scholarly journals Molecular layer perforant path-associated cells contribute to feed-forward inhibition in the adult dentate gyrus

2013 ◽  
Vol 110 (22) ◽  
pp. 9106-9111 ◽  
Author(s):  
Y. Li ◽  
F. J. Stam ◽  
J. B. Aimone ◽  
M. Goulding ◽  
E. M. Callaway ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Molecular Layer ◽  
Perforant Path ◽  
Feed Forward ◽  
Feed Forward Inhibition

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

2019 ◽  
Vol 19 (1) ◽  
pp. 128-141 ◽  
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.

Positive feedback from hilar mossy cells to granule cells in the dentate gyrus revealed by voltage-sensitive dye and microelectrode recording

1996 ◽  
Vol 76 (1) ◽  
pp. 601-616 ◽  
Author(s):  
M. B. Jackson ◽  
H. E. Scharfman
Keyword(s):  
Dentate Gyrus ◽  
Granule Cells ◽  
Excitatory Amino Acid ◽  
Molecular Layer ◽  
Perforant Path ◽  
Field Potentials ◽  
Microelectrode Recording ◽  
Mossy Cells ◽  
Dye Fluorescence ◽  
Site Of Stimulation

1. Microelectrode recording and fluorescence measurement with voltage-sensitive dyes were employed in horizontal hippocampal slices from rat to investigate responses in the dentate gyrus to molecular layer and hilar stimulation. 2. Both field potential and dye fluorescence measurement revealed that electrical stimulation of the molecular layer produced strong excitation throughout large regions of the dentate gyrus at considerable distances from the site of stimulation. 3. Treatment of slices with the excitatory amino acid receptor antagonists 6,7-dinitroquinoxaline-2,3-dione (DNQX) and (+/-)-2-amino-5-phosphonovaleric acid (APV) unmasked dye fluorescence signals in the outer and middle molecular layers corresponding to action potentials in axons, presumably belonging to the perforant path. The spread of these axonal signals away from the site of stimulation was far less extensive than the spread of control signals through the same regions before blockade of excitatory synapses. Large control responses could be seen in regions distant from the stimulation site where the axonal signals were not detectable. A lack of correlation between control signals and axonal signals revealed by DNQX and APV supports the hypothesis that responses in distal regions of the molecular layer were not dependent on perforant path axons. 4. The perforant path was cut by producing a lesion in the outer two-thirds of the molecular layer. Both dye fluorescence and microelectrode recording showed that stimulation on one side of the lesion could produce signals on the same side as well as across the lesion. The lesion did not block the spread of excitation through the molecular layer. Across the lesion from the site of stimulation, negative-going field potentials were observed to peak in the inner molecular layer, which is the major field of projection of hilar mossy cells. 5. Electrical stimulation in the hilus adjacent to the granule cell layer evoked dye fluorescence responses in the molecular layer. Stimulation at this site evoked negative-going field potentials that peaked in the inner molecular layer. These signals were sensitive to excitatory amino acid receptor antagonists but not to gamma-aminobutyric acid-A (GABAA) receptor antagonists. 6. Activation of excitatory amino acid receptors in the hilus by focal application of (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) elicited negative-going field potentials in the granule cell layer and depolarization of granule cells. Field potentials were blocked by tetrodotoxin (TTX), indicating that they were not caused by direct activation of receptors on granule cells, but rather by synapses from hilar neurons on granule cells. 7. These results taken together with previous studies of hilar mossy cells suggest a fundamental circuit consisting of granule cells exciting hilar mossy cells, which then excite more granule cells. This circuit provides positive feedback and can be considered a form of "recurrent excitation" unique to the dentate gyrus. The robustness of this circuit in hippocampal slices under control conditions suggest that mossy cell excitation of granule cells could play an important role in the normal activity of the hippocampus, and, when inhibition is compromised, this circuit could contribute to the generation and spread of seizures.

