Associative long-term potentiation (LTP) among extrinsic afferents of the hippocampal CA3 region in vivo

Monosynaptic perforant path projections to the CA3 region of the hippocampus are anatomically and physiologically substantial pathways that relay cortical input directly to the hippocampus proper. Despite the suggested relevance of these direct pathways in models of information processing within the CA3 region, surprisingly few studies have characterized synaptic plasticity in these direct cortical projections to the CA3 region. We assessed the ability of perforant path projections, and commissural/associational projections to the hippocampal CA3 region to both induce or display associative LTP in vivo. In pentobarbital-anesthetized adult rats, trains delivered to either the medial or lateral perforant pathway at current intensities normally insufficient to induce LTP displayed associative LTP when these same trains were delivered in conjunction with high-intensity trains to the alternate perforant pathway. Similarly, associative LTP is induced at intrinsic commissural/associational–CA3 (C/A–CA3) synapses when weak C/A trains were delivered in conjunction with high-intensity trains to either the medial or lateral perforant pathway. Associative LTP also was observed at medial and lateral perforant path–CA3 synapses when weak perforant path trains were tetanized in conjunction with high-intensity trains delivered to C/A–CA3 synapses. Thus direct perforant path–CA3 synapses and commissural/associational–CA3 synapses can modify and be modified by other CA3 afferents in an associative manner, verifying a requirement for synaptic plasticity explicit in models of autoassociative information processing in the CA3 region.     

Chronic unpredictable stress impairs long-term potentiation in rat hippocampal CA1 area and dentate gyrus in vitro

Rises in corticosteroid levels, e.g. after acute stress, impair synaptic plasticity in the rat hippocampus when compared with the situation where levels are basal, i.e. under rest. We here addressed the question whether basal and raised levels of corticosterone affect synaptic plasticity similarly in animals that experienced chronic stress prior to corticosterone application. To this end, rats were exposed to a 21-day variable stress paradigm. Synaptic plasticity was examined in vitro in the dentate gyrus and CA1 hippocampal region, 24 h after exposure to the last stressor, i.e. when corticosterone levels are basal (low). First we observed that long-term potentiation was greatly impaired in both CA1 and dentate gyrus after 3 weeks of exposure to variable stress, when recorded under conditions where plasma corticosterone levels are low. Second, administration of 100 nm corticosterone in vitro reduced synaptic plasticity in CA1 of control rats, but induced no further impairment of synaptic plasticity in chronically stressed rats. Third, in the dentate gyrus, corticosterone incubation did not affect synaptic plasticity in slices from both control and stressed animals. We conclude that: (i) exposure to chronic variable stress per se reduces synaptic plasticity both in CA1 and dentate gyrus; and (ii) acute rises in corticosterone level induce no additional impairment of synaptic plasticity in the CA1 region of chronically stressed rats. It is tempting to speculate that the stress-induced reduction of hippocampal efficacy provides a cellular substrate for cognitive deficits in hippocampus-dependent learning tasks seen after prolonged exposure to stressful events.     

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.     

Local projections of GABAergic neurons in the dentate gyrus and CA1 region in the rat hippocampal formation

Using retrograde transport of wheat germ agglutinin conjugated colloidal gold (WGA-gold) combined with immunoreactivity for glutamate decarboxylase (GAD), a specific synthesizing enzyme for γ-aminobutyric acid (GABA), local projections of GABAergic neurons in the dentate gyrus and CAI were examined. In the hilus of the dentate gyrus, it was found that GABAergic neurons in the granule cell layer projected to the ipsilateral upper leaf of the molecular layer, with a mediolateral extension of more than 1.2 mm and a rostrocaudal extension of over 0.8 mm. Non-GABAergic neurons in nearly the entire hilar area were found to project to the ipsilateral upper leaf of the molecular layer. In the dorsal CAI region, GABAergic neurons in the stratum pyramidale and radiatum converged onto the ipsilateral stratum pyramidal/oriens, with a mediolateral extension of over 1 mm and a rostrocaudal extension of over 0.7 mm. These results provide direct evidence that in both the dentate gyrus and CAI, GABAergic interneurons from a fairly large field converge onto a very small target area. This suggests that the output signals from GABAergic neurons in the dentate gyrus and CAI, and non-GABAergic neurons in the dentate gyrus, may propagate beyond the anatomical limits contained in conventional slice preparations of the hippocampal formation.     

