Inhibition of glutamate release by presynaptic kappa 1-opioid receptors in the guinea pig dentate gyrus

1. Activation of kappa 1-opioid receptors inhibits excitatory transmission in the hippocampal dentate gyrus of the guinea pig. The present studies used both anatomic and physiological approaches to distinguish between a pre- and postsynaptic localization of these receptors. 2. The entorhinal cortex was lesioned unilaterally to cause degeneration of perforant path afferents to the dentate molecular layer, and kappa 1-opioid binding sites were measured by labeling with the selective agonist, [3H]-U69593. Binding density was reduced significantly in the dentate gyrus molecular layer ipsilateral to the lesion compared with the contralateral molecular layer and with sham-lesioned controls. 3. Paired-pulse facilitation is a neurophysiologic paradigm that has been used to differentiate pre- and postsynaptic sites of action for agents that inhibit excitatory neurotransmission. U69593 reduced the amplitude of single population spikes and increased the degree of paired pulse facilitation. The potentiation of paired-pulse facilitation was maintained when the stimulation intensity was increased to compensate for the inhibition of excitatory transmission. These effects of kappa 1-receptor activation were similar to those seen after presynaptic inhibition of excitatory neurotransmitter release and support the hypothesis that U69593 presynaptically inhibits excitatory amino acid release in the dentate gyrus. 4. Local application of glutamate by pressure ejection in the dentate molecular layer evoked field excitatory postsynaptic potentials that mimicked those evoked by electrical stimulation of the perforant path. Both responses were sensitive to the non-N-methyl-D-aspartate glutamate receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione. U69593 inhibited responses evoked by perforant path stimulation but had no effect on responses evoked by glutamate application.(ABSTRACT TRUNCATED AT 250 WORDS)

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Idazoxan increases perforant path-evoked EPSP slope paired pulse inhibition and reduces perforant path-evoked population spike paired pulse facilitation in rat dentate gyrus

Brain Research ◽

10.1016/j.brainres.2005.12.020 ◽

2006 ◽

Vol 1072 (1) ◽

pp. 36-45 ◽

Cited By ~ 5

Author(s):

John Knight ◽

Carolyn W. Harley

Keyword(s):

Dentate Gyrus ◽

Population Spike ◽

Perforant Path ◽

Paired Pulse ◽

Paired Pulse Facilitation

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Cannabinoids selectively decrease paired-pulse facilitation of perforant path synaptic potentials in the dentate gyrus in vitro

Brain Research ◽

10.1016/0006-8993(95)00521-q ◽

1995 ◽

Vol 688 (1-2) ◽

pp. 114-120 ◽

Cited By ~ 12

Author(s):

M. Todd Kirby ◽

Robert E. Hampson ◽

Sam A. Deadwyler

Keyword(s):

Dentate Gyrus ◽

Perforant Path ◽

Paired Pulse ◽

Paired Pulse Facilitation ◽

Synaptic Potentials

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

Journal of Neurophysiology ◽

10.1152/jn.00981.2007 ◽

2008 ◽

Vol 99 (3) ◽

pp. 1235-1242 ◽

Cited By ~ 16

Author(s):

D. M. Villarreal ◽

B. Derrick ◽

I. Vathy

Keyword(s):

Dentate Gyrus ◽

Opioid Receptor ◽

Prenatal Exposure ◽

Opioid Receptors ◽

Opioid Peptides ◽

Long Term Potentiation ◽

Receptor Activation ◽

Perforant Path ◽

Hippocampal Ca3 ◽

Ca3 Region

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 μ and δ 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.