Activity-mediated changes in feed-forward inhibition in the dentate commissural pathway: relationship to EPSP/spike dissociation in the converging perforant path

1993 ◽  
Vol 69 (1) ◽  
pp. 165-173 ◽  
Author(s):  
R. A. Tomasulo ◽  
J. J. Ramirez
Keyword(s):  
Perforant Path ◽  
Excitatory Postsynaptic Potential ◽  
Feed Forward ◽  
Pulse Trains ◽  
Before And After ◽  
Commissural Pathway ◽  
High Stimulus ◽  
The Relationship ◽  
Feed Forward Inhibition

1. We tested the hypothesis that long-term synaptic potentiation (LTP)-associated excitatory postsynaptic potential (EPSP)/spike dissociation in the dentate gyrus (DG) is determined, in part, by changes in the feed-forward inhibition evoked by perforant path (PP) stimulation. The dentate commissural pathway (CP) and the PP activate a common pool of interneurons. Therefore a change in synaptic efficacy in the inhibitory circuit due to activation of one pathway could lead to changes in inhibitory efficacy in the other. The relationship between changes in feed-forward inhibition in the CP and EPSP/spike (E-S) functions in the PP should provide information about the site(s) of synaptic modification. 2. In urethan-anesthetized rats, we measured the inhibition of evoked PP population spikes by the CP at interstimulus intervals of 6 and 12 ms. This measure of commissural inhibition and conventional E-S functions for the PP input to the DG were obtained before and after 1) PP tetany (400 Hz, 8-pulse trains) at low, medium, and high stimulus intensities, and 2) CP tetany (200 Hz, 7-pulse trains). 3. Low-intensity PP conditioning (just above population spike threshold) led to a decrease in CP inhibition and large left shifts of the E-S function. High- and medium-intensity PP conditioning yielded increases in commissural inhibition and smaller leftward E-S shifts. 4. Commissural conditioning led to increases in commissural inhibition and inconsistent changes in the E-S functions.(ABSTRACT TRUNCATED AT 250 WORDS)

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

1994 ◽  
Vol 72 (4) ◽  
pp. 1697-1705 ◽  
Author(s):  
M. L. Simmons ◽  
G. W. Terman ◽  
C. T. Drake ◽  
C. Chavkin
Keyword(s):  
Guinea Pig ◽  
Dentate Gyrus ◽  
Opioid Receptors ◽  
Molecular Layer ◽  
Receptor Activation ◽  
Perforant Path ◽  
Paired Pulse ◽  
Paired Pulse Facilitation ◽  
Excitatory Transmission ◽  
Sites Of Action

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)

scholarly journals Acute Intrahippocampal Infusion of BDNF Induces Lasting Potentiation of Synaptic Transmission in the Rat Dentate Gyrus

1998 ◽  
Vol 79 (1) ◽  
pp. 496-499 ◽  
Author(s):  
Elhoucine Messaoudi ◽  
Kjetil Bårdsen ◽  
Bolek Srebro ◽  
Clive R. Bramham
Keyword(s):  
Synaptic Transmission ◽  
Dentate Gyrus ◽  
Granule Cells ◽  
Molecular Layer ◽  
Epileptiform Activity ◽  
Population Spike ◽  
Perforant Path ◽  
Excitatory Postsynaptic Potential ◽  
Adult Rats ◽  
Fepsp Slope