High-frequency septal stimulation suppresses long-term potentiation (LTP) in the CA1 region of rat hippocampus

The effects of high-frequency stimulation (HFS) of the medial septum/diagonal band (MSDB) on long-term potentiation (LTP) of CA1 extracellular field potentials were assessed in anesthetized rats. Ten rats received HFS of the Schaffer collateral pathway alone, and 10 received MSDB HFS 10 min prior to hippocampal HFS. Septal HFS suppressed LTP development assessed by change in population spike (PS) amplitude 60 min after hippocampal HFS (ANOVA, P less than 0.03). Septal inhibition of LTP development was most prominent when septal HFS had little direct effect on the CA1 PS. These results provide a novel demonstration of the functional heterogeneity of septohippocampal pathways and in vivo modulation of hippocampal LTP by HFS of natural afferent inputs.     

Large-scale study of phosphoproteins involved in long-term potentiation in the rat dentate gyrus in vivo

The mechanisms underlying the induction of synaptic plasticity and the formation of long-term memory involve activation of cell-signalling cascades and protein modifications such as phosphorylation and dephosphorylation. Based on a protein candidate strategy, studies have identified several protein kinases and their substrates, which show an altered phosphorylation state during the early phases of long-term potentiation (LTP), yet only a limited number of synaptic phosphoproteins are known to be implicated in LTP. To identify new phosphoproteins associated with LTP, we have undertaken a proteomic study of phosphoproteins at different time points following the induction of LTP in the dentate gyrus in vivo (0, 15 and 90 min). For each time point, proteins from the dentate gyrus were separated by two-dimensional gel electrophoresis and stained with Pro−Q^® Diamond, a fluorescent stain specific for phosphoproteins. Fourteen proteins whose phosphorylation state varied significantly following LTP were identified using matrix-assisted laser desorption ionization/time of flight mass spectrometry and electrospray ionization-Orbitrap tandem mass spectrometry (MS/MS). They are involved in various cellular functions implicated in synaptic plasticity, such as intracellular signalling, axonal growth, exocytosis, protein synthesis and metabolism. Our results highlight new proteins whose phosphorylation or dephosphorylation is associated with LTP induction or maintenance. Further studies focusing on the regulation of specific phosphorylation sites will lead to greater understanding of the individual implications of these proteins in LTP as well as of their molecular interactions.     

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.     

Effects of stress and long-term potentiation (LTP) on subsequent LTP and the theta burst response in the dentate gyrus

Exposure to an aversive and stressful events is reported to have similar effects of hippocampal plasticity and behavior as does exposure to high-frequency stimulation of the hippocampus. Here we directly compared the effects of exposure to a stressor vs. a previous induction of LTP on a subsequent induction of LTP and the extracelllular response to a tetanus patterned after endogenous theta rhythms. Stimulating the dentate gyrus via the perforant path, Sprague-Dawley rats(n = 65) were tetanized 2 h after exposure to a stressor consisting of restraint and 60, 1 s, 1 mA tail shocks. Unstressed controls were tetanized once and then again 2 h later. Exposure to the stressor impaired LTP of the EPSP 2 h later, as did a previous induction of LTP. In addition, exposure to the stressor altered the extracellular response to subsequent theta burst stimulation (10, 40 ms bursts at 100 Hz, each separated by 200 ms), as did a previous induction of LTP. Whereas unstressed rats exposed to the first tetanus exhibited a marked decline in the amplitude across successive bursts, stressed rats exhibited no such decline, a response pattern similar to that observed in unstressed rats exposed to a second tetanus. The similarity between the effects of stress and tetanic stimulation on hippocampal plasticity support the hypothesis that stress and LTP are converging on similar neuronal mechanisms.     

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.     

