Expression Of Long-term Depression Research Articles

Mimicking Protein Kinase C Phosphorylation Inhibits Arc/Arg3.1 Palmitoylation and Its Interaction with Nucleic Acids.

Activity-regulated cytoskeleton-associated protein (Arc) plays essential roles in diverse forms of synaptic plasticity, including long-term potentiation (LTP), long-term depression (LTD), and homeostatic plasticity. In addition, it assembles into virus-like particles that may deliver mRNAs and/or other cargo between neurons and neighboring cells. Considering this broad range of activities, it is not surprising that Arc is subject to regulation by multiple types of post-translational modification, including phosphorylation, palmitoylation, SUMOylation, ubiquitylation, and acetylation. Here we explore the potential regulatory role of Arc phosphorylation by protein kinase C (PKC), which occurs on serines 84 and 90 within an α-helical segment in the N-terminal domain. To mimic the effect of PKC phosphorylation, we mutated the two serines to negatively charged glutamic acid. A consequence of introducing these phosphomimetic mutations is the almost complete inhibition of Arc palmitoylation, which occurs on nearby cysteines and contributes to synaptic weakening. The mutations also inhibit the binding of nucleic acids and destabilize high-order Arc oligomers. Thus, PKC phosphorylation of Arc may limit the full expression of LTD and may suppress the interneuronal transport of mRNAs.

TREK-1 inhibition promotes synaptic plasticity in the prelimbic cortex

Synaptic plasticity is one of the putative mechanisms involved in the maturation of the prefrontal cortex (PFC) during postnatal development. Early life stress (ELS) affects the shaping of cortical circuitries through impairment of synaptic plasticity supporting the onset of mood disorders. Growing evidence suggests that dysfunctional postnatal maturation of the prelimbic division (PL) of the PFC might be related to the emergence of depression. The potassium channel TREK-1 has attracted particular interest among many factors that modulate plasticity, concerning synaptic modifications that could underlie mood disorders. Studies have found that ablation of TREK-1 increases the resilience to depression, while rats exposed to ELS exhibit higher TREK-1 levels in the PL. TREK-1 is regulated by multiple intracellular transduction pathways including the ones activated by metabotropic receptors. In the hippocampal neurons, TREK-1 interacts with the serotonergic system, one of the main factors involved in the action of antidepressants. To investigate possible mechanisms related to the antidepressant role of TREK-1, we used brain slice electrophysiology to evaluate the effects of TREK-1 pharmacological blockade on synaptic plasticity at PL circuitry. We extended this investigation to animals subjected to ELS. Our findings suggest that in non-stressed animals, TREK-1 activity is required for the reduction of synaptic responses mediated by the 5HT1A receptor activation. Furthermore, we demonstrate that TREK-1 blockade promotes activity-dependent long-term depression (LTD) when acting in synergy with 5HT1A receptor stimulation. On the other hand, in ELS animals, TREK-1 blockade reduces synaptic transmission and facilitates LTD expression. These results indicate that TREK-1 inhibition stimulates synaptic plasticity in the PL and this effect is more pronounced in animals subjected to ELS during postnatal development.

Differentiated somatic gene expression is triggered in the dorsal hippocampus and the anterior retrosplenial cortex by hippocampal synaptic plasticity prompted by spatial content learning

Hippocampal afferent inputs, terminating on proximal and distal subfields of the cornus ammonis (CA), enable the functional discrimination of ‘what’ (item identity) and ‘where’ (spatial location) elements of a spatial representation. This kind of information is supported by structures such as the retrosplenial cortex (RSC). Spatial content learning promotes the expression of hippocampal synaptic plasticity, particularly long-term depression (LTD). In the CA1 region, this is specifically facilitated by the learning of item-place features of a spatial environment. Gene-tagging, by means of time-locked fluorescence in situ hybridization (FISH) to detect nuclear expression of immediate early genes, can reveal neuronal populations that engage in experience-dependent information encoding. In the current study, using FISH, we examined if learning-facilitated LTD results in subfield-specific information encoding in the hippocampus and RSC. Rats engaged in novel exploration of small items during stimulation of Schaffer collateral-CA1 synapses. This resulted in LTD (> 24 h). FISH, to detect nuclear expression of Homer1a, revealed that the distal-CA1 and proximal-CA3 subcompartments were particularly activated by this event. By contrast, all elements of the proximodistal cornus ammonis-axis showed equal nuclear Homer1a expression following LTD induction solely by means of afferent stimulation. The RSC exhibited stronger nuclear Homer1a expression in response to learning-facilitated LTD, and to novel item-place experience, compared to LTD induced by sole afferent stimulation in CA1. These results show that both the cornus ammonis and RSC engage in differentiated information encoding of item-place learning that is salient enough, in its own right, to drive the expression of hippocampal LTD. These results also reveal a novel role of the RSC in item-place learning.

