LTP-associated EPSP/spike dissociation in the dentate gyrus: GABAergic and non-GABAergic components

The induction of long-term potentiation (LTP) in the dentate gyrus (DG) leads to a change in the firing characteristics of the dentate granule cells. This phenomenon, termed EPSP/spike dissociation, is seen in field potential studies as a shift to the left of the E-S curve, in which population spike amplitude is plotted against pEPSP slope at various stimulus intensities. It has been suggested that EPSP/spike dissociation reflects a decrease in feed-forward inhibition. To test this hypothesis, we blocked GABA-A neurotransmission in a circumscribed area of the DG in urethane-anaesthetized rats by inserting a micropipette filled with 8 mM bibuculline methiodide in saline. We then recorded E-S curves from 9 such electrodes and from 8 control electrodes before and after inducing LTP in the perforant path. Bicuculline prevented the LTP-associated leftward shift of the E-S curves. Instead, the E-S curve showed a consistent shift to the right at the bicuculline sites after LTP, reflecting potentiation of the pEPSP without corresponding increases in the population spike amplitude. The results indicate that the EPSP/spike relationship is controlled largely by GABAergic input, and that potentiation of the population spike in the DG depends largely on a change in the EPSP/spike relationship.     

Calcium-induced long-term potentiation in the hippocampal slice: Characterization of the time course and conditions

A transient increase in extracellular calcium concentration causes a long-lasting enhancement of radiatum fibers evoked excitatory postsynaptic potential and population spike responses of CA1 pyramidal neurons which resembles long-term potentiation (LTP). The duration of this potentiation is much longer than described previously and is probably limited by the survival of the preparation itself (greater than 8 hr). Therefore, Ca-induced LTP can be used for the investigation of a postulated late phase of LTP. Ca effects were activity-independent, since the subsequently evoked responses were facilitated even when the presynaptic fibers were not concurrently stimulated during or immediately after superfusion with the high Ca medium. In contrast, if too frequent testing of the synaptic input was done during the high Ca pulse, a short lasting depression instead of potentiation was observed. A lower extracellular magnesium concentration in the standard medium (1.3 instead of 2.0 mM MgSO4) prevents the potentiation of the EPSP at least for the first few hours. Presumably, both tetanus- and Ca-induced LTP share some common mechanisms, since an additional tetanization after Ca induction was not followed by an additional LTP. Compared to the potentiation following tetanization, the Ca-induced LTP was, however, not accompanied by a potentiation of the EPSP/spike ratio within the range of the population spike threshold intensity.     

Field potential evidence for long-term potentiation of feed-forward inhibition in the rat dentate gyrus

Trains of high-frequency stimulation to the perforant path cause (i) long-term potentiation (LTP) of the population excitatory post-synaptic potential (EPSP), (ii) a lasting increase in the population spike, and (iii) a lasting alteration of the relationship between the EPSP and population spike (E-S relationship), consisting of a decreased x-intercept and decreased slope of the linear regression. To compare the thresholds of these changes, we applied a series of trains, increasing in duration from below LTP threshold. The EPSP potentiated with about the same low threshold as the reduction in E-S slope, whereas the reduction in E-S x-intercept required longer trains. In the second experiment, LTP of the EPSP was reduced by concurrent high-frequency stimulation of the commissural input and a lasting reduction of the population spike height was observed. In a third experiment, picrotoxin, an antagonist of gamma-aminobutyric acid (GABA)-mediated inhibition, blocked the decrease in slope of the E-S relationship which normally accompanies LTP. These results imply that perforant path/granule cell LTP is normally accompanied by long-term potentiation of a feed-forward inhibitory pathway which may involve interneurones.     

