Differential paired-pulse effects of gabazine and bicuculline in rat hippocampal CA3 area

Field potentials were evoked in hippocampal area CA3 of anaesthetised rats by commissural stimulation, in order to study the effect of the prototypic gamma-aminobutyric acid (GABA)A antagonists gabazine (SR-95531; GBZ) and bicuculline methiodide (BMI) on paired-pulse interaction. Prominent paired-pulse inhibition of the orthodromic population spike (PS2) was observed when the interpulse interval (IPI) was < or = 40 ms, while facilitation occurred at IPIs >100 ms. Paired-pulse facilitation was lost at 500 ms. The antidromic population spike (PS1) presented paired-pulse facilitation at low-IPI, which decayed exponentially at increasing IPI. When the recording micropipettes contained millimolar concentrations of either GBZ, or BMI, single stimuli evoked repetitive (epileptiform) orthodromic PS2, of higher amplitude, while the antidromic PS1 was only weakly influenced. BMI reduced, but GBZ enhanced the low-IPI paired-pulse inhibition of the orthodromic PS2. Furthermore, BMI blunted paired-pulse facilitation of the antidromic PS1 at low-IPI, while GBZ caused strong paired-pulse inhibition of PS1 at IPI < or = 60 ms. The differential effects of GBZ and BMI on paired-pulse interaction might reflect different mechanisms of action of these compounds.     

Prenatal protein malnutrition alters behavioral state modulation of inhibition and facilitation in the dentate gyrus.

We have examined the effects of prenatal protein malnutrition on interneuronally mediated inhibition and facilitation in the dentate gyrus of the rat using the paired-pulse technique. Field potentials were recorded in the dentate gyrus in response to paired stimuli delivered to the perforant path. The paired-pulse index (PPI) was used as a measure of the net short-term facilitation or interneuronally mediated inhibition effective at the time of the paired-pulse test and was computed by dividing the amplitude of the second population spike (p2) by the amplitude of the first population spike (p1). PPIs were classified according to p1 in order to compare PPIs between behavioral states and dietary treatments since population spike amplitudes in the dentate gyrus vary in relation to behavioral state. Testing was performed during 4 behavioral states: slow-wave sleep (SWS), paradoxical sleep (REM), immobile waking (IW) and exploratory locomotion (AW) using interpulse intervals (IPI) from 20 to 400 ms. The magnitude and duration of interneuronally mediated inhibition was significantly increased in prenatal protein malnourished animals when compared with controls. Paired-pulse tests performed using an IPI of 20 ms under the high p1 (p1 greater than median) condition showed significantly smaller PPIs in prenatal protein malnourished rats regardless of behavioral state. For IPIs greater than 20 ms PPIs were consistently smaller in prenatal protein malnourished rats during SWS and IW. These data indicate that both the magnitude and duration of interneuronally mediated inhibition are increased in prenatally malnourished rats. No consistent diet-related differences were found during AW and REM using IPIs greater than 20 ms because interneuronally mediated inhibition was relatively suppressed during these behavioral states for both dietary groups. There was no consistent behavioral state modulation of paired-pulse facilitation (IPI = 40 to 80 ms) or late inhibition (IPI = 400 ms) in either diet group. In addition, a new relation between PPI and IPI was found under the low p1 (p1 greater than median) condition. During AW the PPIs observed using IPIs of 40 and 50 ms were smaller than those observed using IPIs of 30 and 60 ms. This depression interrupts what is generally considered the "facilitatory" phase of paired-pulse response and may indicate an interaction between perforant path stimulation and hippocampal theta rhythm which is masked when p1 amplitude is high.(ABSTRACT TRUNCATED AT 400 WORDS)     

A comparison of the ontogeny of excitatory and inhibitory neurotransmission in the CA1 region and dentate gyrus of the rat hippocampal formation.