Dendritic autophagy degrades postsynaptic proteins and is required for long-term synaptic depression in mice

The pruning of dendritic spines during development requires autophagy. This process is facilitated by long-term depression (LTD)-like mechanisms, which has led to speculation that LTD, a fundamental form of synaptic plasticity, also requires autophagy. Here, we show that the induction of LTD via activation of NMDA receptors or metabotropic glutamate receptors initiates autophagy in the postsynaptic dendrites in mice. Dendritic autophagic vesicles (AVs) act in parallel with the endocytic machinery to remove AMPA receptor subunits from the membrane for degradation. During NMDAR-LTD, key postsynaptic proteins are sequestered for autophagic degradation, as revealed by quantitative proteomic profiling of purified AVs. Pharmacological inhibition of AV biogenesis, or conditional ablation of atg5 in pyramidal neurons abolishes LTD and triggers sustained potentiation in the hippocampus. These deficits in synaptic plasticity are recapitulated by knockdown of atg5 specifically in postsynaptic pyramidal neurons in the CA1 area. Conducive to the role of synaptic plasticity in behavioral flexibility, mice with autophagy deficiency in excitatory neurons exhibit altered response in reversal learning. Therefore, local assembly of the autophagic machinery in dendrites ensures the degradation of postsynaptic components and facilitates LTD expression.

Age-Dependent Contributions of NMDA Receptors and L-Type Calcium Channels to Long-Term Depression in the Piriform Cortex.

In the hippocampus, the contributions of N-methyl-D-aspartate receptors (NMDARs) and L-type calcium channels (LTCCs) to neuronal transmission and synaptic plasticity change with aging, underlying calcium dysregulation and cognitive dysfunction. However, the relative contributions of NMDARs and LTCCs in other learning encoding structures during aging are not known. The piriform cortex (PC) plays a significant role in odor associative memories, and like the hippocampus, exhibits forms of long-term synaptic plasticity. Here, we investigated the expression and contribution of NMDARs and LTCCs in long-term depression (LTD) of the PC associational fiber pathway in three cohorts of Sprague Dawley rats: neonatal (1–2 weeks), young adult (2–3 months) and aged (20–25 months). Using a combination of slice electrophysiology, Western blotting, fluorescent immunohistochemistry and confocal imaging, we observed a shift from an NMDAR to LTCC mediation of LTD in aged rats, despite no difference in the amount of LTD expression. These changes in plasticity are related to age-dependent differential receptor expression in the PC. LTCC Cav1.2 expression relative to postsynaptic density protein 95 is increased in the associational pathway of the aged PC layer Ib. Enhanced LTCC contribution in synaptic depression in the PC may contribute to altered olfactory function and learning with aging.

A kinesin 1-protrudin complex mediates AMPA receptor synaptic removal during long-term depression.

The synaptic removal of AMPA-type glutamate receptors (AMPARs) is a core mechanism for hippocampal long-term depression (LTD). In this study, we address the role of microtubule-dependent transport of AMPARs as a driver for vesicular trafficking and sorting during LTD. Here, we show that the kinesin-1 motor KIF5A/C is strictly required for LTD expression in CA3-to-CA1 hippocampal synapses. Specifically, we find that KIF5 is required for an efficient internalization of AMPARs after NMDA receptor activation. We show that the KIF5/AMPAR complex is assembled in an activity-dependent manner and associates with microsomal membranes upon LTD induction. This interaction is facilitated by the vesicular adaptor protrudin, which is also required for LTD expression. We propose that protrudin links KIF5-dependent transport to endosomal sorting, preventing AMPAR recycling to synapses after LTD induction. Therefore, this work identifies an activity-dependent molecular motor and the vesicular adaptor protein that executes AMPAR synaptic removal during LTD.