Induction of long-term depression and potentiation by low- and high-frequency stimulation in the dentate area of the anesthetized rat: magnitude, time course and EEG

We investigated the possible importance of stimulus train frequency for the induction and magnitude of long-term synaptic plasticity in the perforant path-granule cell pathway. Under the same experimental conditions, low- (15 Hz) or high-frequency (400 Hz) stimulation could elicit a profound long-term depression (LTD), or typical long-term potentiation (LTP), of the population spike amplitude, excitatory postsynaptic potential (EPSP) amplitude and spike onset latency. In addition, changes in the relationship between the EPSP and population spike amplitude indicated that granule cell excitability was enhanced during LTP and reduced during LTD. LTD occurred primarily after low-frequency stimulation (5 of 6 cases), and was always accompanied by striking changes in the EEG, most notably a biphasic slow potential. While the EEG changes were confined to the first 5 min after the tetanus, LTD lasted from 1 to 4 h. The nature of the EEG events is still unclear, it is suggested that they may represent a spreading depression-like episode. Finally, we found that LTP evoked by high-frequency stimulation was larger and generally reached peak magnitude faster than when it followed low-frequency stimulation. A possible mechanism and role for hippocampal LTD is proposed.     

Quantitative analysis of long-term potentiation in the hippocampal dentate gyrus of the freely-moving 15-day-old rat

The magnitude and duration of long-term potentiation (LTP) of perforant path/dentate granule cell synapses was examined in freely moving rats beginning at 15 days of age. Measures of dentate granule cell population EPSP slope and population spike amplitude (PSA) obtained before and after tetanization were used to evaluate the level of LTP. Tetanization resulted insignificant enhancement of both the population EPSP slope (≈ +75%) and PSA (≈ +40%) measures. This enhancement was maintained without significant change for 18 h, after which both measures began a steady and continuous rise. Daily input/output response measures from age-matched nontetanized animals were used to factor out enhancement related to normal development. Under this schema, tetanization-induced enhancement of both EPSP slope and PSA measures decayed slowly, beginning 18–24 h after tetanization, returning to base-line 5 days after tetanization. Enhancement obtained from 90-day-old animals decayed to baseline 24 h after tetanization. The longer duration of LTP obtained from preweanlings is discussed with regard to the development of inhibitory systems modulating granule cell excitability.     

The duration of long-term potentiation in the CA1 region of the hippocampal slice preparation

The duration of long-term potentiation (LTP) of the monosynaptic excitatory Schaffer collateral-commissural input to hippocampal neurons of the CA1 region was examined in the in vitro slice. Relatively stable evoked potentials were obtained under conventional perfusion conditions at least for 10 hours. Tetanic stimulation (100 Hz, 1 sec) increased the population spike (pop-spike) amplitude by about 150% and the slope of the field-EPSP by about 30% over the pre-LTP baseline, whereas the latency and peak latency of the pop-spike decreased. In comparison to control experiments (same number of stimuli at 0.2 Hz) the differences were statistically significant for 2 hr (field-EPSP) and for greater than or equal to 10 hr (pop-spike), respectively. Repeated tetanization (3 X 100 Hz/1 sec), however, substantially prolongs EPSP-LTP (greater than or equal to 10 hr) and doubles the approximated half-life of pop-spike LTP. The threshold current intensity to elicit pop-spike responses decreased after the induction of LTP. Furthermore, the smaller field-EPSP values necessary to evoke near-threshold pop-spikes demonstrate an E-S potentiation (left-shift) at least in the low-intensity range. While the total duration of potentiation of the different parameters has not been determined, all the above mentioned effects could be observed at least 10 hr following the repeated tetanization. It is proposed that the slice preparation is suitable for the investigation of mechanisms of a postulated late phase of LTP if appropriate conditions are used.     

