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PubMed1987

Increased inhibition in dentate gyrus granule cells following exposure to GABA-uptake blockers.

Rats anesthetized with urethane had stimulating and recording electrodes placed in the perforant pathway and in the dentate gyrus. They were then exposed to increasing doses of either the vehicle control dimethylsulfoxide (DMSO) or one of two gamma-aminobutyric acid (GABA)-uptake blockers (SKF-100330A or SKF-89976A). Analysis of evoked field potentials from dentate granule cells indicated that the only effect of the GABA uptake blockers was to increase the threshold for evoking the field population spikes (PS). No other measure of excitatory postsynaptic potentials (EPSPs) or PS's were significantly affected. The lack of effect on evoked EPSP by these drugs suggests no direct effect on transmitter release at this synapse, while the increase in PS threshold suggests a slight decrease in granule cell excitability. The effects of the two GABA-uptake blockers on synaptically mediated facilitation and inhibition was tested by using paired-pulse paradigms. Both GABA-uptake blockers increased early GABA-mediated inhibition to a greater extent than they reduced synaptically mediated facilitation. Neither GABA uptake blocker appeared to effect the late inhibition seen at paired-pulse intervals of 400-1000 ms which is presumably associated with calcium-activated increases in potassium conductance. These effects on granule cell responses occurred at doses found previously not to be associated with side effects and yet to be anticonvulsant in unanesthetized rats. These data confirm in vivo that SKF-100330A and SKF-89976A increase GABA-mediated inhibition. The effect on granule cell excitability and late inhibition are minimal. Although facilitation was reduced by exposure to these drugs, the mechanism of this reduction (direct or prolongation of early inhibition) cannot be determined.

Animals↗
PubMed1988

Long-term potentiation in the dentate gyrus is preferentially induced at theta rhythm periodicity.

In urethane-anesthetized rats, high frequency stimulation was applied to the medial perforant pathway at various time intervals (50, 100, 200, 350 and 500 ms) following stimulation of the same pathway by a single pulse of equal intensity. Recordings of dentate gyrus granule cell evoked responses were made to investigate the range of stimuli that are effective in inducing long-term potentiation (LTP). LTP was induced almost exclusively at the 200 ms interval, corresponding to the periodicity of the theta rhythm. Taken in conjunction with similar findings reported in the CA1 field of the hippocampal slice, these results suggest that the correlation between theta rhythm periodicity and LTP is a general phenomenon within the hippocampal formation and lends further support to the hypothesis that the naturally occurring theta rhythm may play a modulatory role in the induction of LTP.

Action Potentials↗
PubMed1988

Long-term potentiation in the dentate gyrus is induced preferentially on the positive phase of theta-rhythm.

Long-term potentiation (LTP), a long lasting enhancement of synaptic efficacy is considered a model for learning and memory. In anesthetized rats, theta-rhythm was induced in the dentate gyrus by midbrain stimulation. Short trains of pulses were applied to the perforant pathway either at the peak of theta-rhythm or its trough. Trains applied at the peak of theta-rhythm induced LTP while trains applied at the trough produced a decrease of synaptic efficacy or had no effect. Thus, theta-rhythm may play a modulating role in the induction of LTP, suggesting a possible mnemonic function for the rhythm during the behaviors in which it occurs.

Animals↗
PubMed1990

In vivo intracellular analysis of rat dentate granule cells.