ЗАКОНОМІРНОСТІ СПОНТАННОГО КВАНТОВОГО ВИВІЛЬНЕННЯ ГЛУТАМАТУ В СИНАПСАХ НЕЙРОНІВ ПЕРВИННОЇ КУЛЬТУРИ ГІПОКАМПА ПРИ ДОВГОТРИВАЛІЙ ДЕПРЕСІЇ СИНАПТИЧНОЇ ПЕРЕДАЧІ

The results of electrophysiological studies of the quantal release features of glutamate in hippocampal neurons' synapses in long-term depression of synaptic transmission are presented. To research the topic, weused the primary culture of the rat hippocampus. Using the patch-clamp technique, the frequencies and amplitudes of excitatory spontaneous postsynaptic currents (EPSCs) were determined, theirdistributions were analyzed and the basicquantal parameters were calculated. Long-term depression of synaptic transmission was achieved by tetanic stimulation of the axon of the presynaptic cell for 5 minutes with a stimulation frequency of 5 Hz. Spontaneous current in depression was recorded 20-30 min after tetanic stimulation. It has been shown that the amplitude of the EPSCs registered in hippocampal neurons decreased in the long-term depression of synaptic transmission. It has been found that two neurotransmitter vesicles are usually released in the control at the same time and one during the long-term depression of synaptic transmission.It means that the probability of release decreased. In addition, the average quantalamplitude and quantum content decreased. It indicates the effect of presynaptic mechanisms in the expression of long-term depression of synaptic neurotransmission between hippocampal neurons in culture.In the conditions of long-term depression, no significant changes were found in the frequency of EPSCs. The analysis of quantum parameters in long-term depression of glutamatergic synaptic transmission between neurons is important for the formation of more complete ideas about the mechanisms that play a fundamental role in the normal functioning of the CNS and the development of neural networks.

Loss of Non-Apoptotic Role of Caspase-3 in the PINK1 Mouse Model of Parkinson's Disease.

Caspases are a family of conserved cysteine proteases that play key roles in multiple cellular processes, including programmed cell death and inflammation. Recent evidence shows that caspases are also involved in crucial non-apoptotic functions, such as dendrite development, axon pruning, and synaptic plasticity mechanisms underlying learning and memory processes. The activated form of caspase-3, which is known to trigger widespread damage and degeneration, can also modulate synaptic function in the adult brain. Thus, in the present study, we tested the hypothesis that caspase-3 modulates synaptic plasticity at corticostriatal synapses in the phosphatase and tensin homolog (PTEN) induced kinase 1 (PINK1) mouse model of Parkinson’s disease (PD). Loss of PINK1 has been previously associated with an impairment of corticostriatal long-term depression (LTD), rescued by amphetamine-induced dopamine release. Here, we show that caspase-3 activity, measured after LTD induction, is significantly decreased in the PINK1 knockout model compared with wild-type mice. Accordingly, pretreatment of striatal slices with the caspase-3 activator α-(Trichloromethyl)-4-pyridineethanol (PETCM) rescues a physiological LTD in PINK1 knockout mice. Furthermore, the inhibition of caspase-3 prevents the amphetamine-induced rescue of LTD in the same model. Our data support a hormesis-based double role of caspase-3; when massively activated, it induces apoptosis, while at lower level of activation, it modulates physiological phenomena, like the expression of corticostriatal LTD. Exploring the non-apoptotic activation of caspase-3 may contribute to clarify the mechanisms involved in synaptic failure in PD, as well as in view of new potential pharmacological targets.

Astrocytic p38\u03b1 MAPK drives NMDA receptor-dependent long-term depression and modulates long-term memory

NMDA receptor-dependent long-term depression (LTD) in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions. The core mechanism for this form of plasticity is thought to be entirely neuronal. However, we now demonstrate that astrocytic activity drives LTD at CA3-CA1 synapses. We have found that LTD induction enhances astrocyte-to-neuron communication mediated by glutamate, and that Ca2+ signaling and SNARE-dependent vesicular release from the astrocyte are required for LTD expression. In addition, using optogenetic techniques, we show that low-frequency astrocytic activation, in the absence of presynaptic activity, is sufficient to induce postsynaptic AMPA receptor removal and LTD expression. Using cell-type-specific gene deletion, we show that astrocytic p38α MAPK is required for the increased astrocytic glutamate release and astrocyte-to-neuron communication during low-frequency stimulation. Accordingly, removal of astrocytic (but not neuronal) p38α abolishes LTD expression. Finally, this mechanism modulates long-term memory in vivo.