Long-lasting potentiations evoked by a brief heterosynaptic tetanus in the guinea pig dentate gyrus in vitro

The heterosynaptic effects induced by a brief afferent tetanization in the molecular layer of the dentate gyrus were investigated in the guinea pig hippocampal slice preparation using extracellular recording technique. At a brief interval (5 ms) between a single stimulation of the test afferents and the tetanus evoked in the conditioning afferents, a long-lasting (greater than 1 h) potentiation of the test field excitatory postsynaptic potential (EPSP) initial slope and amplitude was observed. This potentiation was occluded by prior homosynaptic tetanization of the test afferents, suggesting that it represents long-term potentiation (LTP). Thus, in the dentate gyrus, a single activation of a single test EPSP suffices to induce LTP when coinciding in time with a brief tetanus to other afferents. When not temporally paired with the test stimulation, i.e. at longer test-conditioning intervals (greater than 50 ms), the conditioning tetanus also elicited a long-lasting potentiation of the test field EPSP. This potentiation was, however, seen as a prolongation of the rising phase with no change in the field EPSP initial slope, and may represent a potentiation distinct from LTP.     

Long-term potentiation in the dentate gyrus: Effects of noradrenaline depletion in the awake rat

The chronic rat preparation was utilized to study the effects of noradrenaline (NA) depletion on field potentials recorded from the hilus of the fascia dentata. Both single pulses and high-frequency trains were applied to the perforant path (PP). The effects of NA depletion on baseline responses as well as on long-term potentiation (LTP) were examined. Reduced NA levels resulted in an increase in the population spike amplitude and a depression of the population excitatory postsynaptic potential (EPSP). Depleted animals showed significantly higher levels of LTP of the population EPSP, but reduced levels of population spike LTP (measured 13-15 min after tetanization). There were, however, no differences in LTP levels 1 week after the potentiation tests. These results demonstrate that NA levels do not affect that component of LTP which can persist for several weeks.     

Polymyxin B, an inhibitor of protein kinase C, prevents the maintenance of synaptic long-term potentiation in hippocampal CA1 neurons

The involvement of protein kinase C (PKC)-mediated processes in mechanisms of long-term potentiation (LTP) was suggested by recent studies which have demonstrated a correlation between PKC activation and LTP. However, it was not possible to tell whether there is a causal relationship between the two events. Therefore, we have examined the induction and maintenance of LTP in rat hippocampal slices in the presence of a relatively selective PKC inhibitor, using extracellular electrophysiological techniques. Bath application of 0.1–100 μM polymyxin B did not influence the occurrence of post-tetanic and long-term potentiation usually seen in test responses 1 and 10 min after a 100-Hz/1 s tetanic stimulation of stratum radiatum fibers. However, 20 μM polymyxin B significantly depressed the increase in population spike amplitude and population excitatory postsynaptic potential (EPSP) slope from 30 to 120 min onwards, following repeated tetanization. Immediately after the drug application only weak and reversible effects were seen by the same parameters in test responses of a non-tetanized control input. A late (>6 h) heterosynaptic potentiation of the population spike in the control input was blocked by polymyxin B treatment. Whereas the EPSP-I,TP was fully blocked, some potentiation of the population spike still remained, suggesting the independence of PKC of the additional spike (E/S) potentiation for the first 6 h. These results provide direct evidence that the PKC activation is not essential for the initial phase of LTP, but is a necessary condition for a medium and a late, protein synthesis-dependent phase in this monosynaptic pathway, i.e. for the maintenance of synaptic LTP.     

Vasopressin reverses aluminum-induced impairment of synaptic plasticity in the rat dentate gyrus in vivo

