Involvement of the Metabotropic Glutamate Receptor mGluR5 in NMDA Receptor-Dependent, Learning-Facilitated Long-Term Depression in CA1 Synapses

Learning-facilitated synaptic plasticity describes the ability of hippocampal synapses to respond with persistent synaptic plasticity to the coupling of weak afferent stimulation, which is subthreshold for the induction of plasticity, with a spatial learning experience. The metabotropic glutamate receptor subtype 5 (mGluR5) is critically involved in enabling the persistency of multiple forms of hippocampal synaptic plasticity. We compared the effects of pharmacological allosteric antagonism of mGluR5 in learning-facilitated plasticity with plasticity that had been induced solely by patterned afferent stimulation of the Schaffer collateral pathway to the CA1 stratum radiatum of adult freely behaving rats. Intracerebroventricular injection of the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) had no effect on basal synaptic transmission but significantly prevented both long-term depression (LTD) elicited by electrical stimulation and LTD facilitated by novel object-place configuration learning. NMDA receptor antagonism also prevented learning-facilitated LTD. Habituation to the objects was prevented by MPEP application. Whereas reexposure to the object-place configuration (after 7 days) failed to facilitate LTD in control animals, those who had been treated previously with MPEP expressed LTD, suggesting that inhibition of learning contributed to the initial prevention of LTD. These data support a pivotal role for mGluR5 in both hippocampal LTD and the acquisition of object-place configurations

Frequency Facilitation at Mossy Fiber–CA3 Synapses of Freely Behaving Rats Contributes to the Induction of Persistent LTD via an Adenosine-A1 Receptor-Regulated Mechanism

Frequency facilitation (FF), comprising a rapid and multiple-fold increase in the magnitude of evoked field potentials, is elicited by low-frequency stimulation (LFS) at mossy fiber–CA3 synapses. Here, we show that in freely behaving rats, FF reliably occurs in response to 1 and 2Hz but not in response to 0.25-, 0.3-, or 0.5-Hz LFS. Strikingly, prolonged (∼600 s) FF was tightly correlated to the induction of long-term depression (LTD) in freely moving animals. Although LFS at 2 Hz elicited unstable FF and unstable LTD, application of LFS at 1 Hz elicited pronounced FF, as well as robust LTD that persisted for over 24 h. This correlation of prolonged FF with LTD was absent at stimulation frequencies that did not induce FF. The adenosine-A1 receptor appears to participate in these effects: Application of adenosine-A1, but not adenosine-A3, receptor antagonists enhanced mossy fiber synaptic transmission and occluded FF. Furthermore, adenosine-A1 receptor antagonism resulted in more stable FF at 1 or 2 Hz and elicited more potent LTD. These data support the fact that FF contributes to the enablement of long-term information storage at mossy fiber–CA3 synapses and that the adenosine-A1 receptor may regulate the thresholds for this process

Defective synapse maturation and enhanced synaptic plasticity in Shank2 Δex7(-/-) mice

Autism spectrum disorders (ASDs) are neurodevelopmental disorders with a strong genetic etiology. Since mutations in human SHANK genes have been found in patients with autism, genetic mouse models are used for a mechanistic understanding of ASDs and the development of therapeutic strategies. SHANKs are scaffold proteins in the postsynaptic density of mammalian excitatory synapses with proposed functions in synaptogenesis, regulation of dendritic spine morphology, and instruction of structural synaptic plasticity. In contrast to all studies so far on the function of SHANK proteins, we have previously observed enhanced synaptic plasticity in Shank2 Δex7(-/-) mice. In a series of experiments, we now reproduce these results, further explore the synaptic phenotype, and directly compare our model to the independently generated Shank2 Δex6-7(-/-) mice. Minimal stimulation experiments reveal that Shank2 Δex7(-/-) mice possess an excessive fraction of silent (i.e., α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, short, AMPA receptor lacking) synapses. The synaptic maturation deficit emerges during the third postnatal week and constitutes a plausible mechanistic explanation for the mutants' increased capacity for long-term potentiation, both in vivo and in vitro. A direct comparison with Shank2 Δex6-7(-/-) mice adds weight to the hypothesis that both mouse models show a different set of synaptic phenotypes, possibly due to differences in their genetic background. These findings add to the diversity of synaptic phenotypes in neurodevelopmental disorders and further support the supposed existence of "modifier genes" in the expression and inheritance of ASDs