Inhibition of the Interaction Between Group I Metabotropic Glutamate Receptors and PDZ-Domain Proteins Prevents Hippocampal Long-Term Depression, but Not Long-Term Potentiation.

The group I metabotropic glutamate (mGlu) receptor subtypes, mGlu1 and mGlu5, strongly regulate hippocampal synaptic plasticity. Both harbor PSD-95/discs-large/ZO-1 (PDZ) motifs at their extreme carboxyl terminals, which allow interaction with the PDZ domain of Tamalin, regulate the cell surface expression of group I mGlu receptors, and may modulate their coupling to signaling proteins. We investigated the functional role of this interaction in hippocampal long-term depression (LTD). Acute intracerebral treatment of adult rats with a cell-permeable PDZ-blocking peptide (pep-mGluR-STL), designed to competitively inhibit the interaction between Tamalin and group 1 mGlu receptors, prevented expression of LTD in the hippocampal CA1 region without affecting long-term potentiation (LTP) or basal synaptic transmission. Pep-mGluR-STL prevented facilitation by the group I mGlu receptor agonist, (S)-3,5-Dihydroxyphenylglycine (DHPG), and the mGlu5 agonist, (R,S)-2-chloro-5-Hydroxyphenylglycine (CHPG), of short-term depression (STD) into LTD, suggesting that Tamalin preferentially acts by mediating signaling through mGlu5. These data support that Tamalin is essential for the persistent expression of LTD and that it subserves the effective signaling of group 1 mGlu receptors.

Contribution of Thyrotropin-Releasing Hormone to Cerebellar Long-Term Depression and Motor Learning.

Thyrotropin-releasing hormone (TRH) regulates various physiological activities through activation of receptors expressed in a broad range of cells in the central nervous system. The cerebellum expresses TRH receptors in granule cells and molecular layer interneurons. However, the function of TRH in the cerebellum remains to be clarified. Here, using TRH knockout (KO) mice we studied the role of TRH in the cerebellum. Immunohistochemistry showed no gross morphological differences between KO mice and wild-type (WT) littermates in the cerebellum. In the rotarod test, the initial performance of KO mice was comparable to that of WT littermates, but the learning speed of KO mice was significantly lower than that of WT littermates, suggesting impaired motor learning. The motor learning deficit in KO mice was rescued by intraperitoneal injection of TRH. Electrophysiology revealed absence of long-term depression (LTD) at parallel fiber-Purkinje cell synapses in KO mice, which was rescued by bath-application of TRH. TRH was shown to increase cyclic guanosine monophosphate (cGMP) content in the cerebellum. Since nitric oxide (NO) stimulates cGMP synthesis in the cerebellum, we examined whether NO-cGMP pathway was involved in TRH-mediated LTD rescue in KO mice. Pharmacological blockade of NO synthase and subsequent cGMP production prevented TRH-induced LTD expression in KO mice, whereas increase in cGMP signal in Purkinje cells by 8-bromoguanosine cyclic 3’,5’-monophosphate, a membrane-permeable cGMP analog, restored LTD without TRH application. These results suggest that TRH is involved in cerebellar LTD presumably by upregulating the basal cGMP level in Purkinje cells, and, consequently, in motor learning.

Visualization of Exo- and Endocytosis of AMPA Receptors During Hippocampal Synaptic Plasticity Around Postsynaptic-Like Membrane Formed on Glass Surface.