In vivo intracellular recordings and dentate EEG were obtained in urethanized-curarized rats. Granule cells (GCs) were identified by antidromic activation as well as by intracellular staining with Lucifer yellow (LY). GCs fired spikes which, in 43.6% of the cases, had brief post-hyperpolarization. Slow spikes were recorded at hyperpolarized levels during the rebound of hyperpolarizing pulses or during inhibitory postsynaptic potentials (IPSPs). Medial septal nucleus or perforant pathway stimulation evoked an excitatory postsynaptic potential (EPSP)-IPSP sequence. During theta (theta) rhythm, the membrane potential of 80.3% of the GCs showed rhythmic sine-like waves of up to 15 mV at a theta frequency which were phase-locked with extracellular theta. GCs were classified into 3 types: type 1 (67.1%) showed intracellular theta and rhythmic firing; type 2 (13.2%) revealed intracellular theta and random firing, but spikes tended to occur at a preferred phase of the dentate theta; and type 3 (19.7%) had neither intracellular theta nor rhythmic firing. Intracellular theta amplitude was wider during injection of the hyperpolarizing current and narrower during depolarizing ones, indicating that rhythmic EPSPs contribute to theta genesis. Intracellular theta was unaffected by Cl- or Cs+ diffusion, suggesting that IPSP is not essential to theta genesis.

Action Potentials↗
PubMed1990

Effects of prenatal protein malnutrition on perforant path kindling in the rat.

Rats born to dams fed either a 6% (malnourished) or 25% (control) casein diet during gestation were all fostered to lactating dams on the 25% casein diet 24 h after birth and were maintained on this diet throughout life following weaning. At 90-120 days of age electrographic and behavioral responses to electrical kindling of the medial perforant pathway were investigated in animals from both the straight 25% diet (designated 25%/25% for the pre- and postnatal periods) and the dietary rehabilitated (designated 6%/25% casein diet for the pre- and postnatal periods) groups. Animals of the dietary rehabilitated group (6%/25%) were found to: (1) require a significantly lower stimulus intensity to evoke afterdischarge activity in the ipsilateral dentate gyrus; (2) progress through the various behavioral stages of kindling in a markedly different manner from the 25%/25% group, and; (3) require significantly more daily kindling stimulations to attain the full motor convulsive stage indicative of the kindled state. These results indicate that dietary protein rehabilitation at birth is incapable of reversing or significantly ameliorating the effects of gestational protein deficiency on susceptibility to seizure activity and acquisition of the kindled state. These findings indicate that gestational protein deficiency results in long-lasting, if not permanent, changes in neuronal systems in the hippocampal formation which are involved in both the electrographic and behavioral correlates of the kindling process.

Animals↗
PubMed1990

Effects of MK-801 upon local cerebral glucose utilisation in conscious rats following unilateral lesion of caudal entorhinal cortex.

Local cerebral glucose utilisation was examined in 62 discrete regions of conscious rats following unilateral ibotenic acid lesion of the caudal entorhinal cortex, and subsequent pharmacological challenge with (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. Fourteen days after unilateral lesion of the entorhinal cortex, there were no significant alterations in local cerebral glucose use except within the lesioned entorhinal cortex (reduced by 31% compared to sham-operated control animals). In sham-operated animals, systemic administration of MK-801 (0.5 mg/kg, i.v.) induced anatomically organised alterations in glucose use with increases in olfactory areas, subicular complex and some limbic areas (posterior cingulate cortex, mammillary body and anteroventral thalamic nucleus), and decreases in the inferior colliculus and neocortex (auditory, sensory-motor, somatosensory and frontal cortices). In animals with unilateral entorhinal cortex lesions, the metabolic response to MK-801 differed significantly from the response to the drug in sham-lesioned animals in a number of regions, viz. hippocampus, molecular layer (ipsilateral to lesion), entorhinal cortex (ipsilateral), dentate gyrus (ipsilateral), presubiculum (bilateral), parasubiculum (bilateral) and nucleus accumbens (bilateral). The ability of MK-801 to reduce glucose use in the neocortex was not altered by entorhinal cortex lesion. These data suggest that the functional consequences of non-competitive NMDA receptor blockade are dependent in some areas upon the integrity of the perforant pathway from the entorhinal cortex to the hippocampus.

Animals↗
PubMed1990

Glutamate and glycine induce a negative wave on hippocampal field response through NMDA receptors.

