Brian E. Derrick

NMDA receptor antagonists sustain LTP and spatial memory: active processes mediate LTP decay

Although long-term potentiation (LTP) is long-lasting, it is not permanent and decays within weeks after its induction. Little is known about the processes underlying this decay. Here we assessed the contribution of synaptic activity to LTP decay by determining the effect of the competitive NMDA receptor antagonist CPP on the decay of perforant path–dentate LTP. CPP blocked decay over a one-week period when administered daily following the induction of LTP, and blocked decay of the late, protein-synthesis-dependent phase of LTP when administered two days after LTP induction. CPP administered for a five-day period following spatial memory training enhanced subsequent memory retention. These data suggest that LTP is normally a persistent process that is actively reversed by NMDA receptor activation, and that both the early and late phases of LTP are dynamic processes regulated by NMDA receptors. These data also support the view that LTP is involved in maintaining spatial memory.

Novel environments enhance the induction and maintenance of long-term potentiation in the dentate gyrus

The induction of long-term potentiation (LTP) in the hippocampal formation can be modulated by different behavioral states. However, few studies have addressed modulation of LTP during behavioral states in which the animal is likely acquiring new information. Here, we demonstrate that both the induction and the longevity of LTP in the dentate gyrus are enhanced when LTP is induced during the initial exploration of a novel environment. These effects are independent from locomotor activity, changes in brain temperature, and theta rhythm. Previous exposure to the novel environment attenuated this enhancement, suggesting that the effects of novelty habituate with familiarity. LTP longevity also was enhanced when induced in familiar environments containing novel objects. Together, these data indicate that both LTP induction and maintenance are enhanced when LTP is induced while rats investigate novel stimuli. We suggest that novelty initiates a transition of the hippocampal formation to a mode that is particularly conducive to synaptic plasticity, a process that could allow for new learning while preserving the stability of previously stored information. In addition, LTP induced in novel environments elicited a sustained late LTP. This suggests that a single synaptic population can display distinct profiles of LTP maintenance and that this depends on the animals behavioral state during its induction. Furthermore, the duration of LTP enhanced by novelty parallels the time period during which the hippocampal formation is thought necessary for memory, consistent with the view that dentate LTP is of a duration sufficient to sustain memory in the hippocampal formation.

Increased granule cell neurogenesis in the adult dentate gyrus following mossy fiber stimulation sufficient to induce long-term potentiation

Neurons are continually added at a low rate to the granule cell layer of the dentate gyrus during adulthood in rats. The functional significance of this unusual feature is not completely understood, although recent studies suggest continued granule cell neurogenesis is essential for normal learning and memory. We report here that, in the adult rat, stimulation of the granule cell mossy fibers sufficient to induce long-term potentiation (LTP) increases the number of newly formed granule cells in the dentate gyrus, indicating that granule cell neurogenesis is regulated by efferent activity and, possibly, the induction of LTP.

Associative long-term potentiation (LTP) among extrinsic afferents of the hippocampal CA3 region in vivo

Monosynaptic perforant path projections to the CA3 region of the hippocampus are anatomically and physiologically substantial pathways that relay cortical input directly to the hippocampus proper. Despite the suggested relevance of these direct pathways in models of information processing within the CA3 region, surprisingly few studies have characterized synaptic plasticity in these direct cortical projections to the CA3 region. We assessed the ability of perforant path projections, and commissural/associational projections to the hippocampal CA3 region to both induce or display associative LTP in vivo. In pentobarbital-anesthetized adult rats, trains delivered to either the medial or lateral perforant pathway at current intensities normally insufficient to induce LTP displayed associative LTP when these same trains were delivered in conjunction with high-intensity trains to the alternate perforant pathway. Similarly, associative LTP is induced at intrinsic commissural/associational-CA3 (C/A-CA3) synapses when weak C/A trains were delivered in conjunction with high-intensity trains to either the medial or lateral perforant pathway. Associative LTP also was observed at medial and lateral perforant path-CA3 synapses when weak perforant path trains were tetanized in conjunction with high-intensity trains delivered to C/A-CA3 synapses. Thus direct perforant path-CA3 synapses and commissural/associational-CA3 synapses can modify and be modified by other CA3 afferents in an associative manner, verifying a requirement for synaptic plasticity explicit in models of autoassociative information processing in the CA3 region.

