Irradiation of the Juvenile Brain Provokes a Shift from Long-Term Potentiation to Long-Term Depression.

Radiotherapy is common in the treatment of brain tumors in children but often causes deleterious, late-appearing sequelae, including cognitive decline. This is thought to be caused, at least partly, by the suppression of hippocampal neurogenesis. However, the changes in neuronal network properties in the dentate gyrus (DG) following the irradiation of the young, growing brain are still poorly understood. We characterized the long-lasting effects of irradiation on the electrophysiological properties of the DG after a single dose of 6-Gy whole-brain irradiation on postnatal day 11 in male Wistar rats. The assessment of the basal excitatory transmission in the medial perforant pathway (MPP) by an examination of the field excitatory postsynaptic potential/volley ratio showed an increase of the synaptic efficacy per axon in irradiated animals compared to sham controls. The paired-pulse ratio at the MPP granule cell synapses was not affected by irradiation, suggesting that the release probability of neurotransmitters was not altered. Surprisingly, the induction of long-term synaptic plasticity in the DG by applying 4 trains of high-frequency stimulation provoked a shift from long-term potentiation (LTP) to long-term depression (LTD) in irradiated animals compared to sham controls. The morphological changes consisted in a virtually complete ablation of neurogenesis following irradiation, as judged by doublecortin immunostaining, while the inhibitory network of parvalbumin interneurons was intact. These data suggest that the irradiation of the juvenile brain caused permanent changes in synaptic plasticity that would seem consistent with an impairment of declarative learning. Unlike in our previous study in mice, lithium treatment did unfortunately not ameliorate any of the studied parameters. For the first time, we show that the effects of cranial irradiation on long-term synaptic plasticity is different in the juvenile compared with the adult brain, such that while irradiation of the adult brain will only cause a reduction in LTP, irradiation of the juvenile brain goes further and causes LTD. Although the mechanisms underlying the synaptic alterations need to be elucidated, these findings provide a better understanding of the effects of irradiation in the developing brain and the cognitive deficits observed in young patients who have been subjected to cranial radiotherapy. © 2015 S. Karger AG, Basel.

Optogenetic field potential recording in cortical slices.

We introduce a method that uses optogenetic stimulation to evoke field potentials in brain slices prepared from transgenic mice expressing channelrhodopsin-2-YFP. Cortical slices in a recording chamber were stimulated with a 473 nm blue laser via either a laser scanning photostimulation setup or by direct guidance of a fiber optic. Field potentials evoked by either of the two optogenetic stimulation methods had stable amplitude, consistent waveform, and similar components as events evoked with a conventional stimulating electrode. The amplitude of evoked excitatory postsynaptic potentials increased with increasing laser intensity or pulse duration. We further demonstrated that optogenetic stimulation can be used for the induction and monitoring of long-term depression. We conclude that this technique allows for efficient and reliable activation of field potentials in brain slice preparation, and will be useful for studying short and long term synaptic plasticity.

False recognition in a mouse model of Alzheimer's disease: rescue with sensory restriction and memantine.

Alzheimer's disease is commonly regarded as a loss of memory for past events. However, patients with Alzheimer's disease seem not only to forget events but also to express false confidence in remembering events that have never happened. How and why false recognition occurs in such patients is currently unknown, and treatments targeting this specific mnemonic abnormality have not been attempted. Here, we used a modified object recognition paradigm to show that the tgCRND8 mouse-which overexpresses amyloid ß and develops amyloid plaques similar to those in the brains of patients with Alzheimer's disease-exhibits false recognition. Furthermore, we found that false recognition did not occur when tgCRND8 mice were kept in a dark, quiet chamber during the delay, paralleling previous findings in patients with mild cognitive impairment, which is often considered to be prodromal Alzheimer's disease. Additionally, false recognition did not occur when mice were treated with the partial N-methyl-d-aspartic acid receptor antagonist memantine. In a subsequent experiment, we found abnormally enhanced N-methyl-d-aspartic acid receptor-dependent long-term depression in these mice, which could be normalized by treatment with memantine. We suggest that Alzheimer's disease typical amyloid ß pathology leads to aberrant synaptic plasticity, thereby making memory representations more susceptible to interfering sensory input, thus increasing the likelihood of false recognition. Parallels between these findings and those from the literature on Alzheimer's disease and mild cognitive impairment suggest a mechanism underlying false recognition in these patients. The false recognition phenomenon may provide a novel paradigm for the discovery of potential therapies to treat the mnemonic dysfunction characteristic of this disease.