In rats under urethane anesthesia, iontophoresis of large amounts (30-300 nA) of glutamate in the hippocampus induced a negative wave on the field potential evoked by stimulation of fimbria/commissura or perforant pathway. The amplitudes of the negative waves ranged between 0.2 and 9.8 mV and their mean duration was 341 +/- 12 ms. This activity was antagonized by iontophoresis of N-methyl-D-aspartate (NMDA) antagonists: Mg2+ (80-100 nA), ketamine (50-150 nA), MK-801 (50-150 nA) and by systemic ketamine (5 mg/kg, i.v.) administration. Iontophoresis of N-methyl-DL-aspartate (NMDLA) (20-40 nA) and glycine (25-100 nA) also elicited a negative wave which was blocked by NMDA antagonists. The negative waves were induced in all hippocampal layers except the dentate hilus by glutamate, NMDLA and glycine. Pyramidal regions were found to be as sensitive as dendritic layers; the mean amplitudes of glutamate-induced negative waves on the field response were 4.1 +/- 0.6 and 4.2 +/- 0.5 mV for CA1 stratum pyramidale and radiatum, respectively. These data suggest that large amounts of glutamate activate NMDA receptor/ion channels causing appearance of a long-lasting negative wave on the hippocampal field response. The data also demonstrate that glycine leads to a significant participation of NMDA receptors during glutamatergic transmission which is largely mediated through non-NMDA receptors.

Animals↗
PubMed1990

Effects of protein undernutrition on the dentate gyrus in rats of three age groups.

The effect of an 8% casein and a control 25% casein diet on the granule cells in the dorsal blade of the dentate gyrus of the rat hippocampal formation was studied at 30, 90 and 220 days of age. Female rats were fed either an 8% or 25% casein diet 5 weeks prior to conception and the litters were maintained on these respective diets until killed. In rapid-Golgi-impregnated cells, we measured major and minor axes of the soma of the dentate granule neurons, the number of spines on 50-microns segments of proximal, middle and terminal regions of the largest dendrite per granule cell and the number of dendrites intersecting 8 concentric rings 38 microns apart. At all 3 ages studied undernourished rats showed, when compared to controls, significant reductions of the major and minor axes of the somata and significant reductions in the number of spines on dendrites in the middle and terminal dendritic segments. Dendritic branching was significantly reduced in undernourished rats compared to controls in all but the 4th concentric rings, with the greatest effect being seen on the outer 3 concentric rings at 90 and 220 days of age. The location of the deficit in dendritic synaptic spines and the greatest deficit in dendritic branching correspond to the sites of termination of the lateral and medial perforant pathway projection to the dentate gyrus on the terminal and middle dendritic segments of the granule cells. The deficits noted in the granule cells of the dentate gyrus in this study were more severe than those found in our previous studies on the effect of the low protein diet in these same rats on visual cortical pyramidal cells and on the 3 cell types in the nucleus raphe dorsalis and nucleus locus coeruleus.

Analysis of Variance↗
PubMed1991

Postsynaptic and presynaptic effects of the calcium chelator BAPTA on synaptic transmission in rat hippocampal dentate granule neurons.

When applied to rat hippocampal slices, the permeable calcium chelator, BAPTA-AM, caused a reduction of both post-spike train slow afterhyperpolarizations (AHPs) and spike-frequency adaptation in dentate granule cells. This indicated that BAPTA-AM can, like microinjected EGTA, block calcium-activated potassium channels. At perforant pathway synapses, BAPTA-AM caused a reduction of inhibitory postsynaptic potentials (IPSPs) and an initial increase and later decrease of excitatory postsynaptic potentials (EPSPs). The initial increase in EPSPs may be caused by presynaptic spike-broadening owing to inhibition of calcium-activated potassium channels which normally regulate the duration of the presynaptic action potential. These channels may be affected at lower doses of chelator than synaptic transmitter release. BAPTA salt injected into individual dentate granule cells caused, as expected, decreased AHPs and spike-frequency adaptation. Also, paradoxically, both excitatory and inhibitory synaptic potentials were increased although input resistance was not.