Learning-Facilitated Synaptic Plasticity at CA3 Mossy Fiber and Commissural–Associational Synapses Reveals Different Roles in Information Processing

Subregion-dependent differences in the role of the hippocampus in information processing exist. Recently, it has emerged that a special relationship exists between the expression of persistent forms of synaptic plasticity in hippocampal subregions and the encoding of different types of spatial information. Little is known about this type of information processing at CA3 synapses. We report that in freely behaving rats, long-term potentiation (LTP) is facilitated at both mossy fiber (mf)–CA3 and commissural–associational (AC)–CA3 synapses by exploration of a novel (empty) environment. Exploration of large spatial landmarks facilitates long-term depression (LTD) at mf-CA3 synapses and impairs synaptic depression at AC-CA3 synapses. Novel exploration of small environmental features does not facilitate LTD at mf synapses but facilitates persistent LTD at AC synapses. Thus, depending on the quality of the information synaptic plasticity at AC-CA3 and mf-CA3 synapses is differentially modulated. These data suggest that expression of LTP as a result of environmental change is a common property of hippocampal synapses. However, LTD at mf synapses or AC synapses may subserve distinct and separate functions within the CA3 region

Learning-Facilitated Synaptic Plasticity at CA3 Mossy Fiber and Commissural–Associational Synapses Reveals Different Roles in Information Processing

Subregion-dependent differences in the role of the hippocampus in information processing exist. Recently, it has emerged that a special relationship exists between the expression of persistent forms of synaptic plasticity in hippocampal subregions and the encoding of different types of spatial information. Little is known about this type of information processing at CA3 synapses. We report that in freely behaving rats, long-term potentiation (LTP) is facilitated at both mossy fiber (mf)–CA3 and commissural–associational (AC)–CA3 synapses by exploration of a novel (empty) environment. Exploration of large spatial landmarks facilitates long-term depression (LTD) at mf-CA3 synapses and impairs synaptic depression at AC-CA3 synapses. Novel exploration of small environmental features does not facilitate LTD at mf synapses but facilitates persistent LTD at AC synapses. Thus, depending on the quality of the information synaptic plasticity at AC-CA3 and mf-CA3 synapses is differentially modulated. These data suggest that expression of LTP as a result of environmental change is a common property of hippocampal synapses. However, LTD at mf synapses or AC synapses may subserve distinct and separate functions within the CA3 region

Locus Coeruleus Activation Facilitates Memory Encoding and Induces Hippocampal LTD that Depends on β-Adrenergic Receptor Activation

Spatial memory formation is enabled through synaptic information processing, in the form of persistent strengthening and weakening of synapses, within the hippocampus. It is, however, unclear how relevant spatial information is selected for encoding, in preference to less pertinent information. As the noradrenergic locus coeruleus (LC) becomes active in response to novel experiences, we hypothesized that the LC may provide the saliency signal required to promote hippocampal encoding of relevant information through changes in synaptic strength. Test pulse stimulation evoked stable basal synaptic transmission at Schaffer collateral (SC)–CA1 stratum radiatum synapses in freely behaving adult rats. Coupling of these test pulses with electrical stimulation of the LC induced long-term depression (LTD) at SC–CA1 synapses and induced a transient suppression of theta-frequency oscillations. Effects were N-methyl-D-aspartate and β-adrenergic receptor dependent. Activation of the LC also increased CA1 noradrenalin levels and facilitated the encoding of spatial memory for a single episode via a β-adrenoceptor–dependent mechanism. Our results demonstrate that the LC plays a key role in the induction of hippocampal LTD and in promoting the encoding of spatial information. This LC–hippocampal interaction may reflect a means by which salient information is distinguished for subsequent synaptic processing

Defective Synapse Maturation and Enhanced Synaptic Plasticity in Shank2 Δex7-/- Mice

