Denise Manahan-Vaughan

Dopamine D1/D5 Receptors Gate the Acquisition of Novel Information through Hippocampal Long-Term Potentiation and Long-Term Depression

Hebbian learning models require that neurons are able to both strengthen and weaken their synaptic connections. Hippocampal synaptic plasticity, in the form of long-term potentiation (LTP) and long-term depression (LTD), has been implicated in both spatial memory formation as well as novelty acquisition. In addition, the ventral tegmental area–hippocampal loop has been proposed to control the entry of information into long-term memory, whereas the dopaminergic system is believed to play an important role in information acquisition and synaptic plasticity. D1/D5 dopamine receptors are positively coupled to adenylyl cyclase and have been to modulate certain forms of synaptic plasticity, particularly in vitro. We investigated how D1/D5 dopamine receptors modify long-lasting synaptic plasticity at CA1 synapses of adult freely moving rats and found that receptor activation lowered the threshold for the induction of both LTP and LTD. Specific types of learning are associated with specific types of hippocampal synaptic plasticity. We found that object-configuration learning, facilitation of late-phase LTD by object exploration, and late-phase LTP by exploration of empty space were all prevented by D1/D5 receptor antagonism. Furthermore, receptor antagonism prevented electrically induced late-LTP, whereas receptor activation facilitated induction of both LTP and LTD by patterned electrical stimulation. These findings suggest that the dopaminergic system, acting via D1/D5 receptors, gates long-term changes in synaptic strength and that these changes are a critical factor in the acquisition of novel information.

Hippocampal long-term depression: master or minion in declarative memory processes?

The neural mechanisms for the formation of declarative memory (memory for facts and events) are believed to be integrated from processes mediated by hippocampal long-term potentiation (LTP) and long-term depression (LTD). Traditionally, LTP has been designated as the main mediator of spatial memory storage in the hippocampus, whereas LTD has been assigned an auxiliary role in signal-to-noise regulation or in forgetting. It has recently become apparent, however, that LTD contributes directly to hippocampal information storage. In fact, LTD could dominate in the processing of precise spatial characteristics. Accumulating evidence supports the idea that LTP and LTD enable distinct and separate forms of information storage, which together facilitate the generation of a spatial cognitive map.

Long-Term Depression: A Cellular Basis for Learning?

Long-term depression (LTD) comprises a persistent activity-dependent reduction in synaptic efficacy which typically occurs following repeated low frequency afferent stimulation. Hippocampal LTD has been a subject of particular interest due to the established role of the hippocampus in certain forms of information storage and retrieval. Recently, it was reported that LTD in the CA1 region may be associated with novelty acquisition in rats. CA1 LTD expression may also be increased in stressful conditions. This suggests a more complex role for this form of plasticity than the oft-cited hypothesis that it simply serves to prevent synapse saturation, by means, for example, of enabling reversal of long-term potentiation (LTP). One possibility is that LTD may be directly involved in the creation of a memory trace. Alternatively, LTD may prime a synapse in readiness for the expression of LTP, thereby contributing indirectly to information storage. There is increasing evidence that LTD is not mechanistically the reverse of LTP. Although some common processes exist, molecular, biochemical, electrophysiological and pharmacological studies all point to several quite distinct induction and maintenance mechanisms for this form of synaptic plasticity. Taken together these findings suggest that hippocampal LTD must be considered in a new light. This review focuses on the interpretation of novel and established information with regard to LTD in the hippocampal CA1 region in terms of its possible role as a cellular basis for learning and memory.

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.

Dopamine D1/D5 Receptors Mediate Informational Saliency that Promotes Persistent Hippocampal Long-Term Plasticity

Dopamine (DA) plays an essential role in the enablement of cognition. It adds color to experience-dependent information storage, conferring salience to the memories that result. At the synaptic level, experience-dependent information storage is enabled by synaptic plasticity, and given its importance for memory formation, it is not surprising that DA comprises a key neuromodulator in the enablement of synaptic plasticity, and particularly of plasticity that persists for longer periods of time: Analogous to long-term memory. The hippocampus, that is a critical structure for the synaptic processing of semantic, episodic, spatial, and declarative memories, is specifically affected by DA, with the D1/D5 receptor proving crucial for hippocampus-dependent memory. Furthermore, D1/D5 receptors are pivotal in conferring the properties of novelty and reward to information being processed by the hippocampus. They also facilitate the expression of persistent forms of synaptic plasticity, and given reports that both long-term potentiation and long-term depression encode different aspects of spatial representations, this suggests that D1/D5 receptors can drive the nature and qualitative content of stored information in the hippocampus. In light of these observations, we propose that D1/D5 receptors gate hippocampal long-term plasticity and memory and are pivotal in conferring the properties of novelty and reward to information being processed by the hippocampus.