Action Potentials↗
PubMed1991

An alpha 2 antagonist, idazoxan, enhances EPSP-spike coupling in the rat dentate gyrus.

The effect of the alpha 2 antagonist, idazoxan (IDA), on the excitability of neurons in the dentate gyrus of the hippocampus was studied. Population field potentials (PS) evoked by stimulation of the perforant pathway were measured before and after drug treatment. IDA enhanced the amplitude of the PS, while decreasing the slope of the EPSP. Neurotoxic destruction of noradrenergic nerve terminals completely abolished the IDA effect, arguing that its mechanism of action is through enhanced release of noradrenaline (NA). It is proposed that NA enhances the EPSP-to-spike coupling component of the PS.

Adrenergic alpha-Antagonists↗
PubMed1991

The influence of long-term potentiation on the spatial relationship between astrocyte processes and potentiated synapses in the dentate gyrus neuropil of rat brain.

The influence of long-term potentiation (induced by repeated high-frequency stimulation of the perforant pathway) on the distribution pattern of astrocyte processes in the neuropil of the hippocampal dentate area containing the potentiated synapses was investigated by quantitative electronmicroscopy. It has been found that significant changes occurred in the ramification of astrocyte processes as well as in their topographic relation to synaptic complexes. When comparing the results obtained in LTP animals with active control or sham-operated animals, we found significant higher numerical density, but smaller volume, higher surface density and closer apposition of astrocyte processes to the synaptic clefts, boutons terminaux or spines in the potentiated synapses containing neuropil. The glial reaction to synaptic activation has been seen most pronounced 8 h after the LTP induction. The results are pointing to a participation of the glia cells in the maintenance of the LTP effect as well as to a metabolic coupling between synaptic transmission and glia function for equilibrating the homeostasis by clearing the extracellular space next to the transmission zones.

Animals↗
PubMed1992

Long-term potentiation is associated with increased [3H]AMPA binding in rat hippocampus.

The location and nature of the changes underlying long-term potentiation (LTP) remain controversial issues. In this study, we tested the possibility that changes in binding properties of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA/quisqualate and N-methyl-D-aspartate (NMDA) subtype of glutamate receptors are associated with LTP. LTP was elicited in vivo by stimulation of the perforant pathway in anesthetized rats. One hour following stimulation the animals were sacrificed. We performed quantitative ligand binding autoradiography on frozen brain sections using [3H]AMPA and [3H]N-(1-(2-thienyl)cyclohexyl)-3,4-piperidine ([3H]TCP) to label the AMPA/quisqualate and the NMDA receptors, respectively. No changes in [3H]TCP binding were detected in any of the treatment groups. However, increases in [3H]AMPA binding were observed only in animals that exhibited LTP. These increases were bilateral and present in several subfields of the hippocampus and cortical areas. Administration of the NMDA receptor antagonist, ketamine, prior to tetanic stimulation prevented both the increase in binding and the induction of LTP. These results suggest that changes in the characteristics of AMPA/quisqualate receptors are a biochemical correlate of LTP.

Analysis of Variance↗
PubMed1992

Hippocampal pyramidal cell response to 6-hydroxydopamine lesions of the rat ventral tegmental area.

The occurrence of neurofibrillary tangles (NFT) in the perforant pathway in association with dopaminergic cell loss in the ventral tegmental area (VTA) in human mesolimbic dementia, raises the possibility that denervation is a cause of NFT formation. This was tested in the rat by lesioning dopaminergic neurons which project to the hippocampus from the ventral tegmental area by means of stereotaxic injections of 6-hydroxydopamine. This resulted in the appearance of immunoreactivity to the paired helical filament protein plus an increase of tau and MAP-2 proteins in pyramidal neurons of CA-1 and CA-2. These neuronal responses to dopaminergic denervation are consistent with a precursor stage to NFT development.