Aluminum (Al), an important neurotoxin, contributes to a variety of cognitive dysfunction and mental diseases. Previous studies have demonstrated that Al impairs hippocampal long-term potentiation (LTP) in vitro and in vivo. In the present study, both LTP and LTD (long-term depression) were recorded in the same animal to investigate the Al-induced impairment of synaptic plasticity. Another aim of the present research was to verify whether the impairment of synaptic plasticity induced by Al could be reversed by vasopressin (VP) treatment. Neonatal Wistar rats were exposed to Al from parturition through adulthood (pre- and post-weaning) by the drinking of 0.3% aluminum chloride (AlCl(3)) solution. The input-output (I/O) function, paired-pulse reaction (PPR), excitatory postsynaptic potential (EPSP) and population spike (PS) amplitude were measured in the dentate gyrus (DG) of adult rats (60-90 days) in response to stimulation applied to the lateral perforant path. The results showed: (1) Al reduced the amplitudes of both EPSP LTP (control: 132+/-7%, n=7; Al-exposed: 115+/-10%, n=8, P<0.05) and PS LTP (control: 242+/-18%, n=7; Al-exposed: 136+/-7%, n=8, P<0.01) significantly. The amplitudes of EPSP LTD (control: 82+/-6%, n=7; Al-exposed: 92+/-7%, n=8, P<0.05) and PS LTD (control: 81+/-4%, n=7; Al-exposed: 98+/-5%, n=8, P<0.05) were also decreased by Al treatment. The Al-induced impairments of PS LTP and PS LTD were more serious than that of EPSP LTP and EPSP LTD. (2) In control rats, VP had an increase in the PS LTP amplitude (control: 242+/-18%, n=7; control+VP: 358+/-23%, n=6, P<0.01), while it had no significant effects on PS LTD (control: 81+/-4%, n=7; control+VP: 76+/-7%, n=6, P>0.05). (3) In Al-exposed rats, VP had a significant increase in the amplitudes of both PS LTP (Al-exposed: 136+/-7%, n=8, Al-exposed+VP: 255+/-16%, n=6, P<0.01) and PS LTD (Al-exposed: 98+/-5%, n=8; Al-exposed+VP: 81+/-6%, n=6, P<0.05). After the application of VP, the range of synaptic plasticity (PS LTP+PS LTD) in Al-exposed rats increased from 38% to 174%, which surpassed that in control rats (161%). It was suggested that VP could reverse Al-induced impairment of synaptic plasticity and might be an effective medicine to cure Al-induced neurological disorders.     

Developmental changes in long-term potentiation in CA1 of rat hippocampal slices

Long-term potentiation (LTP) was examined in the CA1 region of rat hippocampal slices at postnatal day 9 (P9), P15, P30, P60, P90, P120, and P300. A single 100 Hz × 1 sec tetanus failed to induce LTP in P9 slices, while similar degrees of LTP were observed at P15, P30, and P60. At P30, changes in population spike (PS) amplitudes were accurately predicted by changes in dendritic excitatory postsynaptic potentials (EPSPs). However, at P15, the predicted increase in PS calculated from corresponding changes in dendritic EPSPs was significantly less than the observed increase, suggesting that EPSP-PS dissociation (ES-dissociation) plays a substantial role in LTP at P15. Additionally, the corresponding changes in somatic EPSP height measured in the CA1 cell layer did not predict the E-S dissociation at P15, suggesting that the E-S dissociation arises largely from changes in the excitability of the soma. Using a single 100 Hz × 1 sec tetanus, LTP proved difficult to induce in slices from rats ≥ P90, with slices showing initial enhancement that faded over 60 min of monitoring. © 1995 Wiley-Liss, Inc.     

Maturation of long-term potentiation in the hippocampal dentate gyrus of the freely moving rat

The ability of the perforant path/dentate granule cell synapse of the hippocampal formation to establish and maintain enhanced levels of synaptic transmission in response to tetanization (long-term potentiation, LTP) was investigated in freely moving rats at 15, 30, and 90 days of age. Measures of (1) the slope of the population excitatory postsynaptic potential (EPSP), and (2) the population spike amplitude (PSA) obtained before, and at several times following tetanization, were used to evaluate the magnitude and duration of LTP as a function of age. Significant enhancement of both EPSP slope and PSA measures was obtained from animals of all three ages in response to perforant path tetanization. The initial degree of enhancement was essentially the same across the age groups, ranging from +27% to +38% of pretetanization levels for EPSP slope measures and +60% to +75% of pretetanization levels for PSA measures, obtained 15 min after tetanization. The duration of this enhancement obtained from animals of the preweaning group was significantly longer than that obtained from either 30- or 90-day-old animals. Enhanced measures of both EPSP slope and PSA decayed to baseline levels in these older animals 18 to 24 h after tetanization, while animals tetanized at 15 days of age maintained potentiated levels of both measures for a period of 5 days following tetanization. Tetanization of 15-day-old animals resulted in a significant reduction in the latency to EPSP onset without affecting the time-based relationships among the other measured parameters, which included latency of the population spike onset, population spike minimum, and population spike offset. Tetanization had no effect on the latency measure of any of these parameters in either of the two older age groups. The primarily postnatal development of the dentate granule cell population suggests that both functionally immature GABAergic modulation of granule cell activity and the differential development of components of the N-methyl-D-aspartate receptor complex may be involved in the age-related differences in the induction and expression of the LTP phenomenon. This study represents the first developmental characterization of LTP in the perforant path/dentate granule cell synapse in freely moving rats during early development. The results indicate that LTP can be reliably established and maintained in behaving rats as young as 15 days of age. Whereas the degree of potentiation at this age is equivalent to that obtained from juveniles and young adults, the duration of the effect significantly outlasts that obtained from older animals in which development of the dentate gyrus is more functionally mature. © 1994 Wiley-Liss, Inc.     