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Paired-pulse facilitation in the dentate gyrus: a patch-clamp study in rat hippocampus in vitro

Journal of Neurophysiology ◽

10.1152/jn.1994.72.1.326 ◽

1994 ◽

Vol 72 (1) ◽

pp. 326-336 ◽

Cited By ~ 64

Author(s):

M. Andreasen ◽

J. J. Hablitz

Keyword(s):

Patch Clamp ◽

Dentate Gyrus ◽

Time Constant ◽

Rise Time ◽

Time Course ◽

Nmda Antagonist ◽

Paired Pulse ◽

Stimulation Intensity ◽

Paired Pulse Facilitation ◽

Epsc Amplitude

1. Whole-cell patch-clamp recordings were used to study paired-pulse facilitation (PPF) of the lateral perforant path input to the dentate gyrus in thin hippocampal slices. 2. Orthodromic stimulation of the lateral perforant pathway evoked a excitatory postsynaptic current (EPSC) with a latency of 3.3 +/- 0.1 ms (mean +/- SE) that fluctuated in amplitude. The EPSC had a rise time (10-90%) of 2.79 +/- 0.06 ms (n = 35) and decayed with a single exponential time course with a time-constant of 9.14 +/- 0.24 ms (n = 35). No correlation was found between the amplitude of the EPSC and the rise time or decay time-constant. The non-N-methyl-D-aspartate (NMDA) antagonist 6-cyano-7-nitroquinoxaline-2,3-dione completely blocked the EPSC whereas the NMDA antagonist D-aminophosphonovaleric acid (APV) had modest effects. 3. When a test (T-)EPSC was preceded at an interval of 100 ms by a conditioning (C-)EPSC, a significant increase in the amplitude of the T-EPSC was seen in 38 out of 44 trials analyzed from a total of 27 granule cells. The average amount of PPF was 35.7 +/- 2.1%. There was no apparent correlation between the amount of PPF and the stimulation intensity or mean amplitude of the C-EPSC. The time course of the facilitated T-EPSC was not significantly different from that of the C-EPSC. 4. No correlation was found between the amplitude of the C-EPSC and that of the T-EPSC. Estimates of quantal content (mcv) were determined by calculating the ratio of the squared averaged EPSC amplitude (from 48 responses) to the variance of these responses (M2/sigma 2) whereas quantal amplitudes (qcv) were estimated by calculating the ratio of the response variance to average EPSC amplitude (sigma 2/M). PPF was found to be associated with an average increase in mcv of 64.8 +/- 7.2% (n = 38) whereas qcv was decreased by 12.1 +/- 3.8%. 5. The time course of PPF was studied by varying the interval between the C- and T-pulse from 10 to 400 ms while keeping the stimulation intensity constant. Maximal facilitation of the T-EPSC was obtained with interpulse intervals < or = 25 ms where the average facilitation amounted to approximately 70% (n = 6). The decline of facilitation was nearly exponential and was no longer evident with intervals > 350 ms.(ABSTRACT TRUNCATED AT 400 WORDS

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NMDA receptors have a dominant role in population spike-paired pulse facilitation in the dentate gyrus of urethane-anesthetized rats

Brain Research ◽

10.1016/0006-8993(93)90379-2 ◽

1993 ◽

Vol 604 (1-2) ◽

pp. 273-282 ◽

Cited By ~ 44

Author(s):

Robert M. Joy ◽

Timothy E. Albertson

Keyword(s):

Dentate Gyrus ◽

Nmda Receptors ◽

Dominant Role ◽

Population Spike ◽

Paired Pulse ◽

Paired Pulse Facilitation ◽

Anesthetized Rats

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NMDA-Dependent Currents in Granule Cells of the Dentate Gyrus Contribute to Induction but Not Permanence of Kindling

Journal of Neurophysiology ◽

10.1152/jn.1999.81.2.564 ◽

1999 ◽

Vol 81 (2) ◽

pp. 564-574 ◽

Cited By ~ 24

Author(s):

Ümit Sayin ◽

Paul Rutecki ◽

Thomas Sutula

Keyword(s):