Regulation of exo- and endocytosis of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor (AMPAR) plays a critical role in the expression of synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD) at excitatory central synapses. Enhanced AMPAR exocytosis or endocytosis has been suggested to contribute to LTP or LTD, respectively. However, several unsettled fundamental questions have remained about AMPAR exo- and endocytosis in the basal condition and during synaptic plasticity: (1) Does the size of each exo- or endocytosis event, and/or do the frequencies of these events change during LTP or LTD? If they change, what are the time courses of the respective changes? (2) Where does the exo- or endocytosis preferentially occur in each condition: inside or in the vicinity of postsynaptic membrane, or in the extrasynaptic membrane? (3) Do different types of AMPAR, such as GluA1 homo-tetramer, GluA1/2 hetero-tetramer and GluA2/3 hetero-tetramer, show distinct exo- and endocytosis changes? To address these questions, we developed new methods to observe individual events of AMPAR exo- or endocytosis with a high signal to noise (SN) ratio in a culture preparation using total internal reflection fluorescence microscopy (TIRFM). In these studies, hippocampal neurons were cultured on a neurexin (NRX)-coated glass coverslip, which induced formation of postsynaptic-like membrane (PSLM) directly on the glass surface. Then, a super-ecliptic pHluorin (SEP)-tagged AMPAR subunit such as GluA1 (GluA1-SEP) was expressed in neurons and its fluorescence changes during LTP induced by high frequency electrical field stimulation were observed with TIRFM, which showed different time courses of exocytosis changes of GluA1-, GluA2-, or GluA3-SEP in and around PSLM. In addition, a new method to detect individual endocytosis events of AMPAR was developed by combining TIFRM observation of GluA-SEP around PSLM with a rapid extracellular pH exchange method using a U-tube. Recent results on exo- and endocytosis changes of GluA-SEP during N-methyl-D-aspartate (NMDA)-induced LTD suggested that suppression of AMPAR exocytosis rather than enhancement of AMPAR endocytosis primarily contributes to LTD expression, although the NMDA application transiently enhances clathrin-dependent endocytosis of GluA1-containing AMPAR.

Hippocampal Long-Term Depression in the Presence of Calcium-Permeable AMPA Receptors.

The GluA2 subunit of AMPA glutamate receptors (AMPARs) has been shown to be critical for the expression of NMDA receptor (NMDAR)-dependent long-term depression (LTD). However, in young GluA2 knockout (KO) mice, this form of LTD can still be induced in the hippocampus, suggesting that LTD mechanisms may be modified in the presence of GluA2-lacking, Ca2+ permeable AMPARs. In this study, we examined LTD at the CA1 synapse in GluA2 KO mice by using several well-established inhibitory peptides known to block LTD in wild type (WT) rodents. We showed that while LTD in the KO mice is still blocked by the protein interacting with C kinase 1 (PICK1) peptide pepEVKI, it becomes insensitive to the N-ethylmaleimide-sensitive factor (NSF) peptide pep2m. In addition, the effects of actin and cofilin inhibitory peptides were also altered. These results indicate that in the absence of GluA2, LTD expression mechanisms are different from those in WT animals, suggesting that there are multiple molecular processes enabling LTD expression that are adaptable to physiological and genetic manipulations.

MGluR1-Dependent Long Term Depression in Rodent Midbrain Dopamine Neurons Is Regulated by Neuregulin 1/ErbB Signaling.

Increasing evidence demonstrates that the neurotrophic factor Neuregulin 1 (NRG1) and its receptors, ErbB tyrosine kinases, modulate midbrain dopamine (DA) transmission. We have previously reported that NRG1/ErbB signaling is essential for proper metabotropic glutamate receptors 1 (mGluR1) functioning in midbrain DA neurons, thus the functional interaction between ErbB receptors and mGluR1 regulates neuronal excitation and in vivo striatal DA release. While it is widely recognized that mGluR1 play a pivotal role in long-term modifications of synaptic transmission in several brain areas, specific mGluR1-dependent forms of synaptic plasticity in substantia nigra pars compacta (SNpc) DA neurons have not been described yet. Here, first we aimed to detect and characterize mGluR1-dependent glutamatergic long-term depression (LTD) in SNpc DA neurons. Second, we tested the hypothesis that endogenous ErbB signaling, by affecting mGluR1, fine-tunes glutamatergic synaptic plasticity in DA cells. We found that either pharmacological or synaptic activation of mGluR1 causes an LTD of AMPAR-mediated transmission in SNpc DA neurons from mice and rat slices, which is reliant on endogenous NRG1/ErbB signaling. Indeed, LTD is counteracted by a broad spectrum ErbB inhibitor. Moreover, the intracellular injection of pan-ErbB- or ErbB2 inhibitors inside DA neurons reduces mGluR1-dependent LTD, suggesting an involvement of ErbB2/ErbB4-containing receptors. Interestingly, exogenous NRG1 fosters LTD expression during minimal mGluRI activation. These results enlarge our cognizance on mGluR1 relevance in the induction of a novel form of long-term synaptic plasticity in SNpc DA neurons and describe a new NRG1/ErbB-dependent mechanism shaping glutamatergic transmission in DA cells. This might have important implications either in DA-dependent behaviors and learning/memory processes or in DA-linked diseases.