Nicotine accelerates reversal of long-term potentiation and enhances long-term depression in the rat hippocampal CA1 region

In the hippocampal CA1 region, low-frequency stimulation (LFS; 200 pulses at 1 Hz) causes reversal of long-term potentiation (depotentiation, DP) and long-term depression (LTD), both of which are thought to be the cellular substrate of learning and memory. Because nicotine enhances learning and memory, we examined if nicotine modulates DP and LTD in the hippocampal CA1 region. Bath application of nicotine during LFS accelerated DP, that is, potentiated synaptic responses in hippocampal CA1 neurons returned to pre-tetanic control levels more rapidly in the presence of nicotine. Because a similar acceleration of DP was observed using the alpha7 nicotinic acetylcholine receptor (nAChR)-selective antagonist methyllcaconitine (MLA), the nicotine effect appeared to be at least partly mediated by nicotine-induced desensitization of alpha7 nAChRs. Delivery of LFS in the presence of nicotine or MLA also depressed synaptic responses in a naive pathway and facilitated LTD, that is, the magnitude of LTD was larger when the drug was present during LFS. Thus, these results demonstrate that nicotine facilitates DP and LTD, which may represent, at least in part, the cellular mechanism underlying nicotine-induced cognitive enhancement.     

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.     

Chronic lead exposure accelerates decay of long-term potentiation in rat dentate gyrus in vivo

Long-term potentiation (LTP) is a model of synaptic plasticity believed to encompass the underlying neurobiological mechanisms that support memory function. Chronic developmental lead (Pb) exposure is known to be associated with cognitive dysfunction in children and animals. Disruption of the induction of long-term potentiation (LTP) has been reported in the hippocampus following chronic exposure to environmentally relevant levels of Pb in rats. Under urethane anesthesia, we have previously observed Pb-induced increases in the threshold for LTP induction. With higher train intensities, LTP was induced and no declines in the amplitude of responses within a 60-min posttrain period were evident. The present study was designed to assess the effects of Pb on the more enduring forms of LTP in the dentate gyrus of the conscious rat. Beginning in the late gestational period, rats were chronically exposed to 0.2% Pb²⁺-acetate through the drinking water of the pregnant dam, and directly through their own water supply at weaning. As adults, electrodes were permanently implanted in male offspring and field potentials evoked by perforant path stimulation were recorded from the dentate gyrus over several weeks. LTP was induced by delivering theta-burst patterned stimulation at a maximal stimulus intensity through the perforant path electrode, and input/output (I/O) functions were monitored for 1 month. Population spike (PS) amplitude was increased maximally 1 h after train delivery. The time constant of decay (τ) calculated from pooled data for each group yielded declines in PS amplitude by 63% in 17.4 days in controls and 13.4 days in Pb-exposed animals. Quantitative estimates of decay in individual animals were achieved in two ways: (1) by calculating difference scores in I/O functions from the maximal LTP at 1 h, and (2) by interpolating day to decay by 63% from declines from maximal LTP. The interpolated values were used to compare the incidence of animals showing decay of 63% within 1 week posttrain. Both analyses revealed a more accelerated rate of decay of LTP in animals developmentally exposed to Pb relative to controls. Endurance of potentiated responses for days to weeks is believed to be supported by structural modifications and synaptic growth. The reported effects of Pb on growth-related processes may thus contribute to a reduced persistence of LTP and the resulting cognitive deficits engendered by developmental Pb exposure.     

Nicotine reverses consolidated long-term potentiation in the hippocampal CA1 region

