Differences In Long-term Potentiation Research Articles

Continuous exercise training rescues hippocampal long-term potentiation in the VPA rat model of Autism: Uncovering sex-specific effects

Long‐term potentiation (LTP) impairment has been reported in many studies of autistic models. The aim of the present study was to investigate the effects of interval training (IT) and continuous training (CT) exercises on LTP in the hippocampal dentate gyrus (DG) neurons of valproic acid (VPA) rat model of autism. To induce an autism-like model, pregnant rats were injected 500 mg/kg NaVPA (intraperitoneal) on the embryonic day 12.5. IT and CT aerobic exercises started on postnatal day 56 in the offspring. Four weeks after IT and/or CT exercises, the offspring were urethane-anesthetized and placed into a stereotaxic apparatus for surgery, electrode implantation, and field potential recording. In the DG region, excitatory post synaptic potentials (EPSP) slope and population spike (PS) amplitude were measured. Sex differences in LTP were evident for control rats but not for VPA-exposed offspring. LTP was significantly smaller in VPA-exposed male offspring compared with control male rats. In contrast to males, there was no difference between VPA-exposed female offspring and control female rats. Interestingly, we observed a sex difference in the response to exercise between VPA-exposed male and female offspring. CT exercise training (but not IT) increased LTP in VPA-exposed male offspring. Both IT and CT exercise trainings had no effect on intact LTP in VPA-exposed female offspring. Our work suggests that there may be differences in the benefits of exercise interventions based on sex, and CT exercise training could be more beneficial for LTP improvements.

Age-related differences in long-term potentiation-like plasticity and short-latency afferent inhibition and their association with cognitive function

BackgroundThe neurophysiological differences in cortical plasticity and cholinergic system function due to ageing and their correlation with cognitive function remain poorly understood.AimsTo reveal the differences in long-term potentiation (LTP)-like plasticity...

Generation and characterization of a knock-in mouse model for spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM).

Solute carrier family 1 member 4(SLC1A4), also referred to as Alanine/Serine/Cysteine/Threonine-preferring Transporter 1(ASCT1), is a sodium-dependent neutral amino acid transporter. It is expressed in many tissues, including the brain, where it is expressed primarily on astrocytes and plays key roles in neuronal differentiation and development, maintaining neurotransmitter homeostasis, and N-methyl-D-aspartate neurotransmission, through regulation of L- and D-serine. Mutations in SLC1A4 are associated with the rare autosomal recessive neurodevelopmental disorder spastic tetraplegia, thin corpus callosum, and progressive microcephaly (SPATCCM, OMIM 616657). Psychomotor development and speech are significantly impaired in these patients, and many develop seizures. We generated and characterized a knock-in mouse model for the most common mutant allele, which results in a single amino acid change (p.Glu256Lys, or E256K). Homozygous mutants had increased D-serine uptake in the brain, microcephaly, and thin corpus callosum and cortex layer 1. While p.E256K homozygotes showed some significant differences in exploratory behavior relative to wildtype mice, their performance in assays for motor coordination, endurance, learning, and memory was normal, and they showed no significant differences in long-term potentiation. Taken together, these results indicate that the impact of the p.E256K mutation on cognition and motor function is minimal in mice, but other aspects of SLC1A4 function in the brain are conserved. Mice homozygous for p.E256K may be a good model for understanding the developmental basis of the corpus callosum and microcephaly phenotypes observed in SPATCCM patients and assessing whether they are rescued by serine supplementation.

Strain-dependent regulation of hippocampal long-term potentiation by dopamine D1/D5 receptors in mice.

The magnitude and persistency of long-term potentiation (LTP) in the rodent hippocampus is species-dependent: rats express more robust and more prolonged LTP in response to a broader afferent frequency range than mice. The C57Bl/6 mouse is an extremely popular murine strain used in studies of hippocampal synaptic plasticity and spatial learning. Recently it was reported that it expresses impoverished LTP compared to other murine strains. Given the important role of the dopamine D1/D5 receptor (D1/D5R) in the maintenance of LTP and in memory consolidation, we explored to what extent strain-dependent differences in LTP in mice are determined by differences in D1/D5R-control. In CaOlaHsd mice, robust LTP was induced that lasted for over 24 h and which was significantly greater in magnitude than LTP induced in C57Bl/6 mice. Intracerebral treatment with a D1/D5R-antagonist (SCH23390) prevented both the early and late phase of LTP in CaOlaHsd mice, whereas only late-LTP was impaired in C57Bl/6 mice. Treatment with a D1/D5R-agonist (Chloro-PB) facilitated short-term potentiation (STP) into LTP (> 24 h) in both strains, whereby effects became evident earlier in CaOlaHsd compared to C57Bl/6 mice. Immunohistochemical analysis revealed a significantly higher expression of D1-receptors in the stratum lacunosum moleculare of CaOlaHsd compared to C57Bl/6 mice. These findings highlight differences in D1/D5R- dependent regulation of strain-dependent variations in hippocampal LTP in C57Bl/6 and CaOlaHsd mice, that may be mediated, in part, by differences in the expression of D1R in the hippocampus.