Subtype-specific involvement of metabotropic glutamate receptors in two forms of long-term potentiation in the dentate gyrus of freely moving rats

In this study, the role of metabotropic glutamate receptors in N-methyl-D-aspartate receptor-dependent and voltage-gated calcium channel-dependent long-term potentiation in the dentate gyrus of freely moving rats was investigated. Antagonists for group 1 metabotropic glutamate receptors ((S)-4-carboxyphenylglycine), group 1/2 metabotropic glutamate receptors ((RS)-alpha-methyl-4-carboxyphenylglycine) and group 2 metabotropic glutamate receptors ((RS)-alpha-methylserine O-phosphate monophenylester) were used. The N-methyl-D-aspartate receptor antagonist, D(-)-2-amino-5-phosphonopentanoic acid, and the L-type voltage-gated calcium channel antagonist, methoxyverapamil were used to investigate the N-methyl-D-aspartate receptor and voltage-gated calcium channel contribution to the long-term potentiation recorded. Field excitatory postsynaptic potential slope and population spike amplitude were measured. Drugs were applied, prior to tetanus, via a cannula implanted into the lateral cerebral ventricle. 200 Hz tetanization produces a long-term potentiation which is inhibited by application of D(-)-2-amino-5-phosphonopentanoic acid and (RS)-alpha-methyl-4-carboxyphenylglycine. In this study, a dose-dependent inhibition of 200 Hz long-term potentiation expression was obtained with (S)-4-carboxyphenylglycine. Long-term potentiation induced by 400 Hz tetanization was not inhibited by D(-)-2-amino-5-phosphonopentanoic acid, although the amplitude of short-term potentiation was reduced. (RS)-alpha-methyl-4-carboxyphenylglycine and (S)-4-carboxyphenylglycine, both in the presence and absence of D(-)-2-amino-5-phosphonopentanoic acid, inhibited the development of 400 Hz long-term potentiation. (RS)-alpha-methylserine O-phosphate monophenylester had no significant effect on long-term potentiation induced by either 200 or 400 Hz tetanization. Application of methoxyverapamil significantly inhibited 400 Hz long-term potentiation, but had no effect on 200 Hz long-term potentiation. These data suggest that 400 Hz long-term potentiation, induced in the presence of D(-)-2-amino-5-phosphonopentanoic acid, requires activation of L-type calcium channels. Furthermore, these results strongly support a critical role for group 1 metabotropic glutamate receptors in both N-methyl-D-aspartate receptor- and voltage-gated calcium channel-dependent long-term potentiation.

Pannexin1 stabilizes synaptic plasticity and is needed for learning.

Pannexin 1 (Panx1) represents a class of vertebrate membrane channels, bearing significant sequence homology with the invertebrate gap junction proteins, the innexins and more distant similarities in the membrane topologies and pharmacological sensitivities with gap junction proteins of the connexin family. In the nervous system, cooperation among pannexin channels, adenosine receptors, and KATP channels modulating neuronal excitability via ATP and adenosine has been recognized, but little is known about the significance in vivo. However, the localization of Panx1 at postsynaptic sites in hippocampal neurons and astrocytes in close proximity together with the fundamental role of ATP and adenosine for CNS metabolism and cell signaling underscore the potential relevance of this channel to synaptic plasticity and higher brain functions. Here, we report increased excitability and potently enhanced early and persistent LTP responses in the CA1 region of acute slice preparations from adult Panx1−/− mice. Adenosine application and N-methyl-D-aspartate receptor (NMDAR)-blocking normalized this phenotype, suggesting that absence of Panx1 causes chronic extracellular ATP/adenosine depletion, thus facilitating postsynaptic NMDAR activation. Compensatory transcriptional up-regulation of metabotropic glutamate receptor 4 (grm4) accompanies these adaptive changes. The physiological modification, promoted by loss of Panx1, led to distinct behavioral alterations, enhancing anxiety and impairing object recognition and spatial learning in Panx1−/− mice. We conclude that ATP release through Panx1 channels plays a critical role in maintaining synaptic strength and plasticity in CA1 neurons of the adult hippocampus. This result provides the rationale for in-depth analysis of Panx1 function and adenosine based therapies in CNS disorders.