Long-term potentiation (LTP) has a memory-like consolidation period during which it becomes progressively stabilized. However, it is unknown how the consolidation is achieved. The present study demonstrates that nicotine reverses stabilized LTP in the hippocampal CA1 region, providing the first evidence that consolidated LTP can be reversed. The nicotine-induced reversal appeared to work by reversing cellular processes involved in stabilizing LTP, as LTP was readily induced again after reversal. The effect of nicotine was mediated, in large part, via desensitization of alpha7 nicotinic acetylcholine receptors (nAChRs), as an alpha7 nAChR-selective antagonist mimicked the nicotine effect. A non-selective N-methyl-d-aspartate receptor (NMDAR) antagonist completely abolished the nicotine-induced reversal, whereas an NR2B-containing NMDAR-selective antagonist had no effect. Furthermore, both the protein phosphatase 1/protein phosphatase 2A inhibitor okadaic acid and the protein phosphatase 2B (calcineurin) inhibitor cyclosporin A blocked the nicotine-induced reversal. Taken together, our results suggest that the reversal of stabilized LTP depends on the activation of NR2A-containing NMDARs and dephosphorylation. Thus, the consolidation of LTP appears to be the interruption of signaling leading to NR2A-containing NMDAR-dependent activation of protein phosphatases, which can be circumvented by nicotine-induced signaling. LTP induced in chronic nicotine-treated hippocampi contained a component that is immune to reversal, and thus acute nicotine was no longer effective to reverse consolidated LTP. These results demonstrate the differential effects of acute and chronic nicotine exposure on the cellular processes that are potentially involved in learning and memory.     

Saffron extract prevents acetaldehyde-induced inhibition of long-term potentiation in the rat dentate gyrus in vivo

We have previously found that alcohol extract of Crocus sativus L. (CSE), commonly known as saffron, prevents ethanol-induced inhibition of hippocampal long-term potentiation (LTP). In the present study, CSE (250 mg/kg, p.o.) was also effective in preventing acetaldehyde-induced inhibition of LTP in the dentate gyrus of anesthetized rats. These results suggest that CSE can prevent aversive effects induced by ethanol and its metabolite acetaldehyde.     

Long-term potentiation in the hippocampal CA1 area and dentate gyrus plays different roles in spatial learning

NMDA receptor-dependent long-term potentiation (LTP) at hippocampal synapses has been considered a crucial component of the cellular basis for learning and memory. This form of LTP occurs in excitatory synapses in both the CA1 area and the dentate gyrus in the hippocampus. However, differential roles of LTP in these areas have not yet been identified. To address this issue, we enhanced the degree of LTP by expressing Ca2+-permeable AMPA receptors at either hippocampal CA1 or dentate gyrus synapses using Sindbis viral vectors (SINs) encoding both green fluorescent proteins and unedited GluR2 (GluR2Q) subunits, and examined their effects on rat spatial learning. The viral vectors were locally injected into the 8-week-old-rat brain in vivo bilaterally. The postsynaptic expression of Ca2+-permeable AMPA receptors enhanced the degree of LTP, and induced NMDA receptor-independent LTP in the presence of the NMDA receptor antagonist in SIN-infected regions in both CA1 and dentate gyrus in hippocampal slice preparations. However, the regional expression of Ca2+-permeable AMPA receptors caused opposite behavioural consequences on the Morris water maze task: rats with SIN-infected CA1 pyramidal cells showed shorter escape latency and better probe test performance, whereas those with SIN-infected dentate gyrus granule cells showed impaired performance. Thus, it was demonstrated that CA1 and dentate gyrus synapses play different functional roles in spatial learning despite their similar mechanism for LTP induction.     

Enhanced bursting activity in the CA3 region of the mouse hippocampal slice without long-term potentiation in the dentate gyrus after systemic pentylenetetrazole kindling

The repeated administration of subconvulsant doses of pentylenetetrazole (24 mg/kg, i.p.) produced chemically kindled seizures in 16 of 20 mice. Hippocampal slices prepared from the mice with kindled seizures were tested for input-output characteristics in the dentate gyrus, and for spontaneous burst discharge frequency in area CA3. The kindled slices displayed no change in the magnitude of the evoked granule cell excitatory postsynaptic potential (pEPSP) to a given stimulus intensity applied to the perforant path, nor in magnitude of the granule cell population spike for a given pEPSP. Although long-term potentiation of synaptic transmission has been proposed as the cellular mechanism of kindling, these results indicate either that long-term potentiation may not underlie kindling or that systemic pentylenetetrazole kindling and focal electrical kindling may be accomplished by different mechanisms. Hippocampal slices from kindled animals did, however, show an increased incidence of spontaneous burst discharges in area CA3 pyramidal neurons in both the absence and the presence of pentylenetetrazole in the bathing medium.     