Opioid receptor modulation of mossy fiber synaptogenesis: Independence from long-term potentiation

Long-term potentiation (LTP) at the mossy fiber-CA3 synapse of the rat hippocampus is an NMDA receptor-independent form of synaptic plasticity that is sensitive to opioid receptor antagonists [12]. In the present study, Timms stain, a zinc detecting histological marker commonly used to infer synaptogenesis in the mossy fiber projection, was used to examine whether synaptogenesis occurs in response to mossy fiber LTP induction in the adult rat in vivo. Seven days following the induction of mossy fiber LTP by non-seizure-inducing high-frequency stimulation of the mossy fibers, a prominent band of Timms staining appeared bilaterally in the infrapyramidal region of the stratum oriens in area CA3. Staining was more prominent on the side contralateral to the stimulation. Systemic administration of the opioid receptor antagonist naloxone, sufficient to block mossy fiber LTP induction, did not block the development of Timms staining in the infrapyramidal region ipsilateral to stimulation, but it did block stimulation-induced increases in Timms staining observed contralaterally. Systemic administration of (+/-) CPP, a competitive NMDA receptor-antagonist, by contrast, did not block the induction of LTP and did not alter the increase in Timms staining observed either ipsilaterally or contralaterally. The increase in Timms staining in the infrapyramidal region suggests that mossy fiber synaptogenesis occurs in response to non-seizure inducing stimulation. Synaptogenesis does not appear to be directly related to opioid receptor-dependent mossy fiber LTP induction, because it occurs in the presence of naloxone which blocks LTP. The mossy fiber synaptogenesis occurring contralaterally appears to be regulated by endogenous opioid peptides, because it is blocked by naloxone.

Modulation of CA3 Afferent Inputs by Novelty and Theta Rhythm

Models of hippocampal function suggest that the modulation of CA3 afferent input during theta rhythm allows for a rapid alternation between encoding and retrieval states, with each phase enhancing either extrinsic or intrinsic CA3 afferents, favoring either encoding or retrieval, respectively. Here, we show that during the initial exploration of a novel environment by rats, intrinsic CA3-CA3 synaptic inputs are attenuated on CA3 theta peaks, favoring extrinsic CA3 inputs, whereas extrinsic perforant path-CA3 synaptic inputs are attenuated on CA3 theta troughs, favoring intrinsic CA3 inputs. This modulation is absent when animals are re-exposed to the same environment 2 or 48 h later and thus habituates with familiarity, suggesting a process involved in learning. Modulation of CA3 synaptic inputs during novelty was blocked by atropine at a dose that blocks type 2 theta rhythm. Re-exposure to the same novel environment 48 h later in the absence of atropine did not result in habituation, but instead modulated CA3 synaptic responses as though the environment were novel and explored for the first time. The NMDA receptor antagonist (±)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), administered in a dose that blocks long-term potentiation induction, did not alter CA3 synaptic modulation during initial exploration. However, like atropine, CPP blocked the habituation of synaptic modulation normally observed with re-exposure, as though the environment were novel and explored for the first time. Thus, as predicted theoretically, recurrent and cortical CA3 afferents are differentially modulated during phases of theta rhythm. This modulation is atropine sensitive and habituates in an NMDA receptor-dependent manner, suggesting an NMDA receptor-dependent process that, in conjunction with theta rhythm, contributes to encoding of novel information in the hippocampus.

NMDA receptor antagonists block heterosynaptic long-term depression (LTD) but not long-term potentiation (LTP) in the CA3 region following lateral perforant path stimulation

High-frequency stimulation of lateral perforant path is accompanied by a heterosynaptic long-term depression (LTD) of medial perforant path synaptic responses in both the dentate gyrus and the CA3 region of the hippocampus. We reported previously that LTP induction at lateral perforant path-CA3 synapses is unaffected by NMDA antagonists. However, it is not known if heterosynaptic LTD that is observed in the CA3 region following lateral perforant path stimulation also is independent from NMDA receptors. We address this question in anesthetized adult rats using systemic administration of the competitive NMDA receptor antagonist CPP. Induction of lateral perforant path-CA3 LTP produced a sustained heterosynaptic depression of medial perforant path-CA3 responses. Systemic administration of CPP (10 mg/kg) was ineffective in blocking the induction of LTP at lateral perforant path-CA3 responses. However, heterosynaptic LTD of medial perforant path-CA3 responses was blocked completely by CPP. These data indicate that NMDA receptors are not required for the induction of lateral perforant path-CA3 LTP, but are involved in the induction of heterosynaptic LTD that accompanies lateral perforant path activity. The requirement for NMDA receptors for heterosynaptic LTD suggests one functional role of NMDA receptors at termination fields of the lateral perforant path.