Regulation of hippocampal long term depression by Neuroligin 1

Neuroligins (NLGs) are postsynaptic adhesion molecules known to play essential roles in synapse development and maturation, but their effects on synaptic plasticity at mature synapses remain unclear. In this study, we investigate the involvement of NLG1 in hippocampal long-term depression (LTD), a key form of long lasting synaptic plasticity, critical for memory formation and brain disorders, by using mice deficient in the expression of NLG1. We find that although NLG1 homozygous (NLG1−/−) mice show no impairments in either NMDA receptor- (NMDAR-LTD) or metabotropic glutamate receptor-dependent LTD (mGluR-LTD), the heterozygous (NLG1+/−) mice are significantly altered in both forms of LTD characterized by the absence of NMDAR-LTD but enhanced mGluR-LTD. Accordingly, the NLG1+/−, but not the NLG1−/− mice are altered in synaptic proteins, including PSD95, GluA2 and phosphorylated GluA1 at serine 845, all of which are involved in the expression of LTD. The NLG1+/− mice also exhibit autistic-like behaviors including increased grooming and impaired recognition memory. We further show that the expression of NLG3, a close family member of NLG1, is elevated in the NLG1−/−, but not in NLG1+/− mice, suggesting that the lack of LTD deficits in the NLG1−/− mice might be due to the increased NLG3. Our results reveal a gene dosage dependent role for NLG1 in the regulation of LTD and suggest that moderate changes in NLG1 protein level may be sufficient to cause synaptic and behavior deficits in brain disorders where copy number variants and hemizygosity of gene mutations are common.

The Molecular Motor KIF21B Mediates Synaptic Plasticity and Fear Extinction by Terminating Rac1 Activation

Fear extinction is a component of cognitive flexibility that is relevant for important psychiatric diseases, but its molecular mechanism is still largely elusive. We established mice lacking the kinesin-4 motor KIF21B as a model for fear extinction defects. Postsynaptic NMDAR-dependent long-term depression (LTD) is specifically impaired in knockouts. NMDAR-mediated LTD-causing stimuli induce dynamic association of KIF21B with the Rac1GEF subunit engulfment and cell motility protein 1 (ELMO1), leading to ELMO1 translocation out of dendritic spines and its sequestration in endosomes. This process may essentially terminate transient activation of Rac1, shrink spines, facilitate AMPAR endocytosis, and reduce postsynaptic strength, thereby forming a mechanistic link to LTD expression. Antagonizing ELMO1/Dock Rac1GEF activity by the administrationof 4-[3'-(2″-chlorophenyl)-2'-propen-1'-ylidene]-1-phenyl-3,5-pyrazolidinedione (CPYPP) significantly reverses the knockout phenotype. Therefore, we propose that KIF21B-mediated Rac1 inactivation is a key molecular event in NMDAR-dependent LTDexpression underlying cognitive flexibility in fear extinction.

Cortactin regulates endo-lysosomal sorting of AMPARs via direct interaction with GluA2 subunit

AMPA receptor (AMPAR) trafficking is a key determinant of synaptic strength and synaptic plasticity. Under basal conditions, constitutive trafficking maintains surface AMPARs by internalization into the endosomal system, where the majority are sorted and targeted for recycling back to the plasma membrane. NMDA receptor (NMDAR)-dependent Long-Term Depression (LTD) is characterised by a reduction in synaptic strength, and involves endosomal sorting of AMPARs away from recycling pathways to lysosomes. The mechanisms that determine whether AMPARs are trafficked to lysosomes or to recycling endosomes, especially in response to NMDAR stimulation, are unclear. Here, we define a role for the actin-regulatory protein cortactin as a mediator of AMPAR endosomal sorting by direct interaction with the GluA2 subunit. Disrupting GluA2-cortactin binding in neurons causes the targeting of GluA2/A3-containing receptors to lysosomes and their consequent degradation, resulting in a loss of surface and synaptic GluA2 under basal conditions and an occlusion of subsequent LTD expression. Furthermore, we show that NMDAR stimulation causes a dissociation of endogenous cortactin from GluA2 via tyrosine phosphorylation of cortactin. These results demonstrate that cortactin maintains GluA2/A3 levels by directing receptors away from lysosomes, and that disrupting GluA2-cortactin interactions to target GluA2/A3 to lysosomes is an essential component of LTD expression.

