Lateral Perforant Research Articles

Modeling the Nonlinear Dynamic Interactions of Afferent Pathways in the Dentate Gyrus of the Hippocampus

The dentate gyrus is the first region of the hippocampus that receives and integrates sensory information (e.g., visual, auditory, and olfactory) via the perforant path, which is composed of two distinct neuronal pathways: the Lateral Perforant Path (LPP) and the Medial Perforant Path (MPP). This paper examines the nonlinear dynamic interactions among arbitrary stimulation patterns at these two afferent pathways and their combined effect on the resulting response of the granule cells at the dentate gyrus. We employ non-parametric Poisson-Volterra models that serve as canonical quantitative descriptors of the nonlinear dynamic transformations of the neuronal signals propagating through these two neuronal pathways. These Poisson-Volterra models are estimated in the so-called "reduced form" with experimental data from in vitro hippocampal slices and provide excellent predictions of the electrophysiological activity of the granule cells in response to arbitrary stimulation patterns. The data are acquired through a custom-made multi-electrode-array system, which stimulated simultaneously the two pathways with random impulse trains and recorded the neuronal postsynaptic activity at the granule cell layer. The results of this study show that significant nonlinear interactions exist between the LPP and the MPP that may be critical for the integration of sensory information performed by the dentate gyrus of 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.

Reduced synaptic plasticity in the lateral perforant path input to the dentate gyrus of aged C57BL/6 mice.

Hippocampal slices obtained from C57BL/6 mice (3-25 mo) were used to investigate the effects of aging on excitatory postsynaptic potentials (EPSPs) elicited in dentate gyrus with lateral perforant path stimulation. The maximal amplitude of the EPSP, as well as the degree of paired-pulse facilitation, was significantly reduced in animals aged 12 mo or more compared with younger animals (<12 mo). Although all animals showed equivalent short-term potentiation (STP) in response to high-frequency stimulation, this did not translate into a long-lasting increase in synaptic efficacy in the older animals. A significant degree of long-term potentiation (LTP) of synaptic efficacy was only observed in animals <12 mo of age when measured 30 min after induction. Blocking GABAA-mediated inhibition significantly enhanced STP in younger and older animals; however, a significant degree of LTP was again only observed in slices taken from younger animals. These data indicate that the lateral perforant path input to the dentate gyrus is altered by the aging process, and that this results in a reduction in the capacity of this input to exhibit long-lasting synaptic plasticity.

Comparative morphometric analysis of lateral and medial perforant path synapses in the dentate gyrus of adult rats

Comparative morphometric analysis of lateral and medial perforant path synapses in the dentate gyrus of adult rats

Endogenous Neurotrophin-3 Regulates Short-Term Plasticity at Lateral Perforant Path–Granule Cell Synapses

In the adult brain, neurotrophin-3 (NT-3) is mainly localized in dentate granule cells, and its expression is decreased by various stimuli, e.g., seizure activity. We have examined the role of endogenous NT-3 for excitatory synaptic transmission at lateral perforant path-dentate granule cell synapses using hippocampal slices from NT-3 knock-out (+/-) and wild-type (+/+) mice. Paired-pulse facilitation (PPF) and also short-term synaptic plasticity induced by a brief, high-frequency train of afferent stimulation were reduced, but the expression of long-term potentiation was not affected in the NT-3+/- mice. Incubation of the slices with recombinant NT-3 reversed the deficit in PPF through a mechanism requiring de novo protein synthesis, implying that the impaired short-term plasticity does not result from a developmental alteration. No changes of overall presynaptic release probability, measured by the progressive block of NMDA receptor-mediated synaptic currents by MK-801, or desensitization of AMPA receptors were detected. Because NT-3 expression is reduced after focal seizures, impaired short-term facilitation may represent a protective response that limits the propagation of epileptiform activity from the entorhinal cortex to the hippocampus.

Endogenous Activation of μ and δ-1 Opioid Receptors Is Required for Long-Term Potentiation Induction in the Lateral Perforant Path: Dependence on GABAergic Inhibition