Roles of endocannabinoids in heterosynaptic long-term depression of excitatory synaptic transmission in visual cortex of young mice.

Tetanic stimulation of one of two afferent pathways converging to neurons in the visual cortex induces long-term depression (LTD) of synaptic transmission in the other, nonactivated pathway under a certain condition. This form of synaptic plasticity called heterosynaptic LTD (hetero-LTD) was not systematically investigated in previous studies, whereas homosynaptic LTD has been extensively studied. To determine whether hetero-LTD is induced in visual cortical slices of mice and, if so, through what mechanisms, we recorded EPSPs evoked in layer II/III neurons by alternating test stimulation of two sites in layer IV at 0.05 Hz. After theta-burst stimulation of one site, EPSPs evoked by test stimulation of the other site were depressed for a long time in most of the neurons, whereas homosynaptic long-term potentiation was induced at activated synapses. Such a hetero-LTD was induced in most mice at postnatal day 7-20 (P7-P20), but not induced in mice at P35-P41. Tests using the paired-pulse stimulation protocol and coefficient of variation analysis suggested that hetero-LTD was expressed at presynaptic sites. Pharmacological analysis indicated that this form of LTD was induced through activation of the type 5 of metabotropic glutamate receptors, not through the NMDA type of glutamate receptors. Additional analysis using a cannabinoid type 1 receptor agonist and an antagonist suggested that endocannabinoids (eCBs) are involved in this type of LTD. Moreover, results suggest that brain-derived neurotrophic factor, which may be released from strongly activated presynaptic sites, prevents eCBs from suppressing the release of transmitters from these sites.

Effects of prolonged exposure to context following contextual fear conditioning on synaptic properties in rat hippocampal slices.

Acute stressful events enhance plasma corticosterone release and profoundly affect synaptic functions, which are involved in the development of stress-related cognitive and mental disorders. However, how exposure to stressful context immediately after stress further modulates the physiological responses is not fully understood. Here, we found that acute stress inhibited paired-pulse facilitation in hippocampal slices of Wistar rats which were subjected to contextual fear conditioning. But such inhibition was reversed by subsequent prolonged exposure to foot-shock context or returning to home cage for 1 h. Interestingly, foot-shock stress-facilitated LTD induced by low frequency stimulation (LFS, 900 pulses at 1 Hz) was maintained by subsequent exposure to foot-shock context but was reversed by returning to home cage environment. Moreover, plasma corticosterone level was still kept higher in rats exposed to foot-shock context but not to home cage. Findings suggest that remaining in stressful environment immediately after stress maintains acute stress-facilitated LTD and higher level of neuroendocrine response. Our results also contribute to further understanding the critical role of timely intervention in mediating stress-related aversive changes in human.

Spike timing-dependent long-term depression requires presynaptic NMDA receptors.

NMDA receptors are necessary for both synaptic potentiation and depression, but the precise location of these receptors has not been established. By loading MK-801 into pre- or postsynaptic neurons during paired recordings of synaptically connected layer 4 and layer 2/3 neurons in mouse barrel cortex, we found that synaptic potentiation requires postsynaptic, but not presynaptic, NMDA receptors, whereas synaptic depression requires presynaptic, but not postsynaptic, NMDA receptors.

Loss of muscarinic autoreceptor function impairs long-term depression but not long-term potentiation in the striatum.