Sex Differences in Hippocampal Long-Term Depression and the N-Methyl-DAspartate Receptor in Rats - Positive Correlation between LTD and Glun2b Subunit

Background: Numerous studies have suggested that sexual dimorphism may exist in learning and memory. Herein, we associated sex differences in the long-term potentiation (LTP) and the long-term depression (LTD) with the N-methyl-D-aspartate (NMDA) receptor subunits, given their well-known roles in the establishment of longterm memory. Methods: After a 15-min baseline recording, LTP and LTD were induced by application of high- and low- frequency stimulation protocols, respectively. The averages of the excitatory postsynaptic potential (EPSP) slopes and population spike (PS) amplitudes between 70-75 minutes were used as a measure of the LTP/LTD. The mRNA level of GluN1, GluN2A and GluN2B subunits were evaluated using real-time quantitative polymerase chain reaction (RT-qPCR) analysis. Results: Male and female rats showed no differences in a pre-LTP and pre-LTD I/O curves. Although the magnitude of LTP was similar between sexes, female animals exhibited LTD in much more easily than their male counterparts in the absence of the difference in I/O curves. Concomitantly, none of transcript significantly differed between sexes for baseline gene expression, while the decreasing NR2A/NR2B ratio in female rats throughout LTP and LTD time courses was only observed after LTP in male rats. In addition, NR1 mRNA expression was increased in male rats compared to female rats 60- min after LTP induction. Conclusion: The capacity for LTD expression is higher in female rats compared to male rats in young adult ages, and this sex difference is paralleled by a sex difference in GluN2B subunit generated by perforant path LFS. The present study suggests that sex differences in hippocampus-dependant learning tasks may be result of sexually dimorphic hippocampal LTD, but not LTP.

Mismatch novelty exploration training enhances hippocampal synaptic plasticity: A tool for cognitive stimulation?

Memory formation relies on experience-dependent changes in synaptic strength such as long-term potentiation (LTP) or long-term depression (LTD) of synaptic activity, that in turn depend on previous learning experiences through metaplasticity. Novelty detection is a particularly important cognitive stimulus in this respect, and mismatch novelty has been associated with the activation of the hippocampal CA1 area in human studies. A single exposure to a new location of known objects in a familiar environment, a behavioural mismatch novelty paradigm, is known to favour the expression of LTD in hippocampal CA3 to CA1 synaptic transmission in vivo, through short-term metaplasticity. Aiming to shape hippocampal responsiveness to synaptic plasticity phenomena we developed a training program based on exploration of a known environment containing familiar objects, everyday presented in a new location. Repeated exposure to this new location of objects for two weeks caused a mild long-lasting decrease in synaptic efficacy. Furthermore, it enhanced both LTP evoked by theta-burst stimulation and depotentiation evoked by low-frequency stimulation of CA3 to CA1hippocampal synaptic transmission in juvenile rats. This suggests that training programs using these behavioural tasks involving mismatch novelty can be used to reshape brain circuits and promote cognitive recovery in pathologies where LTP/LTD imbalance occurs, such as epilepsy, aging or Down’s syndrome, an approach that requires further investigation at the behavioural level.

Orexin receptors mediate long-term depression of excitatory synaptic transmission in the spinal cord dorsal horn.

Neuropeptides orexin-A and -B are related to the regulation of sleep/wakefulness and feeding behaviors. Recently, the peptides have also been shown to yield antinociceptive effects in various pain models. However, it is not clear whether orexins are involved in forms of synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), the increase and the decrease of synaptic efficacy, respectively. In the present study, we examined whether orexin receptor type 1 (OX1) and 2 (OX2) are involved in the induction or maintenance of LTD of excitatory synaptic transmission using transverse spinal cord slices of young rats. Repetitive electrical stimulation of Lissauer's tract zone at 2Hz for 5min (600 pulses), combined with a holding potential of -30mV, induced LTD of the amplitude of excitatory postsynaptic currents (EPSCs) which are evoked by the activation of primary afferent fibers. The maintenance of LTD was significantly prevented by bath application of SB674042 (1μM), an OX1 antagonist, or EMPA (1μM), an OX2 antagonist. In addition, LTD was dependent on the NMDA receptor, as the NMDA receptor antagonist D-AP5 blocked the maintenance of LTD. Our study suggests that orexins, via activation of both OX1 and OX2, play a significant role in the expression of NMDA-dependent LTD, thereby contributing to the spinal modulation of pain transmission.