Messaoudi, Elhoucine, Kjetil Bårdsen, Bolek Srebro, and Clive R. Bramham. Acute intrahippocampal infusion of BDNF induces lasting potentiation of synaptic transmission in the rat dentategyrus. J. Neurophysiol. 79: 496–499, 1998. The effect of acuteintrahippocampal infusion of brain-derived neurotrophic factor (BDNF) on synaptic transmission in the dentate gyrus was investigated in urethan-anesthetized rats. Medial perforant path-evoked field potentials were recorded in the dentate hilus and BDNF-containing buffer was infused (4 μl, 25 min) immediately above the dentate molecular layer. BDNF led to a slowly developing increase of the field excitatory postsynaptic potential (fEPSP) slope and population spike amplitude. The potentiation either reached a plateau level at ∼2 h after BDNF infusion or continued to increase for the duration of experiment; the longest time point recorded was 10 h. Mean increases at 4 h after BDNF infusion were 62.2 and 224% for the fEPSP slope and population spike, respectively. No changes in responses were observed in controls receiving buffer medium only or buffer containing cytochrome C. BDNF-induced potentiation developed in the absence of epileptiform activity in the hippocampal electroencephalogram or changes in recurrent inhibition on granule cells as assessed by paired-pulse inhibition of the population spike. We conclude that exogenous BDNF induces a lasting potentiation of synaptic efficacy in the dentate gyrus of anesthetized adult rats.

Influence of raphe nuclei on neuronal transmission from perforant pathway through dentate gyrus

1980 ◽  
Vol 44 (5) ◽  
pp. 937-950 ◽  
Author(s):  
J. Winson
Keyword(s):  
Dentate Gyrus ◽  
Delay Time ◽  
Molecular Layer ◽  
Raphe Nuclei ◽  
Perforant Path ◽  
Perforant Pathway ◽  
Minimum Delay ◽  
Neuronal Transmission ◽  
Raphé Nuclei ◽  
Minimum Delay Time

1. In chronically prepared, freely moving rats, electrical stimulation was applied to the perforant pathway and monosynaptic responses were recorded extracellularly in the ipsilateral dentate gyrus. In some tests a stimulus was also applied to the median raphe nucleus (mr) prior to activating the perforant pathway. Experiments were performed during two behavioral conditions: slow-wave sleep (SWS) and the still, alert state (SAL). Two varieties of evoked responses were recorded: those due to synchronous firing of neuronal action potentials (evoked action potentials or EAPs) and those produced by excitatory synaptic activity (evoked synaptic potentials or ESPs). 2. As reported previously (38), perforant path stimulation elicited EAPs of greater magnitude during SWS than during SAL. The application of a prior stimulus to mr (prestimulation) markedly increased the already elevated EAPs observed during SWS. The EAPs during SAL were unaffected by prestimulation. 3. The minimum delay time (time between mr and perforant path stimuli) at which the augmentation of the EAPs appeared during SWS was approximately 5 ms. The augmentation reached a maximum at delay times of 25-40 ms and was present up to a delay time of 150 ms. 4. As in former experiments (38), ESPs recorded in the molecular layer of the dentate gyrus after perforant path stimulation were found to be greater during SAL than during SWS. Prestimulation of mr had no significant effect on the ESPs at any level of the molecular layer during either SWS or SAL. 5. The perforant path afferent volley was recorded at high gain in the dentate gyrus. Its amplitude was found to be solely dependent on perforant path stimulus intensity and not on behavioral state or the prestimulation of mr. 6. In preparations anesthetized with Chloropent (82% chloral hydrate, 18% pentobarbital; Fort Dodge Laboratories, Fort Dodge, IA), prestimulation was applied at each of a number of loci within the pons and medulla, including mr, As in SWS, prestimulating mr resulted in augmented EAPs with a minimum delay time of 5 ms. Similar augmented responses were observed when stimulation was applied at other raphe nuclei (dorsal raphe, pontis, magnus, and pallidus), but there was no augmentation when stimulation was applied at other brain stem sites. Threshold stimulus intensities for producing augmented EAPs in the raphe nuclei were less than 30 microA. 7. In freely moving animals it was first established that the EAP responses during SWS were markedly greater than during SAL. Midline lesions were then made at the rostrocaudal level of mr. Following the lesions, there was no longer any significant difference in the magnitude of the EAPs recorded during the two behaviors. 8. These findings suggest that tonic influences arising from raphe nuclei during SWS may be involved in the facilitation of neuronal transmission through the dentate gyrus observed during this behavioral state.