In vivo electrophysiological experiments were used to chart the ontogeny of excitatory and inhibitory neurotransmission in the hippocampal formation of rats. Using standardized protocols, responses in the dentate gyrus were quantified and systematically compared to similar measurements obtained in the CA1 region. Measurements were taken at numerous ages, ranging from postnatal day (PN) 6 to adults (PN 60). Excitation was monitored by two parameters recorded with extracellular electrodes in response to monosynaptic inputs to CA1 pyramidal cells or to dentate gyrus granule cells: maximum population spike (PSmax) amplitudes and maximum population excitatory postsynaptic potential slopes (pEPSP slopemax). Inhibition was assessed by a paired-pulse protocol to measure maximal inhibition (the potency of inhibition at an interpulse interval of 20 ms) and duration of inhibition (the interpulse interval at which paired-pulse inhibition changed to paired-pulse facilitation). Excitatory parameters matured later in the dentate gyrus than in CA1, consistent with the later appearance of granule cells. Until PN 21, pEPSPmax values in the dentate gyrus paralleled those in CA1; thereafter they diverged with far larger values in the dentate gyrus. Inhibitory parameters reached adult values between PN 14 and 18. In both regions paired-pulse responses consisted of three phases: (1) an initial inhibition; (2) a second facilitatory phase; and (3) a later inhibition. The maximal inhibition in the initial phase was comparable in both regions, but lasted longer in the CA1 region. The facilitation in the second phase was greater in the dentate gyrus, and the inhibition in the third phase was greater in the dentate gyrus. Results are discussed in terms of neurogenesis of principal cells and GABAergic cells in the regions of interest.     

Regulation of synaptic plasticity by mGluR1 studied in vivo in mGluR1 mutant mice

The role of the metabotropic glutamate receptor 1 (mGluR₁) in synaptic plasticity was investigated in vivo in the intact hippocampus of mutant mice lacking this receptor. In a previous study we showed reduced long-term potentiation (LTP) in the dentate gyrus of mGluR₁ −/− mice in vivo, but not when LTP was studied in a slice preparation. A possible explanation of this difference is that dentate neurons receive more inhibitory synaptic drive in vivo than in slice preparation where many inhibitory axon collaterals are lost. We report here that another form of synaptic plasticity, paired-pulse depression of the population spike, is also abnormal in the dentate gyrus of mGluR₁-deficient mice when tested in vivo. In wild-type mice, stimulation of the medial perforant path produced paired-pulse depression of inter-pulse intervals (IPIs) up to 30 ms. Mutant mGluR₁, on the other hand, showed a significantly longer IPI depression, up to 50 ms. Paired-pulse depression results from the activation of inhibitory interneurons. The GABA_B agonist baclofen, acting presynaptically on the GABA interneurons, attenuated paired-pulse depression and allowed for a normal and stable LTP in mGluR₁ mutant mice. These findings suggest an indirect role for mGluR₁ in synaptic plasticity via a regulation of GABA inhibition.     

Impairment of long-term potentiation and paired-pulse facilitation in rat hippocampal dentate gyrus following developmental lead exposure in vivo

Neonatal rats were exposed to lead from parturition to weaning via the milk of dams drinking 0.2% lead acetate solution. The alterations of long-term potentiation (LTP) and paired-pulse facilitation (PPF) of hippocampal dentate gyrus in adult rats (90–115 days) following developmental lead exposure were studied in vivo. Input/output (I/O) function, paired-pulse facilitation (PPF), excitatory postsynaptic potential (EPSP) and population spike (PS) amplitude were measured in the dentate gyrus (DG) in response to stimulation applied to the lateral perforant path. The results showed that LTP was induced in control rats with an average PS potentiation of 321.1±50.0% (n=18), which was significantly greater than the increase in PS potentiation (173.5±30.0%, n=17, p<0.001) in lead-exposed rats after tetanizing stimulation. The mean EPSP potentiation increased to 172.4±27.0% (n=18) in control and 138.8±21.4% (n=17) in lead-exposed rats after tetanizing stimulation. The lead-induced impairment of LTP of PS potentiation was more serious than that of EPSP potentiation. Following pairs stimulation of perforant fiber at 250 μA and an interpulse interval (IPI) of 10–1000 ms, the average peak facilitation of PS was 211.3±25.0% (n=13) in control and 187.7±23.0% (n=11) in lead-exposed rats. The average facilitation period duration of PS was 243.0±35.8 ms (n=13) in control and 138.0±24.4 ms (n=11) in lead-exposed rats. These results suggested that developmental lead exposure in neonatal rats caused impairments in LTP and PPF of hippocampal dentate gyrus.     

