism , Animals , Cyclic AMP-Dependent Protein Kinases/metabolism , Excitatory Postsynaptic Potentials/physiology , Hippocampus/physiology , Immunoblotting , Male , Organ Culture Techniques , Patch-Clamp Techniques , Rats , Rats, Wistar , Receptors, AMPA/metabolism
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