scholarly journals Somatostatin-positive interneurons in the dentate gyrus of mice provide local- and long-range septal synaptic inhibition

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Mei Yuan ◽  
Thomas Meyer ◽  
Christoph Benkowitz ◽  
Shakuntala Savanthrapadian ◽  
Laura Ansel-Bollepalli ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Spatial Information ◽  
Molecular Layer ◽  
Activity Patterns ◽  
Long Term Potentiation ◽  
Medial Septum ◽  
Perforant Path ◽  
Term Potentiation ◽  
Memory Acquisition

Somatostatin-expressing-interneurons (SOMIs) in the dentate gyrus (DG) control formation of granule cell (GC) assemblies during memory acquisition. Hilar-perforant-path-associated interneurons (HIPP cells) have been considered to be synonymous for DG-SOMIs. Deviating from this assumption, we show two functionally contrasting DG-SOMI-types. The classical feedback-inhibitory HIPPs distribute axon fibers in the molecular layer. They are engaged by converging GC-inputs and provide dendritic inhibition to the DG circuitry. In contrast, SOMIs with axon in the hilus, termed hilar interneurons (HILs), provide perisomatic inhibition onto GABAergic cells in the DG and project to the medial septum. Repetitive activation of glutamatergic inputs onto HIPP cells induces long-lasting-depression (LTD) of synaptic transmission but long-term-potentiation (LTP) of synaptic signals in HIL cells. Thus, LTD in HIPPs may assist flow of spatial information from the entorhinal cortex to the DG, whereas LTP in HILs may facilitate the temporal coordination of GCs with activity patterns governed by the medial septum.

Dynamics of Electrosensory Feedback: Short-Term Plasticity and Inhibition in a Parallel Fiber Pathway

2002 ◽  
Vol 88 (4) ◽  
pp. 1695-1706 ◽  
Author(s):  
John E. Lewis ◽  
Leonard Maler
Keyword(s):  
Pyramidal Neurons ◽  
Molecular Layer ◽  
Parallel Fiber ◽  
Weakly Electric Fish ◽  
Short Term ◽  
Stimulus Interval ◽  
Simple Description ◽  
Feed Forward ◽  
Synaptic Dynamics ◽  
Feed Forward Inhibition

The dynamics of neuronal feedback pathways are generally not well understood. This is due to the complexity arising from the combined dynamics of closed-loop feedback systems and the synaptic plasticity of feedback connections. Here, we investigate the short-term synaptic dynamics underlying the parallel fiber feedback pathway to a primary electrosensory nucleus in the weakly electric fish, Apteronotus leptorhynchus. In open-loop conditions, the dynamics of this pathway arise from a monosynaptic excitatory connection and a disynaptic (feed-forward) inhibitory connection to pyramidal neurons in the electrosensory lateral line lobe (ELL). In a brain slice preparation of the ELL, we characterized the synaptic responses of pyramidal neurons to short trains of electrical stimuli delivered to the parallel fibers of the dorsal molecular layer. Stimulus trains consisted of 20 pulses, at either random intervals or constant intervals, with varying mean frequencies. With random trains, pyramidal neuron responses were well described by a single exponential function of the inter-stimulus interval—suggesting a single facilitation-like process underlies these synaptic dynamics. However, responses to periodic (constant interval) trains deviated from this simple description. Random and periodic stimulus trains delivered when the feed-forward inhibitory component of this pathway was pharmacologically blocked revealed that inhibition and depression also contribute to the observed dynamics. We formulated a simple model of the parallel fiber synaptic dynamics that provided an accurate description of our data. The model dynamics resulted from a combination of three distinct processes. Two of the processes are the classically-described synaptic facilitation and depression, and the third is a novel description of feed-forward inhibition. An analysis of this model suggests that synaptic pathways combining plasticity with feed-forward inhibition can be easily tuned to signal different types of transient stimuli and thus lead to diverse and nonintuitive filtering properties.

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