Animals↗
PubMed1993

Preservation of hippocampal NMDA receptors may be crucial for spatial learning after epileptic seizures in rats.

Sustained electrical stimulation of the perforant pathway (PP) was used to induce hippocampal seizures in conscious rats. About 4.5 h prior to stimulation, animals were given i.p. injections of either saline or CGP 39551 (10 mg/kg), a competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. When tested 2 weeks later in water maze, the saline pretreated rats showed a severe impairment in spatial learning whereas the animals treated with CGP 39551 had the same escape latencies as the non-stimulated controls. Histological evaluation of cellular degeneration revealed that the number of somatostatin-immunoreactive (SOM-IR) neurons in both stimulated groups was reduced almost equally, but in the CGP 39551 treated animals pyramidal cell damage was partly protected. However, in contrast to the placebo group, NMDA-sensitive [3H]glutamate binding in strata radiatum and oriens of the CA1 area was not significantly reduced in the CGP 39551 group. Thus, the present results suggest that the CGP 39551 treatment was able to protect against the delayed phase of the excitotoxic cell damage, and that the preservation of NMDA receptors partly accounts for the good learning ability of the CGP 39551 pretreated, PP-stimulated rats.

2-Amino-5-phosphonovalerate↗
PubMed1993

Increased sensitivity to adenosine in the rat dentate gyrus molecular layer two weeks after partial entorhinal lesions.

The molecular layer of the dentate gyrus exhibits extensive circuit and receptor reorganization after entorhinal lesions and in Alzheimer's disease, including decreased adenosine (A1) receptor binding in the terminal zone of damaged perforant path fibers. We examined the adenosine-sensitivity of evoked synaptic activity recorded from the rat dentate gyrus molecular layer in hippocampal slices prepared after electrolytic lesions were placed in approximately the middle third of the entorhinal cortex. Extracellular field potentials (EFPs) recorded in slices prepared from animals two days post-lesion were small, upward-going, and exhibited paired-pulse potentiation, but by two weeks post-lesion EFPs had recovered to large, downward-going responses that exhibited paired-pulsed depression. EFPs recorded from two week post-lesion slices were about 2-fold more sensitive (P < or = 0.05) to exposure to adenosine when compared to EFPs recorded from slices from unlesioned animals. Adenosine-induced reduction of paired-pulse depression was similar between unlesioned and post-lesion slices. AChE histochemistry performed after recording revealed dense staining in the dentate gyrus molecular layer of post-lesion slices as compared to slices from unlesioned animals, confirming that sprouting of cholinergic fibers occurred as expected from previous entorhinal lesion studies. Autoradiography performed on adjacent slices showed a decrease in binding to A1-adenosine receptors in the dentate gyrus molecular layer in post-lesion slices as compared to slices from unlesioned animals, indicating that there was a loss of presynaptically located A1-adenosine receptors on damaged perforant pathway terminals. These results indicate that, in addition to the recovery of the major excitatory signal to the hippocampus after entorhinal cell loss, this signal is more sensitive to modulation by adenosine, suggesting an increase in A1-adenosine receptor efficacy in the reinnervated region.

Acetylcholinesterase↗
PubMed1993

Effect of protein malnutrition on CA3 hippocampal pyramidal cells in rats of three ages.