Opioid peptides costored with glutamate have emerged as powerful regulators of long-term potentiation (LTP) induction in several hippocampal pathways. The objectives of the present study were twofold: (1) to identify which opioid receptor types (mu, delta, or kappa) regulate LTP induction at lateral perforant path-granule cell synapses and (2) to test the hypothesis that endogenous opioids regulate LTP induction via modulation of GABAergic inhibition. LTP of lateral perforant path-evoked field EPSPs was induced selectively by high-frequency stimulation applied to the outer third of the molecular layer of the dentate gyrus of rat hippocampal slices. No changes in medial perforant path responses occurred. LTP was blocked when high-frequency stimulation was applied in the presence of the mu receptor antagonist CTAP, the selective delta-1 receptor antagonist BNTX, or the delta-1 and delta-2 receptor antagonist naltrindole. By contrast, the kappa-1 opioid receptor antagonist NBNI had no effect on LTP induction. The role of GABAergic inhibition was investigated by comparing the effect of naloxone on LTP induction in slices maintained in standard buffer and picrotoxin-containing buffer. Naloxone blocked LTP in standard buffer, whereas normal LTP was induced in picrotoxin-treated, disinhibited slices. Finally, NMDA receptor blockade completely inhibited LTP in both standard and disinhibited slices. The results show that mu and delta-1 opioid receptors regulate LTP induction and that this mechanism critically depends on GABAergic inhibition. A key issue then becomes how endogenous opioids fine-tune the activity of intact inhibitory networks in the dentate gyrus, effectively gating synaptic plasticity in specific dendritic strata.

Limbic networks and associative learning: II. Entorhinal contributions to spontaneous alternation, passive avoidance, and taste aversion learning

The hippocampus plays an important role in learning and memory, but the precise nature of that involvement remains uncertain. Transection of the perforant path, a primary input pathway to the hippocampus, has been shown to produce changes in reaction to novelty and acquisition of active avoidance; the nature and magnitude of these changes vary with lateral or medial perforant path damage. In a series of experiments on adult rats, the role of these pathways in spontaneous alternation, exploration, acquisition and extinction of conditioned responses, passive avoidance, and conditioned taste aversion was investigated. Lateral transection reduced exploration while medial transection facilitated acquisition of an active avoidance response; no effects were observed on any other measure. Results are discussed in terms of what perforant path damage might reveal regarding the interactions of the hippocampus with other brain regions.

Activation of AP5‐sensitive NMDA Receptors is Not Required to Induce LTP of Synaptic Transmission in the Lateral Perforant Path

The role of the N-methyl-d-aspartate (NMDA) type of glutamate receptor in long-term potentiation (LTP) of the medial (MPP) and lateral (LPP) divisions of the perforant path - granule cell system was investigated in urethane-anaesthetized rats. A stimulating electrode was positioned in the dorsomedial or ventrolateral aspect of the angular bundle for selective activation of either the MPP or LPP, respectively. A push - pull cannula served to focally perfuse artificial cerebrospinal fluid (ACSF) across the perforant path synaptic zone, while evoked potentials were monitored in the dentate hilus. Identification of LPP and MPP responses was based on (1) differences in population excitatory postsynaptic potential (EPSP) waveform obtained during stimulus depth profiles, and (2) differential sensitivity of evoked EPSPs to the glutamate receptor agonist l-aminophosphonobutyrate (AP4), and the antagonist gamma-d-glutamylglycine (DGG). High-frequency stimulation (400 Hz, 8 bursts of 8 pulses) applied to the lateral and medial perforant path elicited LTP of the EPSP and population spike in rats perfused with standard medium. In the MPP, LTP was almost completely blocked when d-aminophosphonopentanoate (AP5; 100 microM), a selective NMDA receptor antagonist, was perfused during the tetanus. Surprisingly, in the LPP experiments, AP5 did not impair induction of the 'synaptic' EPSP component of LTP. This occurred despite the ability of AP5 to block LTP of the LPP evoked population spike. The results suggest the existence of a novel, NMDA receptor-independent form of synaptic LTP in the lateral perforant path.

The localization of leucine-enkephalin immunoreactivity within the guinea pig hippocampus.

The distribution of enkephalin immunoreactive fibres has been studied in the hippocampus, subiculum and entorhinal cortex of the guinea pig. Two immunoreactive enkephalin fibre systems were found. One system corresponds to the mossy fibre system from the fascia dentata to CA3 and courses at the level of the mossy fibre end bulb in a longitudinal direction along the main axis of the hippocampus. Another system originates in the medial and lateral entorhinal cortex, traverses the subiculum, and then courses in the stratum moleculare/lacunosum to CA1 and CA3; part of these fibres crosses the hippocampal fissure and reaches the stratum moleculare of the fascia dentata. In the fascia dentata intense immunoreactivity was observed in the distal and middle one-third of the stratum moleculare at the side of the terminations of the lateral and medial perforant path fibres. Various types of immunoreactive cell bodies were found in the fascia dentata, CA3, CA1, subiculum and in the entorhinal cortex.