Muscarinic autoreceptors regulate cholinergic tone in the striatum. We investigated the functional consequences of genetic deletion of striatal muscarinic autoreceptors by means of electrophysiological recordings from either medium spiny neurons (MSNs) or cholinergic interneurons (ChIs) in slices from single M(4) or double M(2)/M(4) muscarinic acetylcholine receptor (mAChR) knock-out (-/-) mice. In control ChIs, the muscarinic agonist oxotremorine (300 nM) produced a self-inhibitory outward current that was mostly reduced in M(4)(-/-) and abolished in M(2)/M(4)(-/-) mice, suggesting an involvement of both M(2) and M(4) autoreceptors. In MSNs from both M(4)(-/-) and M(2)/M(4)(-/-) mice, muscarine caused a membrane depolarization that was prevented by the M(1) receptor-preferring antagonist pirenzepine (100 nM), suggesting that M(1) receptor function was unaltered. Acetylcholine has been involved in striatal long-term potentiation (LTP) or long-term depression (LTD) induction. Loss of muscarinic autoreceptor function is predicted to affect synaptic plasticity by modifying striatal cholinergic tone. Indeed, high-frequency stimulation of glutamatergic afferents failed to induce LTD in MSNs from both M(4)(-/-) and M(2)/M(4)(-/-) mice, as well as in wild-type mice pretreated with the M(2)/M(4) antagonist AF-DX384 (11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5,1 1-dihydro-6H-pyrido[2,3b][1,4] benzodiazepin-6-one). Interestingly, LTD could be restored by either pirenzepine (100 nM) or hemicholinium-3 (10 microM), a depletor of endogenous ACh. Conversely, LTP induction did not show any difference among the three mouse strains and was prevented by pirenzepine. These results demonstrate that M(2)/M(4) muscarinic autoreceptors regulate ACh release from striatal ChIs. As a consequence, endogenous ACh drives the polarity of bidirectional synaptic plasticity.

Corequirement of PICK1 binding and PKC phosphorylation for stable surface expression of the metabotropic glutamate receptor mGluR7.

The presynaptic metabotropic glutamate receptor (mGluR) mGluR7 modulates excitatory neurotransmission by regulating neurotransmitter release and plays a critical role in certain forms of synaptic plasticity. Although the dynamic regulation of mGluR7 surface expression governs a form of metaplasticity in the hippocampus, little is known about the molecular mechanisms regulating mGluR7 trafficking. We now show that mGluR7 surface expression is stabilized by both PKC phosphorylation and by receptor binding to the PDZ domain-containing protein PICK1. Phosphorylation of mGluR7 on serine 862 (S862) inhibits CaM binding, thereby increasing mGluR7 surface expression and receptor binding to PICK1. Furthermore, in mice lacking PICK1, PKC-dependent increases in mGluR7 phosphorylation and surface expression are diminished, and mGluR7-dependent plasticity at mossy fiber-interneuron hippocampal synapses is impaired. These data support a model in which PICK1 binding and PKC phosphorylation act together to stabilize mGluR7 on the cell surface in vivo.

Src-family protein tyrosine kinase negatively regulates cerebellar long-term depression.

Protein phosphorylation is a major mechanism for the regulation of synaptic transmission. Previous studies have shown that several serine/threonine kinases are involved in the induction of long-term depression (LTD) at excitatory synapses on a Purkinje neuron (PN) in the cerebellum. Here, we show that Src-family protein tyrosine kinases (SFKs) are involved in the regulation of the LTD induction. Intracellular application of c-Src suppressed LTD. We also show that application of a SFK-selective inhibitor PP2 recovered LTD from the suppression caused by the inhibition of mGluR1 activity. These results indicate that SFKs negatively regulate the LTD induction at excitatory synapses on a cerebellar PN.

The glutamate receptor-interacting protein family of GluR2-binding proteins is required for long-term synaptic depression expression in cerebellar Purkinje cells.