Prenatal and postnatal protein deprivation effects on CA3-hippocampal pyramidal cells were investigated in 30-, 90- and 220-day-old rats. Female rats were fed either a 6% or a 25% casein diet 5 wk before conception and the litters were maintained on their respective diet until sacrificed. In 216 rapid Golgi-impregnated cells, we measured somal size, length and diameter of apical dendrite, number of apical dendrites intersecting 10 concentric rings 38 microns apart, thorny excrescence area and length, head diameter and density of synaptic spines on 50-microns segments of apical dendrite. The present experiments showed that malnutrition produced significant reductions of somal size in animals at 220 days of age. There were significant reductions of apical dendrite diameters in animals of 30 and 90 days, and of density and head diameter of synaptic spines at the three ages studied, and significant decrease of the thorny excrescence area at 220 days of age. At this latter age, dendritic branching was significantly decreased in the last four rings representing the area into which the perforant pathway projects. In 30-day malnourished rats, dendritic branching showed a significant increase in rings 4-6 representing the area in which the Schaffer collaterals synapse. The location of the deficit in dendritic spines corresponds to the sites where mossy fibers synapse on the apical dendrites of CA3 neurons. Age-related changes normally observed in control rats (e.g., the 30-day-old control group showed the smallest somal size and 220-day-old controls the largest size) failed to occur in the malnourished rats. The deficits in spine density and dendritic branching (in animals of 220 days old) were similar to those found in our previous studies on fascia dentata.

Animals↗
PubMed1994

Direct measurement of glutamate release in the brain using a dual enzyme-based electrochemical sensor.

The in vivo measurement of the rapid changes in the extracellular concentrations of L-glutamic acid in the mammalian brain during normal neuronal activity or following excessive release due to episodes of anoxia or ischemia has not been possible to this date. Current techniques for the measurement of the release of endogenous glutamate into the extracellular space of the central nervous system are relatively slow and do not measure the actual concentration of free glutamate in the extracellular space. An enzyme-based electrode with rapid response times (about 1 s) and high degree of sensitivity (less than 2 microM) and selectivity for L-glutamic acid is described in this paper. This electrode has both L-glutamate and ascorbate oxidase immobilized on its surface. The latter enzyme removes almost completely any interferences produced by the high levels of extracellular ascorbate present in brain tissue. The response of the electrode to glutamate and other potentially interfering substances was fully characterized in vitro and its selectivity, sensitivity and rapidity in responding to a rise in extracellular glutamate concentrations was also demonstrated in vivo. Placement of the electrode in the dentate gyrus of the hippocampus led to the detection of both KCl-induced release of L-glutamic acid and the release induced by stimulation of the axons in the perforant pathway. The development of this selective, sensitive and rapidly responding glutamate sensor should make it now possible to measure the dynamic events associated with glutamate neurotransmission in the central nervous system.

Animals↗
PubMed1994

Synapse alterations in the hippocampal-entorhinal formation in Alzheimer's disease with and without Lewy body disease.

We quantified by microdensitometry the immunoreactivity (IR) to monoclonal antibodies (SP6, SP12, SP15 and SP18) against various synaptic proteins in the molecular layers of the dentate gyrus, CA4, CA3, CA1, subiculum and entorhinal cortex in Alzheimer's disease (AD), Lewy body variant of AD (LBV) and diffuse Lewy body disease (DLBD). A significant decrease in SP6 IR was observed in almost all regions in AD (28.4-70.1%, mean 41.3%), LBV (19.0-42.5%, mean 26.8%) and DLBD (19.9-31.7%, mean 27.1%) compared to controls. In addition, SP6 IR in the outer molecular layer of the dentate gyrus was strongly correlated with tangle count in the entorhinal cortex (r = -0.70, P < 0.002), suggesting loss of perforant pathway projection. Although the decrease in SP12 and SP15 IR was less pronounced, the mean values were decreased in dementia. Furthermore, SP12 and SP15 labeled a large number of neuritic plaques, and SP15 occasionally stained cortical LBs. The present findings indicate (i) that in the hippocampal-entorhinal formation, the decrease of synapse protein IR in AD is more severe than that in LBV and DLBD, (ii) that synaptic markers detect a subset of dystrophic neurites in the plaques and (iii) that synapse proteins are involved in the formation of cortical LBs.

Aged↗