Synaptic interface surface area increases with long-term potentiation in the hippocampal dentate gyrus

The present study continues our attempt to understand the ultrastructural changes that accompany and may underlie long-term potentiation (LTP). This report describes changes with LTP in the surface area of the pre- and postsynaptic membrane apposition at the synapses formed by entorhinal cortical (EC) axons with granule cell dendritic spines of the dentate gyrus (DG). The electrophysiology and electron microscopy of the DGs from each animal followed conventional procedures. The trace length of the pre- and postsynaptic apposition was measured for identified asymmetric synapses in the dentate molecular layer. The total apposed membrane surface area per unit volume (Sv) was then computed for 4 categories of synaptic profiles for each third of the molecular layer. Statistical analysis of the Sv data used multivariate analyses of variance. Across the entire molecular layer, total apposed Sv does not change significantly with LTP. However, in the activated portion of the molecular layer, total apposed Sv increases significantly, reflecting a significant increase in the apposed Sv for the concave spine profiles there. For these spine profiles, the increased apposed Sv is due to the increased membrane area both at the postsynaptic density and beyond. The average apposed surface area per individual synapse also increases markedly with LTP. The present data support the hypothesis of coordinated pre- and postsynaptic anatomical changes with LTP in the EC-DG system.     

Blockade of long-term potentiation in rat hippocampal CA1 region by inhibitors of protein synthesis

Long-term potentiation (LTP) in the hippocampus has attracted attention as a model of neuronal plasticity in the central nervous system. Although accumulating evidence associates protein synthesis with LTP, there is no direct proof that protein synthesis is actually required for the production of LTP. Therefore, we have examined the ability of some inhibitors of protein synthesis to modify LTP in the CA1 region of the rat hippocampal slice. Incubation for 30 min in the presence of emetine, cycloheximide, or puromycin decreased the frequency of occurrence of LTP in field CA1 elicited by repetitive stimulation of the Schaffer collaterals. This blockade was dose dependent and correlated with the ability of individual inhibitors to inhibit incorporation of [3H]valine into proteins. LTP blockade was irreversible for the irreversible inhibitor emetine and was reversible for the reversible inhibitor cycloheximide. Blockade of LTP required a substantial preincubation period to be effective. Even at the highest concentration of emetine used to block LTP, no effect on any intracellularly recorded membrane properties was observed. In contrast, the protein synthesis inhibitor anisomycin was unable to block LTP. Puromycin aminonucleoside, a structural analogue of puromycin which is inactive in inhibiting protein synthesis, was ineffective in blocking LTP. These experiments demonstrate that a variety of protein synthesis inhibitors are able to block the production of LTP in field CA1, suggesting the necessity for a set of newly synthesized or rapidly turned over proteins for hippocampal LTP.     

Hypothyroidism impairs late LTP in CA1 region but not in dentate gyrus of the intact rat hippocampus: MAPK involvement

Thyroid hormone activates extracellular signal-regulated kinases (ERK1 and ERK2), which are important in late long-term potentiation (L-LTP). The aim of this study was to determine the possible mechanism underlying the impairment of L-LTP as a result of hypothyroidism. We investigated the effect of hypothyroidism on L-LTP of the two associative pathways in the hippocampus: the Schaffer collateral synapses and the perforant path synapses. We also examined the effect of hypothyroidism on ERK1 and ERK2 levels in both the CA1 and dentate gyrus (DG) regions of the hippocampus. Electrophysiological recordings from hippocampi of anesthetized rats show that hypothyroidism impairs L-LTP in CA1 region, but not in the DG. Western blot analysis of the CA1 region shows that hypothyroidism decreases phosphorylated ERK1 and ERK2 levels without affecting their total levels. In the DG of the hypothyroid rat, however, there was no significant change in the levels of phosphorylated or total ERKs. The correlation between the effect of hypothyroidism on L-LTP and enzyme levels suggests that hypothyroidism-induced impairment of L-LTP in CA1 may be due to decreased levels of phosphorylated ERK1 and ERK2.