Long-lasting reduction of dentate paired-pulse depression following LTP-inducing tetanic stimulations of perforant path

Effects of high-frequency stimulations of the perforant path on the dentate paired-pulse depression were examined in urethane-anesthetized rats. The tetanic stimulations produced a long-term potentiation (LTP) of the excitatory synaptic transmission at the perforant path-dentate granule cell synapses in almost all animals examined. The strength of the early paired-pulse depression at an inter-pulse interval (IPI) of 20 ms decreased significantly for at least 60 min after the tetanic stimulations, whereas the late paired-pulse depression at an IPI of 2 s remained almost unchanged. The reduction of the early paired-pulse depression was stepwise augmented by each of successive tetanic stimulations given at an interval of 10 min. A preceding antidromic stimulation of the mossy fibers depressed the population spike amplitude of perforant path response at an interval of 5-9 ms. The strength of the antidromic depression of population spike also decreased following the perforant path tetanic stimulations. These results suggest that tetanic stimulations of the perforant path produce a long-lasting reduction of the GABAergic recurrent inhibition in the dentate area associated with LTP. The possible mechanisms of the decrease in GABAergic inhibition produced by tetanic stimulations and its possible effects on the development of LTP with succeeding tetanic stimulations were discussed.     

Effects of bicuculline and baclofen on paired-pulse depression in the dentate gyrus of epileptic patients

Paired-pulse field responses were recorded from the granule cell layer of the dentate gyrus in brain slices from temporal lobe epileptic patients. Paired-pulse depression (PPD) was examined using perforant path stimulation of low to moderate intensity at an inter-stimulus interval (ISI) of 20 ms. The paired-pulse ratio (PS₂/PS₁) was expressed as the population spike amplitude of the second response (PS₂) relative to that of the first response (PS₁). Representative tissue responses from each patient biopsy were divided into two groups that were significantly different based on the magnitude of the highest paired-pulse ratio recorded for each biopsy specimen: the strong paired-pulse depression group (PS₂/PS₁ = 0.12 ± 0.03; n = 15) and the weak paired-pulse depression group (PS₂/PS₁ = 0.68 ± 0.06; n = 13). Paired-pulse ratios from the strong PPD group were relatively independent of stimulus intensity, whereas, PPD was dependent on stimulus intensity in the weak PPD group; i.e., PPD was greatest at the lowest intensity and reached a plateau at higher intensities. Bicuculline (20 μM) and low concentrations of baclofen (0.1–0.2 μM) reduced paired-pulse depression in the strong PPD group, but did not significantly change the paired-pulse ratio in the weak PPD group. Paired-pulse facilitation was observed in some cases after inhibition was blocked pharmacologically. The number of population spikes was increased in the presence of bicuculline but was unchanged by baclofen. In the strong PPD group, baclofen significantly altered the EPSP-population spike (E-S) relationship by increasing the slope of the relationship for the second response, without having an effect on the slope of the first response. Baclofen had no effect on the E-S relationship of either response in the weak PPD group. The data are consistent with (1) less inhibition in the weak PPD group compared to the strong PPD group, (2) reduction of feedback inhibition in the strong PPD group by bicuculline and by low concentrations of baclofen, and (3) the occurrence of paired-pulse facilitation when inhibition was pharmacologically reduced in the dentate gyrus of temporal lobe epileptic patients. The results are also consistent with the presence of GABA_B receptors on human inhibitory interneurons that, when activated by baclofen, result in disinhibition of granule cells through feedback circuits. Although inhibition may be compromised in some epileptic human biopsy specimens, the presence of strong inhibition in other patients' biopsy material suggests the re-evaluation of the role of inhibition in epilepsy.     