Nmda Receptor ◽

Dentate Gyrus ◽

Time Course ◽

Granule Cells ◽

Receptor Activation ◽

Perforant Path ◽

Synaptic Current ◽

Synaptic Currents ◽

Class V ◽

Dependent Component

NMDA-dependent currents in granule cells of the dentate gyrus contribute to induction but not permanence of kindling. Single-electrode voltage-clamp techniques and bath application of the N-methyl-d-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovaleric acid (APV) were used to study the time course of seizure-induced alterations in NMDA-dependent synaptic currents in granule cells of the dentate gyrus in hippocampal slices from kindled and normal rats. In agreement with previous studies, granule cells from kindled rats examined within 1 wk after the last of 3 or 30–35 generalized tonic-clonic (class V) seizures demonstrated an increase in the NMDA receptor–dependent component of the perforant path–evoked synaptic current. Within 1 wk of the last kindled seizure, NMDA-dependent charge transfer underlying the perforant path–evoked current was increased by 63–111% at a holding potential of −30 mV. In contrast, the NMDA-dependent component of the perforant-evoked current in granule cells examined at 2.5–3 mo after the last of 3 or 90–120 class V seizures did not differ from age-matched controls. Because the seizure-induced increases in NMDA-dependent synaptic currents declined toward control values during a time course of 2.5–3 mo, increases in NMDA-dependent synaptic transmission cannot account for the permanent susceptibility to evoked and spontaneous seizures induced by kindling. The increase in NMDA receptor–dependent transmission was associated with the induction of kindling but was not responsible for the maintenance of the kindled state. The time course of alterations in NMDA-dependent synaptic current and the dependence of the progression of kindling and kindling-induced mossy fiber sprouting on repeated NMDA receptor activation are consistent with the possibility that the NMDA receptor is part of a transmembrane signaling pathway that induces long-term cellular alterations and circuit remodeling in response to repeated seizures, but is not required for permanent seizure susceptibility in circuitry altered by kindling.

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The Proteome of the Dentate Terminal Zone of the Perforant Path Indicates Presynaptic Impairment in Alzheimer Disease

Molecular & Cellular Proteomics ◽

10.1074/mcp.ra119.001737 ◽

2019 ◽

Vol 19 (1) ◽

pp. 128-141 ◽

Cited By ~ 5

Author(s):

Hazal Haytural ◽

Georgios Mermelekas ◽

Ceren Emre ◽

Saket Milind Nigam ◽

Steven L. Carroll ◽

...

Keyword(s):

Alzheimer Disease ◽

Dentate Gyrus ◽

Molecular Mechanisms ◽

Molecular Layer ◽

Synaptic Proteins ◽

Perforant Path ◽

Synaptic Dysfunction ◽

Complexin 2 ◽

Terminal Zone ◽

Vesicle Cycle

Synaptic dysfunction is an early pathogenic event in Alzheimer disease (AD) that contributes to network disturbances and cognitive decline. Some synapses are more vulnerable than others, including the synapses of the perforant path, which provides the main excitatory input to the hippocampus. To elucidate the molecular mechanisms underlying the dysfunction of these synapses, we performed an explorative proteomic study of the dentate terminal zone of the perforant path. The outer two-thirds of the molecular layer of the dentate gyrus, where the perforant path synapses are located, was microdissected from five subjects with AD and five controls. The microdissected tissues were dissolved and digested by trypsin. Peptides from each sample were labeled with different isobaric tags, pooled together and pre-fractionated into 72 fractions by high-resolution isoelectric focusing. Each fraction was then analyzed by liquid chromatography-mass spectrometry. We quantified the relative expression levels of 7322 proteins, whereof 724 showed significantly altered levels in AD. Our comprehensive data analysis using enrichment and pathway analyses strongly indicated that presynaptic signaling, such as exocytosis and synaptic vesicle cycle processes, is severely disturbed in this area in AD, whereas postsynaptic proteins remained unchanged. Among the significantly altered proteins, we selected three of the most downregulated synaptic proteins; complexin-1, complexin-2 and synaptogyrin-1, for further validation, using a new cohort consisting of six AD and eight control cases. Semi-quantitative analysis of immunohistochemical staining confirmed decreased levels of complexin-1, complexin-2 and synaptogyrin-1 in the outer two-thirds of the molecular layer of the dentate gyrus in AD. Our in-depth proteomic analysis provides extensive knowledge on the potential molecular mechanism underlying synaptic dysfunction related to AD and supports that presynaptic alterations are more important than postsynaptic changes in early stages of the disease. The specific synaptic proteins identified could potentially be targeted to halt synaptic dysfunction in AD.

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