Plastic processes in the dentate gyrus: a computational perspective.

The dentate gyrus has the capacity for numerous types of synaptic plasticity that use diverse mechanisms and are thought essential for the storage of information in the hippocampus. Here we review the various forms of synaptic plasticity that involve afferents and efferents of the dentate gyrus, and, from a computational perspective, relate how these plastic processes might contribute to sparse, orthogonal encoding, and the selective recall of information within the hippocampus.

Prenatal Morphine Exposure Attenuates the Maintenance of Late LTP in Lateral Perforant Path Projections to the Dentate Gyrus and the CA3 Region In Vivo

Previously we reported that prenatal exposure to morphine twice daily during gestation decreases proenkephalin levels in adult progeny within the brain, including the dentate gyrus, and alters mu and delta opioid receptors in the hippocampal CA3 region. The lateral aspect of the perforant path contains and releases enkephalin-derived opioid peptides, and induction of long-term potentiation (LTP) in lateral perforant path projections to both the dentate gyrus and the hippocampal CA3 region is blocked by antagonists of opioid receptors. Thus LTP induction at these synapses involves opioid receptor activation mediated by the release of proenkephalin-derived opioid peptides with lateral perforant path activation. Here we show in adult behaving animals, neither LTP induction nor the early phase of LTP (E-LTP) maintenance is altered by prenatal morphine exposure in the lateral perforant path projections to the dentate gyrus and the CA3 region. However, maintenance and longevity of late LTP (L-LTP), as reflected in the magnitude of LTP over days, was attenuated in animals prenatally exposed to morphine. In contrast, in medial perforant path projections to the dentate gyrus and CA3 region, both LTP induction and the maintenance of E- and L-LTP were unaffected by prenatal morphine treatment. Thus a brief prenatal exposure to the opiate morphine produces sustained, and possibly permanent, alterations in L-LTP in the opioidergic lateral perforant path projection. This suggests that prenatal morphine exposure disrupts LTP via disruption of opioid mechanisms involved in LTP maintenance or via disruption of opioid receptor activation during LTP induction, which can subsequently alter LTP maintenance.

Low-frequency stimulation induces long-term depression and slow onset long-term potentiation at perforant path-dentate gyrus synapses in vivo

The expression of homosynaptic long-term depression (LTD) is thought to mediate a crucial role in sustaining memory function. Our in vivo investigations of LTD expression at lateral (LPP) and medial perforant path (MPP) synapses in the dentate gyrus (DG) corroborate prior demonstrations that PP-DG LTD is difficult to induce in intact animals. In freely moving animals, LTD expression occurred inconsistently among LPP-DG and MPP-DG responses. Interestingly, following acute electrode implantation in anesthetized rats, low-frequency stimulation (LFS; 900 pulses, 1 Hz) promotes slow-onset LTP at both MPP-DG and LPP-DG synapses that utilize distinct induction mechanisms. Systemic administration of the N-methyl-d-aspartate (NMDA) receptor antagonist (+/-)-cyclopiperidine-6-piperiperenzine (CPP; 10 mg/kg) 90 min before LFS selectively blocked MPP-DG but not LPP-DG slow onset LTP, suggesting MPP-DG synapses express a NMDA receptor-dependent slow onset LTP whereas LPP-DG slow onset LTP induction is NMDA receptor independent. In experiments where paired-pulse LFS (900 paired pulses, 200-ms paired-pulse interval) was used to induce LTD, paired-pulse LFS of the LPP resulted in rapid onset LTP of DG responses, whereas paired-pulse LFS of the MPP induced slow onset LTP of DG responses. Although LTD observations were very rare following acute electrode implantation in anesthetized rats, LPP-DG LTD was demonstrated in some anesthetized rats with previously implanted electrodes. Together, our data indicate in vivo PP-DG LTD expression is an inconsistent phenomenon that is primarily observed in recovered animals, suggesting perturbation of the dentate through surgery-related tissue trauma influences both LTD incidence and LTP induction at PP-DG synapses in vivo.