Monosynaptic activation of CA3 by the medial perforant path

The functional projection of the medial perforant path (MPP) to different CA3 subfields was studied in urethan-anesthetized rats using current source density analysis. MPP stimulation resulted in an early-latency (presumed monosynaptic) sink with onset of 2–3 ms at the distal apical dendritic layer of CA3 (stratum lacunosum molecule) and a long-latency (presumed disynaptic, >7 ms) sink at stratum lucidum and radiatum of CA3. The population spike (onset 5.3–6.1 ms), a sink at CA3 pyramidal cell layer, was observed 67% of the time (12 of 18 rats) in CA3a, 44% (8 of 18) in CA3b and 58% (7 of 12 rats) in CA3c following MPP stimulation. Population spike was not observed during presumed disynaptic excitation of CA3. Both early-latency sink (excitatory postsynaptic potential) and population spike in CA3 revealed robust paired-pulse facilitation (PPF). In contrast, little PPF was found for the MPP-evoked excitatory sink at the middle molecular layer of the dentate gyrus. The data suggested that the entorhinal cortex provides a strong monosynaptic excitation of different subfields of CA3. A direct entorhinal to CA3 input bypasses the dentate gyrus and may play a role in normal hippocampal signal processing and neural plasticity.     

Weaker synaptic inhibition in CA1 region of ventral compared to dorsal rat hippocampal slices

Extracellular and intracellular recordings were made from slices taken from the dorsal (DH) and ventral (VH) part of rat hippocampus. Using paired-pulse stimulation of Schaffer collaterals, at different interpulse intervals (IPIs), and records of the population spike (PS) we found that the strength and duration of paired-pulse inhibition was much weaker in VH compared to DH slices: at the IPI of 10 ms the decrease of PS in VH (40%) was significantly smaller compared to that in DH slices (76%), while at 20 ms the decrease of PS in DH slices (60%) corresponded to facilitation in VH slices. Moreover, the amplitude and duration of intracellularly recorded fast inhibitory postsynaptic potentials (fast-IPSPs) were found significantly smaller in VH (5.2+/-0.6 mV, 54.8+/-5.8 ms) than in DH (11.2+/-1.1 mV, 105+/-10 ms) neurons. The smaller and shorter fast-IPSP recorded in VH neurons may at least in part explain the results in paired-pulse inhibition. The demonstrated weaker inhibition may underlie the higher propensity of the ventral hippocampus for epileptiform activity.     

A comparison of recurrent inhibition and of paired-pulse facilitation in hippocampal slices from normal and genetically epileptic mice.

Tottering mice exhibit inherited generalized epilepsy of the 'absence' type. In hippocampal slices from these mutant mice studied in vitro, pairing an alvear antidromic stimulus to an orthodromic one revealed a strong recurrent inhibition (RI) of CA1 pyramidal neurons. RI was maximal at 10 ms inter-pulse interval (IPI 70% decrease of population spike, PS) gradually decreasing to 15% at 320 ms IPI. At 10 ms IPI it shifted the input/output curves to the right and decreased maximum PS. In the group of slices from epileptic mice the early part of RI (2.5-60 ms) was indistinguishable from that of normal mice, with respect to both its strength and its liability to activity-dependent decrement induced by a train of antidromic stimuli (8 s, 5 Hz). However, the delayed part (80-320 ms) was slightly stronger in the epileptic group. Also in this group only the train of antidromic pulses caused a significant and lasting decrease in the unconditioned orthodromic PS. Paired-pulse facilitation was equally strong in the 2 groups of slices. It is concluded that mechanisms underlying epileptogenic hyperexcitability in the tottering mutant may not include a failure of inhibition, at least in the CA1 area of the hippocampus. On the contrary some inhibitory mechanisms may be stronger.     

Perinatal exposure to polychlorinated biphenyls alters excitatory synaptic transmission and short-term plasticity in the hippocampus of the adult rat