Glutamate receptor-interacting protein 1 (GRIP1) and GRIP2 are closely related proteins that bind GluR2-containing AMPA receptors and couple them to structural and signaling complexes in neurons. Cerebellar long-term synaptic depression (LTD) is a model system of synaptic plasticity that is expressed by persistent internalization of GluR2-containing AMPA receptors. Here, we show that genetic deletion of both GRIP1 and GRIP2 blocks LTD expression in primary cultures of mouse cerebellar neurons but that single deletion of either isoform allows LTD to occur. In GRIP1/2 double knock-out Purkinje cells, LTD can be fully rescued by a plasmid-driving expression of GRIP1 and partially rescued by a GRIP2 plasmid. These results indicate that the GRIP family comprises an essential molecular component for cerebellar LTD.

Layer 2/3 synapses in monocular and binocular regions of tree shrew visual cortex express mAChR-dependent long-term depression and long-term potentiation.

Acetylcholine is an important modulator of synaptic efficacy and is required for learning and memory tasks involving the visual cortex. In rodent visual cortex, activation of muscarinic acetylcholine receptors (mAChRs) induces a persistent long-term depression (LTD) of transmission at synapses recorded in layer 2/3 of acute slices. Although the rodent studies expand our knowledge of how the cholinergic system modulates synaptic function underlying learning and memory, they are not easily extrapolated to more complex visual systems. Here we used tree shrews for their similarities to primates, including a visual cortex with separate, defined regions of monocular and binocular innervation, to determine whether mAChR activation induces long-term plasticity. We find that the cholinergic agonist carbachol (CCh) not only induces long-term plasticity, but the direction of the plasticity depends on the subregion. In the monocular region, CCh application induces LTD of the postsynaptic potential recorded in layer 2/3 that requires activation of m3 mAChRs and a signaling cascade that includes activation of extracellular signal-regulated kinase (ERK) 1/2. In contrast, layer 2/3 postsynaptic potentials recorded in the binocular region express long-term potentiation (LTP) following CCh application that requires activation of m1 mAChRs and phospholipase C. Our results show that activation of mAChRs induces long-term plasticity at excitatory synapses in tree shrew visual cortex. However, depending on the ocular inputs to that region, variation exists as to the direction of plasticity, as well as to the specific mAChR and signaling mechanisms that are required.

Electrical low-frequency stimulation induces homotopic long-term depression of nociception and pain from hand in man.

OBJECTIVE: Electrical low-frequency stimulation (LFS) of cutaneous afferents evokes long-term depression (LTD) of nociception. In vitro studies suggest a sole homosynaptic effect on the conditioned pathway. The present study addresses homotopy of LTD in human nociception and pain. METHODS: In 30 healthy volunteers, nociceptive Adelta fibers were electrically stimulated by a concentric electrode. Test stimulation (0.125 Hz) was alternately applied unilateral to radial and ulnar side of right hand dorsum (ExpUni) or bilateral to radial side of right and left hand dorsum (ExpBi). Conditioning LFS (1 Hz, 1,200 pulses) was applied to radial side of right hand dorsum. Somatosensory evoked cortical vertex potentials (SEP) were recorded, and volunteers rated stimulus intensity. RESULTS: After homotopic LFS, SEP amplitude (ExpUni: -34.6%; ExpBi: -33.6%) and pain rating (ExpUni: -44.1%; ExpBi: -29.1%) significantly decreased. Amplitude reduction after heterotopic LFS did not differ from habituation effects in Control experiment without LFS. Heterotopic pain perception was not affected. CONCLUSIONS: The electrophysiological and psychophysical study on synaptic plasticity in healthy man demonstrates homotopic organization of LTD. SIGNIFICANCE: Homotopy is probably due to a homosynaptic effect at first nociceptive synapse, but descending inhibitory systems may also be involved. These experiments may help to judge the potency of LTD for future therapy in chronic pain.