The supramammillary nucleus contributes to associative EPSP-spike potentiation in the rat dentate gyrus in vivo

The supramammillary nucleus (SUM) of the hypothalamus sends neural projections to the hippocampus and is supposed to be involved in learning and memory. To test the possibility that SUM afferents modulate hippocampal functions, we investigated the effect of electrical stimulation of the SUM on the induction of long-term potentiation (LTP) at medial perforant path (PP)--granule cell synapses in the dentate gyrus (DG) of anaesthetized rats. High-frequency stimulation of the SUM (100 pulses at 100 Hz) alone did not change PP--DG field potentials. However, when the SUM stimulation was applied simultaneously with weak tetanic stimulation of the PP (20 pulses at 20 Hz) which alone did not induce any potentiation, it produced a long-lasting potentiation of the population spike, without an accompanying increase in the population excitatory postsynaptic potential (EPSP). The EPSP-spike (E-S) potentiation induced by pairing SUM and PP stimulation was abolished by lesions of the fimbria--fornix, a major pathway of SUM afferents. SUM stimulation applied 1 s before or after PP stimulation failed to produce E-S potentiation, and SUM stimulation augmented PP--DG field potentials during tetanic stimulation. Furthermore, the E-S potentiation was abolished by blocking GABAergic neurotransmission with picrotoxin. These results suggest that coactivation of SUM and PP inputs produces a long-lasting increase of granule cell excitability by modulating GABAergic inhibition. SUM afferents may contribute to associative memory processing by modulating hippocampal excitability.     

Synaptic plasticity at the levels of the archicortex and neocortex

A review of the author's studies of properties and mechanisms of long-term potentiation (LTP) is presented. LTP of field potentials and neuronal responses at hippocampal CA1 and CA3 regions of unanaesthetized rabbit was found. Excitatory and inhibitory post-synaptic potentials increased after tetanization. Microiontophoretic and histochemical studies revealed no appropriate changes in acetylcholine sensitivity or in acetylcholinesterase activity to explain LTP. Quantal analysis of EPSP evoked by microstimulation indicated increase in the number of transmitter quanta released by a presynaptic spike. LTP of field potentials evoked by white matter stimulation at neocortical slices and sensorimotor cortex of unanaesthetized rabbit are described. Changes in short-latency neuronal responses and "indirect" component of pyramidal tract response suggest monosynaptic LTP at neocortex. It is concluded that the main mechanism of both hippocampal and neocortical LTP consists of an increase in efficacy of excitatory synapses. It is suggested that these synapses are used in learning and memory processes.     