Developmental exposure to polychlorinated biphenyls (PCBs) has been associated with cognitive deficits in humans and laboratory animals. Previous work has demonstrated a reduced capacity to support long-term potentiation (LTP) in animals exposed to a PCB mixture, Aroclor 1254 (A1254) via the dam in utero and throughout the preweaning period [Brain Res. 850;1999:87-95; Toxicol. Sci. 57;2000:102-11]. Assessment of normalized input/output (I/O) functions collected prior to LTP induction failed to reveal consistent differences in baseline synaptic transmission between control and PCB-exposed groups. The present study was designed to systematically evaluate excitatory and inhibitory synaptic transmission using a more extensive I/O analysis and paired pulse functions to assess short-term plasticity. Pregnant Long-Evans rats were administered either corn oil (control) or 6 mg/kg per day of A1254 by gavage from gestational day (GD) 6 until pups were weaned on postnatal day (PND) 21. In adult male offspring (5-11 months of age), field potentials evoked by perforant path stimulation were recorded in the dentate gyrus under urethane anesthesia. Detailed I/O functions were assessed by averaging the responses evoked in the dentate gyrus to stimulus pulses delivered to the perforant path in an extensive ascending intensity series. Population spike (PS) and postsynaptic potential (PSP) amplitudes recorded in the dentate gyrus were significantly enhanced in PCB-exposed animals relative to controls at midrange intensities. No group differences were observed in EPSP slope amplitudes. Short-term plasticity was assessed by delivering pairs of stimulus pulses at interpulse intervals (IPIs) ranging from 10 to 70 ms. In the dentate gyrus this range of intervals activates both inhibitory and excitatory mechanisms leading to a pattern of depression at brief intervals (<30 ms) followed by facilitation as the interval between pulses is extended. Paired pulse depression was decreased at an intermediate IPI (30 ms) with submaximal stimulus intensities. These data augment previous work demonstrating persistent changes in hippocampal plasticity as a result of exposure to PCBs during development. Furthermore, as increases in field potential amplitudes were observed, these findings support previous conclusions that A1254-induced LTP deficits are not readily attributable to reductions in synaptic excitability. Thus, in addition to impairment in use-dependent synaptic plasticity reported previously, the present report reveals that basic components of information processing within the hippocampus are permanently altered as a result of perinatal exposure to PCBs.     

Interactions between septal and entorhinal inputs to the rat dentate gyrus: Facilitation effects

We examined facilitation effects between the medial septum and perforant path inputs to the dentate gyrus for the four possible combinations of paired-pulse activation. Facilitation effects occurred in all cases. The largest facilitation effects occurred when the septal pulse served as the conditioning pulse for the population spike subsequently evoked by a perforant path pulse. Using 3 pulses, we also examined the influence of septal activation on paired-pulse facilitation of the perforant path-granule cell population spike. A septal stimulation pulse, applied 6-10 ms prior to the onset of the population spike evoked by a perforant path conditioning pulse, did not affect the perforant path-dentate test response at any interpulse interval. If the septal pulse occurred immediately prior to population spike onset, however, there was a significantly greater depression of the test response from 70-3000 ms, but no effect at early intervals (20-50 ms). The effect of the septal pulse appears more consistent with a direct action of the septal terminals on granule cells than with an indirect action via the recurrent inhibitory interneurons.     

Excitability of rat dentate gyrus granule cells in vivo is controlled by tonic and evoked GABA(B) receptor-mediated inhibition

Tonic or evoked gamma-aminobutyric acid(B) (GABA(B)) receptor-mediated modulation of dentate gyrus excitability was evaluated in vivo in urethane-anesthetized rats. Two stimuli at an interpulse interval (IPI) of 10-9000 ms were given to the medial perforant path. Population excitatory postsynaptic potentials (pEPSPs) and population spikes (PSs) were recorded in the dentate gyrus using a glass micropipette or a multichannel silicon probe. The GABA(B) receptor antagonist CGP35348, delivered intracerebroventricularly (i.c.v.) or locally, caused a significant increase in the PS amplitude evoked by the first pulse (PS1) without an increase in either the slope or current sink of the population EPSP evoked by the first pulse (pEPSP1). The average spontaneous firing rate of putative granule cells was also increased following i. c.v. CGP35348. The PS evoked by the second pulse (PS2) relative to PS1 (PS2/PS1) was consistently suppressed at IPIs from 30 to 70 ms, even when PS1 was matched before and after CGP35348. CGP35348 increased PS1 mainly by blocking tonic postsynaptic GABA(B) receptors and decreased PS2 at 30-70 ms IPI by blocking presynaptic GABA(B) autoreceptors. These data suggest that GABA(B) receptors are tonically active in the dentate gyrus in vivo.     

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.     