The role of NMDA receptors in regulating group II metabotropic glutamate receptor-mediated long-term depression in rat medial prefrontal cortex.

Previous work has shown that brief application of group II metabotropic glutamate receptor (mGluR) agonist (2S,2'R,3'R)-2-(2',3'-dicarbox-ycyclopropyl) glycine (DCG-IV) can induce long-term depression (LTD) of excitatory transmission on layer V pyramidal neurons of rat medial prefrontal cortex (mPFC). An unusual feature of this LTD is that it relies on activation of both group II mGluRs and N-methyl-D-aspartate receptors (NMDARs). However, it is not known whether other specific group II mGluR agonists also induce LTD and whether they depend on the conjoint activation of group II mGluRs and NMDARs. We show here that the ability of DCG-IV to induce LTD was mimicked by a more selective group II mGluR agonist, LY379268. The induction of LTD by a lower concentration of DCG-IV (0.2 microM) or LY379268 (0.03 microM) was blocked by the NMDAR antagonist APV or the interruption of synaptic stimulation during drug application. In contrast, application of a higher concentration of DCG-IV (1 microM) or LY379268 (0.1 microM) can induce LTD that was independent of synaptic NMDAR activation. These results suggest that although molecular cooperation between group II mGluRs and synaptic NMDARs may facilitate the induction of group II mGluR-mediated LTD at excitatory synapses onto mPFC layer V pyramidal neurons, enhancing group II mGluR activation may remove NMDAR involvement in this form of synaptic plasticity.

Protein phosphatase 1-dependent bidirectional synaptic plasticity controls ischemic recovery in the adult brain.

Protein kinases and phosphatases can alter the impact of excitotoxicity resulting from ischemia by concurrently modulating apoptotic/survival pathways. Here, we show that protein phosphatase 1 (PP1), known to constrain neuronal signaling and synaptic strength (Mansuy et al., 1998; Morishita et al., 2001), critically regulates neuroprotective pathways in the adult brain. When PP1 is inhibited pharmacologically or genetically, recovery from oxygen/glucose deprivation (OGD) in vitro, or ischemia in vivo is impaired. Furthermore, in vitro, inducing LTP shortly before OGD similarly impairs recovery, an effect that correlates with strong PP1 inhibition. Conversely, inducing LTD before OGD elicits full recovery by preserving PP1 activity, an effect that is abolished by PP1 inhibition. The mechanisms of action of PP1 appear to be coupled with several components of apoptotic pathways, in particular ERK1/2 (extracellular signal-regulated kinase 1/2) whose activation is increased by PP1 inhibition both in vitro and in vivo. Together, these results reveal that the mechanisms of recovery in the adult brain critically involve PP1, and highlight a novel physiological function for long-term potentiation and long-term depression in the control of brain damage and repair.

Homer interactions are necessary for metabotropic glutamate receptor-induced long-term depression and translational activation.

Group I metabotropic glutamate receptors (mGluRs) induce a form of long-term synaptic depression (mGluR-LTD) in area CA1 of the hippocampus that requires rapid protein synthesis. Although much is known about the mechanisms underlying mGluR-LTD, it is unclear how mGluRs couple to the effectors necessary for translation initiation. A clue comes from work in the mouse model of Fragile X syndrome [Fmr1 knock-out (KO) mice], where group 1 mGluR stimulation of protein synthesis is absent and mGluRs are less associated with the postsynaptic scaffolding protein Homer (Giuffrida et al., 2005). Here, we examined the role of Homer interactions in mGluR-LTD and mGluR signaling to protein synthesis machinery in wild-type and Fmr1 KO animals. A peptide that mimics the C-terminal tail of mGluR5 (mGluR5ct), shown previously to disrupt Homer interactions with mGluRs, blocks mGluR-LTD and mGluR-signaling to protein synthesis initiation in wild-type animals. Disruption of mGluR-Homer interactions selectively blocks mGluR activation of the phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR), but not ERK (extracellular signal-regulated kinase), pathway and translation of a 5' terminal oligopyrimidine tract containing mRNA, Elongation factor 1alpha. In Fmr1 KO mice, mGluR-LTD is insensitive to disruption of Homer interactions and mGluR activation of PI3K-mTOR is lost. Our results find specific roles for Homer in mGluR signaling and plasticity and suggest that reduced mGluR-Homer interactions in Fmr1 KO mice lead to a deficit in mGluR stimulation of translation initiation.