Mechanisms of long-term potentiation: EPSP/spike dissociation, intradendritic recordings, and glutamate sensitivity

Synaptic efficacy is modified following a brief train of high-frequency stimulation (HFS) to a cell's afferent fibers (long-term potentiation; LTP). An alteration in the postsynaptic response to endogenous neurotransmitter, as a result of an increase in the number of postsynaptic receptors, has been proposed (Baudry and Lynch, 1980). We tested this hypothesis in the CA1 hippocampus by intracellularly recording the postsynaptic response to localized application of glutamate before and after induction of LTP. When LTP was produced, there was no corresponding change in neuronal sensitivity to glutamate application. These findings are not consistent with the hypothesis that HFS of fibers in CA1 stratum radiatum induces an increase in the number of postsynaptic glutamate receptors in CA1 pyramidal cells. Previous reports concerning LTP have indicated a dissociation between the degree of potentiation in the population EPSP and population spike. Simultaneous recordings of the CA 1 population EPSP and population spike in hippocampal slices confirmed that the degree of potentiation of the population spike was not predicted by the degree of potentiation in the population EPSP. Intradendritic impalements were obtained to more accurately assess changes in the intracellular EPSP following HFS. When the population EPSP was potentiated, there was also a potentiated intradendritic EPSP. When the population spike was potentiated following HFS, however, the intradendritic EPSP was often unchanged; in the same cell, there was an increased probability of action potential discharge to stimulation which was originally (i.e., pre-HFS) subthreshold for spike initiation. These results indicate that the EPSP (intracellular or extracellular) may be potentiated following HFS, but this potentiation is not a prerequisite for, or a correlation of, potentiation in the population spike. Furthermore, these findings suggest that LTP is composed of 2 independent components--a synaptic component and an EPSP-to-spike coupling component.     

Permissive role of interneurons in corticostriatal synaptic plasticity

Two different forms of synaptic plasticity have been found at corticostriatal synapses: long-term depression (LTD) and long-term potentiation (LTP). Both these enduring changes in the efficacy of excitatory neurotransmission in the striatum have a major impact on the physiological activity of the basal ganglia and are triggered by the stimulation of complex and independent cascades of intracellular second messenger systems. Striatal LTD and LTP are evoked following the repetitive stimulation of corticostriatal fibers and are dependent on the glutamate ionotropic receptor subtype activated. Recent experimental evidence indicates that two different subtypes of interneurons attend in the correct processing of information flow arising from the cortex and leading to striatal LTD or LTP. Acetylcholine (Ach) and nitric oxide (NO) producing striatal interneurons, in fact, are activated by the cortex during the induction phase of striatal plasticity, and stimulate, in turn, the intracellular changes in projection neurons required for LTD or LTP. Interneurons, therefore, exerts a feed-forward control of the excitability of striatal projection neurons ensuring the coordinate expression of two alternative forms of synaptic plasticity at the same type of excitatory synapse.     

Anisomycin blocks the late phase of long-term potentiation in the dentate gyrus of freely moving rats

Freely moving rats, chronically implanted with stimulation electrodes in the medial entorhinal cortex and recording electrodes in the dentate gyrus, received two 400 micrograms intraventricular injections of anisomycin during a tetanization procedure that induced a long-lasting potentiation (72 hours) of the monosynaptic field potential. Inhibition of protein synthesis during the tetanization procedure did not immediately influence the induction of long-term potentiation (LTP). However, 3-4 hours after the beginning of tetanization the potentiation effect decayed progressively and was abolished totally during the remaining 7 day observation period. In control experiments anisomycin did not affect the slope of field EPSP's and produced a reversible depression of the population spike amplitude. These data indicate a relatively specific effect of the protein synthesis inhibitor on mechanisms involved in a late phase of LTP stabilization.     

Dissociation between long-term potentiation and associated changes in field epsp waveform in the hippocampal CA1 region: An in vitro study in guinea pig brain slices