Postsynaptic action potentials do not alter short-term potentiation in the dentate gyrus

The dendrites of neocortical neurons have been shown to support active action potentials which back-propagate from the soma after an output spike has been initiated. This observation has led to speculation that dendritic action potentials may participate in various forms of synaptic plasticity. The contribution of dendritic spikes to paired-pulse facilitation (PPF), a form of short-term plasticity, was investigated in the dentate gyrus of hippocampal slices. Paired orthodromic stimulation of the perforant path produced an average facilitation of the test population spike (PS) amplitude of 167% (n = 16, conditioning RESPONSE = 100%). There was also a small but significant increase in slope of the field EPSP (fEPSP) of 108%. To determine whether increased presynaptic drive could account for this facilitation, the relationship between fEPSP slope and spike amplitude (I-O) was determined for a range of stimulus intensities. An increase in fEPSP slope of 171% was associated with an increase in PS amplitude equal to the facilitation produced by paired-pulse stimulation (167%), suggesting a postsynaptic component in PPF. Electric field effects were then used as a tool to alter the excitability of granule cells during the conditioning response without changing synaptic drive. Any change in the test response associated with manipulation of the conditioning population spike amplitude would suggest that dendritic spikes may contribute to the postsynaptic component of PPF. Surprisingly, altering the number of neurons responding to the conditioning stimulus with an action potential had no effect on the test response, suggesting that dendritic action potentials do not participate in this form of short-term synaptic plasticity.     

Excitability of rat dentate gyrus granule cells in vivo is controlled by tonic and evoked GABAB receptor-mediated inhibition

Tonic or evoked γ-aminobutyric acid_B (GABA_B) receptor-mediated modulation of dentate gyrus excitability was evaluated in vivo in urethane-anesthetized rats. Two stimuli at an interpulse interval (IPI) of 10–9000 ms were given to the medial perforant path. Population excitatory postsynaptic potentials (pEPSPs) and population spikes (PSs) were recorded in the dentate gyrus using a glass micropipette or a multichannel silicon probe. The GABA_B receptor antagonist CGP35348, delivered intracerebroventricularly (i.c.v.) or locally, caused a significant increase in the PS amplitude evoked by the first pulse (PS1) without an increase in either the slope or current sink of the population EPSP evoked by the first pulse (pEPSP1). The average spontaneous firing rate of putative granule cells was also increased following i.c.v. CGP35348. The PS evoked by the second pulse (PS2) relative to PS1 (PS2/PS1) was consistently suppressed at IPIs from 30 to 70 ms, even when PS1 was matched before and after CGP35348. CGP35348 increased PS1 mainly by blocking tonic postsynaptic GABA_B receptors and decreased PS2 at 30–70 ms IPI by blocking presynaptic GABA_B autoreceptors. These data suggest that GABA_B receptors are tonically active in the dentate gyrus in vivo.     

Paired-pulse depression of excitatory postsynaptic current sinks in hippocampal CA1 in vivo

Paired-pulse depression (PPD), a short-term neural plasticity, was studied in hippocampal CA1 of urethane-anesthetized rats in vivo, using field potential recordings and current source density analysis. PPD was robust when an ipsilateral CA3 (iCA3) conditioning pulse of moderate stimulus intensity was followed 30-200 ms later by a contralateral CA3 (cCA3) test pulse; the ratio of the conditioned (C) to the nonconditioned (NC) response, as measured by the peak excitatory sink at the apical dendrites, ranged from 0.6 to 0.8. An alveus conditioning pulse evoked a large antidromic population spike in CA1 and a modest depression of the CA3-evoked excitatory sink (C/NC ratio of approximately 0.85). High-intensity paired pulses, both delivered to iCA3, also showed PPD of the proximal excitatory sinks; however, paired-pulse facilitation of the dendritic sinks was found at the mid-apical dendrites, >250 microm from the soma. Local injection of GABA(A) antagonist picrotoxin or bicuculline increased the C/NC ratio at IPIs of <150 ms, as well as the ratio of the amplitude of the population spikes (P2/P1; where P2 and P1 are the population spikes evoked by the second and first pulse, respectively). GABA(B) receptor antagonists, CGP35348 given intracerebroventricularly or CGP56999A administered locally, increased C/NC and P2/P1 at IPIs of 150-400 ms. It is concluded that conditioned depression of the excitatory sinks was caused by mainly feedforward and some feedback inhibition at the apical dendrites. GABA(A)-mediated postsynaptic inhibition dominated at early latencies, while GABA(B)-mediated inhibition prevailed at long latencies, probably at both presynaptic and postsynaptic sites. PPD of the excitatory sinks provides a measure of population dendritic inhibition in vivo.     