Timing dependence of the induction of cerebellar LTD.

Long-term depression (LTD) of the granule cell to Purkinje cell synapse is thought to contribute to motor learning. According to the Marr/Albus/Ito model, sensory inputs drive granule cells to fire, thereby exciting Purkinje cells and influencing motor output. Inappropriate motor output causes neurons in the inferior olive to fire and activate Purkinje cells via the powerful climbing fiber (CF) synapse. CF activity is an error signal and the association of CF and granule cell parallel fiber (PF) activity results in LTD at coactivated PF synapses. Here we examine the timing dependence of LTD by using an induction protocol consisting of a single CF activation paired with a PF burst, with the relative timing of CF and PF activation systematically varied. LTD was most prominent when PF activation occurred before CF activation. A plot of LTD magnitude as a function of PF and CF timing was well approximated by a fit in which LTD peaked for PF activity approximately 80 ms before CF activation and the half width was approximately 300 ms. This indicates that the timing dependence of LTD is well suited to allow a CF to depress preceding PF inputs that generated inappropriate motor outputs. We also find that LTD induction and endocannabinoid release have a similar dependence on PF and CF timing. This suggests that the properties of endocannabinoid release may underlie the timing dependence of some forms of motor learning.

Role of the cyclic-AMP/PKA cascade and of P/Q-type Ca++ channels in endocannabinoid-mediated long-term depression in the nucleus accumbens.

Glutamate transmission between prefrontal cortex (PFC) and accumbens (NAc) plays a crucial role in the establishment and expression of addictive behaviors. At these synapses exogenous cannabinoid receptor 1 (CB1R) agonists reversibly inhibit excitatory transmission, and the sustained release of endogenous cannabinoids (eCB) following prolonged cortical stimulation leads to long-term depression (LTD). Activation of presynaptic K(+) channels mediates the effects of exocannabinoids, but the transduction pathway underlying the protracted phase of eCB-LTD is unknown. Here we report that the maintenance of eCB-LTD does not involve presynaptic K(+) channels: eCB-LTD was not affected by blockade of K(+) channels with 4-AP (100 microM) and BaCl(2) (300 microM) (fEPSP=78.9+/-5.4% of baseline 58-60 min after tetanus, compared to 78.9+/-5.9% in control slices). In contrast, eCB-LTD was blocked by treatment of the slices with the adenylyl cyclase (AC) activator forskolin (10 microM), and with the protein kinase A (PKA) inhibitor KT5720 (1 microM) (fEPSP=108.9+/-5.7% in forskolin and 110.5+/-7.7% in KT5720, compared to 80.6+/-3.9% in control conditions). Additionally, selective blockade of P/Q-type Ca(2+) channels with omega-agatoxin-IVA (200 nM) occluded the expression of eCB-LTD (fEPSP=113.4+/-15.9% compared to 78.6+/-4.4% in control slices), while blockade of N- with omega-conotoxin-GVIA (1 microM) or L-type Ca(2+) channels with nimodipine (1 microM), was without effect (fEPSP was 83.7+/-5.3% and 87+/-8.9% respectively). These data show that protracted inhibition of AC/PKA activity and P/Q-type Ca(2+) channels are necessary for expression of eCB-LTD at NAc synapses.

Homer 1a suppresses neocortex long-term depression in a cortical layer-specific manner.