Autism spectrum disorders (ASDs) are neurodevelopmental disorders with a strong genetic etiology. Since mutations in human SHANK genes have been found in patients with autism, genetic mouse models are used for a mechanistic understanding of ASDs and the development of therapeutic strategies. SHANKs are scaffold proteins in the postsynaptic density of mammalian excitatory synapses with proposed functions in synaptogenesis, regulation of dendritic spine morphology, and instruction of structural synaptic plasticity. In contrast to all studies so far on the function of SHANK proteins, we have previously observed enhanced synaptic plasticity in Shank2 Δex7-/- mice. In a series of experiments, we now reproduce these results, further explore the synaptic phenotype, and directly compare our model to the independently generated Shank2 Δex6-7-/- mice. Minimal stimulation experiments reveal that Shank2 Δex7-/- mice possess an excessive fraction of silent (i.e., α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, short, AMPA receptor lacking) synapses. The synaptic maturation deficit emerges during the third postnatal week and constitutes a plausible mechanistic explanation for the mutants' increased capacity for long-term potentiation, both in vivo and in vitro. A direct comparison with Shank2 Δex6-7-/- mice adds weight to the hypothesis that both mouse models show a different set of synaptic phenotypes, possibly due to differences in their genetic background. These findings add to the diversity of synaptic phenotypes in neurodevelopmental disorders and further support the supposed existence of "modifier genes" in the expression and inheritance of ASDs

Metabotropic glutamate receptor 1 (mGluR1) and 5 (mGluR5) regulate late phases of LTP and LTD in the hippocampal CA1 region in vitro

The group I metabotropic glutamate receptors, mGluR1 and mGluR5, exhibit differences in their regulation of synaptic plasticity, suggesting that these receptors may subserve separate functional roles in information storage. In addition, although effects in vivo are consistently described, conflicting reports of the involvement of mGluRs in hippocampal synaptic plasticity in vitro exist. We therefore addressed the involvement of mGluR1 and mGluR5 in long-term potentiation (LTP) and long-term depression (LTD) in the hippocampal CA1 region of adult male rats in vitro. The mGluR1 antagonist (S)-(+)-α-amino-4-carboxy-2-methylbenzene-acetic acid (LY367385) impaired both induction and late phases of both LTP and LTD, when applied before high-frequency tetanization (HFT; 100 Hz) or low-frequency stimulation (LFS; 1 Hz), respectively. Application after either HFT or LFS had no effect. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), when given before HFT, inhibited both the induction and late phases of LTP. When given after HFT, late LTP was inhibited. MPEP, given prior to LFS, impaired LTD induction, although stable LTD was still expressed. Application after LFS significantly impaired late phases of LTD. Activation of protein synthesis may comprise a key mechanism underlying the group I mGluR contribution to synaptic plasticity. The mGluR5 agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG) converted short-term depression into LTD. Effects were prevented by application of the protein synthesis inhibitor anisomycin, suggesting that protein synthesis is triggered by group I mGluR activation to enable persistency of synaptic plasticity. Taken together, these data support the notion that both mGluR1 and mGluR5 are critically involved in bidirectional synaptic plasticity in the CA1 region and may enable functional differences in information encoding through LTP and LTD

PDE4 inhibition enhances hippocampal synaptic plasticity in vivo and rescues MK801-induced impairment of long-term potentiation and object recognition memory in an animal model of psychosis

Inhibition of phosphodiesterase type 4 (PDE4) by rolipram (4-(3-(cyclopentyloxy)-4-methoxyphenyl)-pyrrolidin-2-one) has been the focus of many behavioral and molecular studies in the recent years. Rolipram exhibits memory-enhancing effects in rodents. In vitro studies have shown that long-term potentiation (LTP), which may comprise a cellular substrate for learning, is also enhanced by rolipram. However, effects have not been assessed in vivo. Rolipram has antipsychotic properties. Psychosis affects cognition and in animal models of psychosis LTP is impaired. In this study, we investigated if PDE4 inhibition improves LTP in healthy animals in vivo and if PDE4 inhibition rescues impaired LTP and prevents object recognition memory deficits in an animal model of psychosis. Recordings were made from the hippocampus of adult, freely behaving Wistar rats. Thirty minutes after treatment with rolipram or vehicle, a tetanus was applied to the medial perforant path to elicit short-term potentiation (STP) in the dentate gyrus. At this time-point, radioimmunoassay revealed that rolipram significantly elevated cyclic adenosine monophosphate levels in the dorsal hippocampus, in line with reports by others that rolipram mediates decreased PDE4 activity. In healthy animals, both intracerebroventricular and subcutaneous treatment with rolipram facilitated STP into LTP, suggesting that PDE4 inhibition may have a permissive role in plasticity mechanisms that are relevant for learning and memory. One week after a single systemic treatment with the irreversible N-methyl--aspartate antagonist, MK801, LTP and object recognition memory were significantly impaired, but could be rescued by PDE4 inhibition. These data suggest that the relief of cognitive disturbances in psychosis models by rolipram may be mediated in part by a rescue of hippocampal LTP