Electrophysiological characterization of associational pathway terminating on dentate gyrus granule cells in the rat.

The functional topography and parameters of excitation and inhibition were determined in the in situ associational pathway of the rat dentate gyrus. The functional topography was found to be consistent with previous anatomical studies. The greatest amplitude population spikes and the strongest paired-pulse inhibition were generated with the stimulating electrode placed in the hilus at least 1.5 mm caudal to the ipsilateral dentate gyrus recording electrode. With this standard electrode configuration, neither long-term potentiation of the population spike nor of the population excitatory postsynaptic potential occurred. Hilar associational pathway activation of dentate gyrus granule cells elicited paired-pulse responses similar to those produced in granule cells by perforant path stimulation. Thus, the associational pathway provides another way to assess dentate granule cell function electrophysiologically.     

Age-related impairments of synaptic plasticity in the lateral perforant path input to the dentate gyrus of galanin overexpressing mice

In the present study, electrophysiological recordings were made from hippocampal slices obtained from mice overexpressing galanin under the promoter for the platelet-derived growth factor-B (GalOE mice). In these mice, a particularly strong galanin expression is seen in the granule cell layer/mossy fibers. Paired-pulse facilitation (PPF) of excitatory postsynaptic field potentials (fEPSPs) at the lateral perforant path (LPP)-dentate gyrus synapses was elicited in the dentate gyrus after stimulation with different interpulse intervals. Slices from young adult wild-type (WT) animals showed significant PPF of the 2nd EPSP evoked with paired-pulse stimuli, while PPF was reduced in slices from young adult GalOE mice, as well as aged WT mice, but were not observed at all in slices from aged GalOE animals. Application of the putative galanin antagonist M35 increased PPF in slices from aged WT mice as well as from adult and aged GalOE mice, but had no effect in slices taken from young adult WT mice. These data indicate that galanin is involved in hippocampal synaptic plasticity, in particular in age-related reduction of synaptic plasticity in the LPP input to the dentate gyrus. Galaninergic mechanisms may therefore represent therapeutic targets for treatment of age-related memory deficits and Alzheimer's disease.     

Comparison of the effects of ethanol and chlordiazepoxide on electrophysiological activity in the fascia dentata and hippocampus regio superior.

Acute intoxicating doses of ethanol-producing blood alcohol levels of 120-200 mg% increase paired-pulse (PP) inhibition in the dentate gyrus of anesthetized rats suggesting that ethanol increases recurrent inhibitory processes (Wiesner, J.B., and S.J. Henriksen (1987) Ethanol enhances recurrent inhibition in the dentate gyrus of the hippocampus. Neurosci. Lett. 79:169-173). To further understanding of the neuronal mechanisms underlying this phenomenon, the authors studied the effects of the benzodiazepine (BZ), chlordiazepoxide, and acute intoxicating levels of ethanol on extracellular field potential recordings and single-unit activity in the dentate gyrus and area CA1 of the hippocampus. In the dentate, ethanol had no effect on population excitatory postsynaptic potential (pEPSP) amplitudes or slopes; decreased population spike (PS) amplitudes (25%); increased PP inhibition; decreased dentate granule cell (DGC) spontaneous activity (58%); had no effect on putative interneuron spontaneous activity; and markedly increased post field potential-evoked interneuron discharges (IDs, 218%). Chlordiazepoxide had no effect on pEPSP amplitudes or slopes or PS amplitudes; increased PP inhibition; decreased DGC (62%) and interneuron (72%) spontaneous activity; and markedly decreased IDs (89%). In CA1, ethanol had no effect on pEPSP amplitudes or slopes; decreased PS amplitudes (26%); had no effect on PP responses; decreased pyramidal cell (PC) spontaneous activity (39%); had no effect on interneuron spontaneous activity; and markedly increased IDs (97%). Chlordiazepoxide had no effect on pEPSP amplitudes or slopes or PS amplitudes; had no effect on PP responses; decreased PC spontaneous activity (41%); and had no effect on interneuron spontaneous activity or IDs. The results suggest that the BZs decrease principal cell excitability by postsynaptic facilitation of inhibitory processes, whereas ethanol decreases principal cell excitability indirectly by increasing the excitability of inhibitory interneurons.