Homer1a/Vesl-1S is an activity-dependently induced member of the scaffold protein family Homer/Vesl, which is known to link group I metabotropic glutamate receptors (mGluRs) to endoplasmic calcium release channels and to regulate them. Here we studied roles of Homer 1a in inducing long-term depression (LTD) in rat visual cortex slices. Homer 1a protein was injected by diffusion from whole cell patch pipettes. In layer VI pyramidal cells, LTD was reduced in magnitude with Homer 1a. LTD in layer VI was suppressed by applying antagonists of mGluR5, a subtype of group I mGluRs expressed with higher density than mGluR1 in neocortex pyramidal cells, or inositol-1,4,5-triphosphate receptors (IP3Rs) but not that against N-methyl-d-aspartate receptors (NMDARs). In layer II/III or layer V, Homer 1a injection was unable to affect LTD, which is mostly dependent on NMDARs and not on group I mGluRs in these layers. To examine the effects of endogenous Homer 1a, electroconvulsive shock (ECS) was applied. Homer 1a thereby induced, as did Homer 1a injection, reduced LTD magnitude in layer VI pyramidal cells and failed to do so in layer II/III or layer V pyramidal cells. These results indicate that both exo- and endogenous Homer 1a suppressed LTD in a cortical layer-specific manner, and its layer-specificity may be explained by the high affinity of Homer 1a to group I mGluRs.

Modulation by group 1 metabotropic glutamate receptors of depotentiation in the dentate gyrus of freely moving rats.

In the hippocampus, synaptic depression of potentiated synapses in the form of depotentiation, or of naive synapses in the form of long-term depression (LTD) is mediated by distinct molecular mechanisms. Activation of group 1 metabotropic glutamate receptors (mGluRs) is critically required for both hippocampal long-term potentiation (LTP) and LTD in vivo, but their involvement in depotentiation is unclear. In this study, we investigated whether this class of mGluRs contributes to depotentiation in freely moving rats. Male adult Wistar rats underwent chronic implantation of stimulating and recording electrodes in the perforant path and dentate gyrus granule cell layer, respectively, as well as an injection cannula in the ipsilateral cerebral ventricle. Robust LTP which endured for over 24 h, was induced by high frequency tetanization (HFT, 200 Hz). Depotentiation was induced with LFS (5 Hz, 600 pulses) given 5 min after the LTP-inducing tetanus was applied. The selective group 1 mGluR antagonists, (S)-4-carboxyphenylglycine and (R,S)-1-aminoindan-1,5-dicarboxylic acid significantly inhibited both depotentiation and LTP. Activation of group I mGluRs leads to changes in postsynaptic intracellular calcium levels. These findings suggest that activation of group I mGluRs mediate thresholds for depotentiation and for persistent LTP. Effects may be linked to the intensity and duration of the calcium signal elicited by LFS and HFT.

D-serine augments NMDA-NR2B receptor-dependent hippocampal long-term depression and spatial reversal learning.

The contributions of hippocampal long-term depression (LTD) to explicit learning and memory are poorly understood. Electrophysiological and behavioral studies examined the effects of modulating NMDA receptor-dependent LTD on spatial learning in the Morris water maze (MWM). The NMDA receptor co-agonist D-serine substantially enhanced NR2B-dependent LTD, but not long-term potentiation (LTP) or depotentiation, in hippocampal slices from adult wild type mice. Exogenous D-serine did not alter MWM acquisition, but substantially enhanced subsequent reversal learning of a novel target location and performance in a delayed-matching-to-place task. Conversely, an NR2B antagonist disrupted reversal learning and promoted perseveration. Endogenous synaptic D-serine likely saturates during LTP induction because exogenous D-serine rescued deficient LTP and MWM acquisition in Grin1(D481N) mutant mice having a lower D-serine affinity. Thus, D-serine may enhance a form of hippocampal NR2B-dependent LTD that contributes to spatial reversal learning. By enhancing this form of synaptic plasticity, D-serine could improve cognitive flexibility in psychiatric disorders characterized by perseveration of aberrant ideation or behaviors.