BDNF contributes to the facilitation of hippocampal synaptic plasticity and learning enabled by environmental enrichment

Sensory, motor, and cognitive stimuli, resulting from interactions with the environment, play a key role in optimizing and modifying the neuronal circuitry required for normal brain function. An experimental animal model for this phenomenon comprises environmental enrichment (EE) in rodents. EE causes profound changes in neuronal and signaling levels of excitation and plasticity throughout the entire central nervous system and the hippocampus is particularly affected. The mechanisms underlying these changes are not yet fully understood. As brain‐derived neurotrophic factor (BDNF) supports hippocampal long‐term potentiation (LTP), we explored whether it participates in the facilitation of synaptic plasticity and hippocampus‐dependent learning that occurs following EE. In the absence of EE, LTP elicited by high‐frequency stimulation was equivalent in wildtype mice and heterozygous BDNF+/− siblings. LTP elicited by theta‐burst stimulation in BDNF+/− mice was less than in wildtypes. Long‐term depression (LTD) was also impaired. EE for three weeks, beginning after weaning, improved hippocampal LTP in both wildtype and transgenic animals, with LTP in transgenics achieving levels seen in wildtypes in the absence of EE. Object recognition memory was evident in wildtypes 24 h and 7 days after initial object exposure. EE improved memory performance in wildtypes 24 h but not 7 days after initial exposure. BDNF+/− mice in the absence of EE showed impaired memory 7 days after initial object exposure that was restored by EE. Western blotting revealed increased levels of BDNF, but not proBDNF, among both EE cohorts. These data support that BDNF plays an intrinsic role in improvements of synaptic plasticity and cognition that occur in EE.

Time-dependent induction of depotentiation in the dentate gyrus of freely moving rats: involvement of group 2 metabotropic glutamate receptors.

Depotentiation comprises a reversal of tetanization‐induced long‐term potentiation (LTP) which occurs following low‐frequency stimulation (LFS) in the hippocampus in vivo. Although depotentiation has been consistently demonstrated in the CA1 region, no positive reports of the existence of depotentiation in the dentate gyrus in vivo have occurred. This study therefore investigated whether depotentiation is possible in the dentate gyrus in vivo. We found that depotentiation can be induced, but it is very tightly dependent on the interval between tetanization and LFS. Thus, LFS given 2 or 5 min following tetanization produced significant depotentiation, whereas LFS given 10–30 min following tetanization had no significant effect on the expression of LTP. Depotentiation occurred in two phases: a transient depression of evoked responses to below pre‐tetanization values, which occurred in the first 60 min following LFS, and a recovery of this response to a stable level of synaptic transmission which comprised a significant reduction in the magnitude of LTP. Group 2 metabotropic glutamate receptors (mGluRs) play an important role in the expression of long‐term depression in vivo. We therefore investigated whether group 2 mGluRs contribute to depotentiation. The group 2 antagonist (2S)‐α‐ethylglutamic acid (EGLU) inhibited the early transient depression at a concentration which inhibits LTD in vivo, but did not block the expression of depotentiation. EGLU also inhibited the transient depression induced by 5 Hz given alone. Increasing the concentration of EGLU prevented depotentiation, however. The group 2 agonist (S)‐4‐carboxy‐3‐hydroxyphenyl‐ glycine (4C3HPG) inhibited LTP and enhanced depotentiation. These data suggest a role for group 2 mGluRs in depotentiation.

Pharmacological antagonism of metabotropic glutamate receptor 1 regulates long-term potentiation and spatial reference memory in the dentate gyrus of freely moving rats via N-methyl-d-aspartate and metabotropic glutamate receptor-dependent mechanisms

Group I metabotropic glutamate receptors (mGluRs) are critically required for multiple forms of hippocampal synaptic plasticity in vivo. The role of the receptor subtype mGluR1 in long‐term potentiation (LTP) and learning is unclear. We examined the contribution of mGluR1 to hippocampal LTP and spatial learning using the selective antagonist (S)‐(+)‐α‐amino‐4carboxy‐2‐methylbenzene‐acetic acid (LY367385). Male Wistar rats were chronically implanted with recording and stimulating electrodes to enable measurement of evoked potentials from medial perforant path–dentate gyrus granule cell synapses. An injection cannula was inserted into the ipsilateral cerebral ventricle to enable drug application. Experiments were begun 10 days after the implantation procedure. We induced a robust LTP which lasted over 25 h with a 200‐Hz tetanization. Injections of LY367385 at all concentrations under investigation (4–32 nmol in a 5‐µL injection volume) did not affect basal synaptic transmission. In contrast, we observed a dose‐dependent impairment of LTP expression: LY367385 (4 nmol) had no effect on LTP induction, whereas 8 and 16 nmol LY367385 reduced both LTP induction and expression, suggestive of an interaction with N‐methyl‐d‐aspartate receptors. We assessed the effects of daily LY367385 application (8 nmol) on performance in an eight‐arm radial maze. LY367385‐treated rats showed deficits in reference but not working memory performance compared with vehicle‐treated controls. Rearing, grooming and locomotor activity were unaffected by LY367385. These data suggest an important role for mGluR1 in LTP and learning and highlight the specific significance of this mGluR subtype for reference memory.