The present study examines changes in field excitatory postsynaptic potential (EPSP) waveform in association with long-term potentiation (LTP) in the CA1 region of the hippocampal slice preparation. Experiments were performed in the presence of the GABA_A-antagonist picrotoxin. With test field EPSP about one-third the size of that evoking spike activity (measured in the cell body layer along the same somatodendritic axis as the dendritic recording) a decreased decay time constant (approximately 8%) was seen in association with LTP. This change in field EPSP waveform was not associated with any apparent spike activity in the cell body recording. Nevertheless, several findings suggest that increased spike activity explains the change in the decay time constant of the field EPSP during LTP. First, when reducing the stimulation strength after the induction of LTP to obtain a field EPSP of the same magnitude as the pretetanus one, the change of the decay time constant was reduced to only 2.8%. Second, when using small test field EPSP (about one-fourth the size of that evoking spike activity) the decay time constant was not significantly affected in association with LTP. Third, when cutting the slice in such a manner that spike activity originating from somatic regions closer to the stimulating electrode was removed, the EPSPs decay time constant was not significantly affected in association with LTP. It is concluded that LTP is not associated with a change in the shape of the field EPSP. © 1994 Wiley-Liss, Inc.     

Polymyxin B, an inhibitor of protein kinase C, prevents the maintenance of synaptic long-term potentiation in hippocampal CA1 neurons

The involvement of protein kinase C (PKC)-mediated processes in mechanisms of long-term potentiation (LTP) was suggested by recent studies which have demonstrated a correlation between PKC activation and LTP. However, it was not possible to tell whether there is a causal relationship between the two events. Therefore, we have examined the induction and maintenance of LTP in rat hippocampal slices in the presence of a relatively selective PKC inhibitor, using extracellular electrophysiological techniques. Bath application of 0.1–100 μM polymyxin B did not influence the occurrence of post-tetanic and long-term potentiation usually seen in test responses 1 and 10 min after a 100-Hz/1 s tetanic stimulation of stratum radiatum fibers. However, 20 μM polymyxin B significantly depressed the increase in population spike amplitude and population excitatory postsynaptic potential (EPSP) slope from 30 to 120 min onwards, following repeated tetanization. Immediately after the drug application only weak and reversible effects were seen by the same parameters in test responses of a non-tetanized control input. A late (>6 h) heterosynaptic potentiation of the population spike in the control input was blocked by polymyxin B treatment. Whereas the EPSP-I,TP was fully blocked, some potentiation of the population spike still remained, suggesting the independence of PKC of the additional spike (E/S) potentiation for the first 6 h. These results provide direct evidence that the PKC activation is not essential for the initial phase of LTP, but is a necessary condition for a medium and a late, protein synthesis-dependent phase in this monosynaptic pathway, i.e. for the maintenance of synaptic LTP.     

Neonatal stress alters LTP in freely moving male and female adult rats

We previously reported that neonatal isolation stress significantly changes measures of hippocampal long-term potentiation (LTP) in male and female juvenile rats, i.e., at 30 days of age. The changes in dentate granule population measures, i.e., excitatory postsynaptic potential (EPSP) and population spike amplitude (PSA), evoked by tetanization of the medial perforant pathway, indicated that juvenile rats exposed to neonatal isolation exhibit different enhancement profiles with respect to both the magnitude and duration of LTP in a sex-specific manner. Isolated males showed a significantly greater enhancement of LTP, while female "isolates" showed significantly longer LTP duration when compared to all other groups. The present study was designed to determine whether the effects of the neonatal isolation stress paradigm endures into adulthood. Rats isolated from their mothers for 1 h per day during postnatal days 2-9 were surgically prepared at 70-90 days of age, with stimulating and recording electrodes placed in the medial perforant pathway and the hippocampal dentate gyrus, respectively. Prior to tetanization, no significant effect of sex or treatment was obtained for baseline measures of EPSP slope or PSA. In order to rule out baseline differences in hippocampal cell excitability in female adult rats, we measured the response of dentate granule cells for one estrus cycle and found no pretetanization enhancement in the evoked response in either controls or previously stressed rats. Following tetanization, there was a significant treatment and sex effect. During the induction of LTP, PSA values were significantly enhanced in both isolated males and females and had significantly longer LTP duration when compared to the unhandled control group. Additionally, we observed that females took longer to reach baseline levels than males. Taken together, these results indicate that repeated infant isolation stress enhances LTP induction and duration in both males and females. These results indicate that infant stress alters hippocampal neuroplasticity in such a way that its effect endures into adulthood.