Enhanced synaptic properties of the prefrontal cortex and hippocampus after learning a spatial working memory task in adult male mice

Working memory (WM) is the ability to hold on-line and manipulate information. The prefrontal cortex (PFC) is a key brain region involved in WM, while the hippocampus is also involved, particularly, in spatial WM. Although several studies have investigated the neuronal substrates of WM in trained animals, the effects and the mechanisms underlying learning WM tasks have not been explored. In our study, we investigated the effects of learning WM tasks in mice on the function of PFC and hippocampus, by training mice in the delayed alternation task for 9days (adaptive group). This group was compared to naïve mice (which stayed in their homecage) and mice trained in the alternation procedure only (non-adaptive). Following training, a cohort of mice (Experiment A) was tested in the left-right discrimination task and the reversal learning task, while another cohort (Experiment B) was tested in the attention set-shifting task (AST). The adaptive group performed significantly better in the reversal learning task (Experiment A) and AST (Experiment B), compared to non-adaptive and naïve groups. At the end of the behavioral experiments in Experiment A, field excitatory post-synaptic potential (fEPSP) recordings were performed in PFC and hippocampal brain slices. The adaptive group had enhanced the long-term potentiation (LTP) in the PFC, compared to the other groups. In the hippocampus, both the adaptive and the non-adaptive groups exhibited increased fEPSP compared to the naïve group, but no differences in LTP. In Experiment B, the dendritic spine density was measured, which, in the PFC, was found increased in the adaptive group, compared to the non-adaptive and naïve groups. In the hippocampus, there was an increase in mature dendritic spine density in the adaptive group, compared to the other two groups. Our results indicate a role for LTP and dendritic spine density in learning WM tasks.

Decreased circadian fluctuation in cognitive behaviors and synaptic plasticity in APP/PS1 transgenic mice.

Cognitive decline, memory impairment and circadian rhythm disturbance are iconic manifestations of Alzheimer's disease (AD). APPswe/PS1dE9 (APP/PS1) mice, a model of AD, show deficits in multiple learning and memory abilities, synaptic plasticity, and behavioral circadian rhythm, but whether circadian differences in cognitive performance and synaptic plasticity could be affected in AD remain unclear. Here, the cognitive behaviors of 6-month-old APP/PS1 mice were assessed by multiple behavior tests in the rest phase (light period) or active phase (dark period) of the day. The possible electrophysiological mechanism was subsequently investigated by in vivo hippocampal long-term potentiation (LTP) recording, and the locomotor activity rhythm of the mice was detected using wheel-running activities. Compared to wild-type (WT) mice, APP/PS1 mice exhibited long-term spatial memory impairment and in vivo hippocampal LTP suppression. In addition, in APP/PS1 mice, circadian differences in new object recognition memory and LTP were lost, and the circadian difference in long-term spatial memory was decreased, accompanied by a less robust locomotor activity rhythm. These results indicate that the loss of circadian differences in new object recognition memory and the decrease in the circadian difference in long-term spatial memory in APP/PS1 mice, which are closely associated with the loss of the circadian difference in LTP and less robust locomotor activity, might occur early in the course of AD.

Polarity and subfield specific effects of transcranial direct current stimulation on hippocampal plasticity.

An increasing number of studies using human subjects substantiate the use of transcranial direct current stimulation (tDCS) as a noninvasive approach to treat various neurological symptoms. tDCS has been tested in conditions from motor to cognition dysfunctions. Performance enhancement of healthy subjects using tDCS has also been explored. The underlying physiological mechanism for tDCS effects is hypothesized to be through changes in neuroplasticity and we have previously demonstrated that in vivo anodal tDCS can enhance neuroplasticity of hippocampal CA1 neurons. The purpose of this study was to determine whether the underlying electrophysiological changes that occur following in vivo tDCS are polarity specific. We also examined both the CA1 and CA3 regions of the hippocampus to determine whether the tDCS effects were subfield specific. We conducted in vivo tests of cathodal tDCS versus anodal tDCS on synaptic plasticity of CA1 and CA3 neurons of male rats. In each region we assessed long term potentiation (LTP), paired pulse facilitation (PPF) and long term depression (LTD). In the CA1 region, we found anodal tDCS significantly enhanced not only LTP and PPF, but also LTD. There was no statistical difference in LTP, PPF or LTD of hippocampal CA1 neurons resulting from cathodal tDCS. Neither anodal nor cathodal tDCS induced significant changes in neuroplasticity of hippocampal CA3 neurons. Results indicate that the effects of tDCS are subfield specific and polarity dependent with anodal tDCS having greater impact on synaptic activity in the rat hippocampus than cathodal tDCS.

Melatonin modulates daytime-dependent synaptic plasticity and learning efficiency.

Mechanisms of hippocampus-related memory formation are time-of-day-dependent. While the circadian system and clock genes are related to timing of hippocampal mnemonic processes (acquisition, consolidation, and retrieval of long-term memory [LTM]) and long-term potentiation (LTP), little is known about temporal gating mechanisms. Here, the role of the neurohormone melatonin as a circadian time cue for hippocampal signaling and memory formation was investigated in C3H/He wildtype (WT) and melatonin receptor-knockout ( ) mice. Immunohistochemical and immunoblot analyses revealed the presence of melatonin receptors on mouse hippocampal neurons. Temporal patterns of time-of-day-dependent clock gene protein levels were profoundly altered in mice compared to WT animals. On the behavioral level, WT mice displayed better spatial learning efficiency during daytime as compared to nighttime. In contrast, high error scores were observed in mice during both, daytime and nighttime acquisition. Day-night difference in LTP, as observed in WT mice, was absent in mice and in WT animals, in which the sympathetic innervation of the pineal gland was surgically removed to erase rhythmic melatonin synthesis. In addition, treatment of melatonin-deficient C57BL/6 mice with melatonin at nighttime significantly improved their working memory performance at daytime. These results illustrate that melatonin shapes time-of-day-dependent learning efficiency in parallel to consolidating expression patterns of clock genes in the mouse hippocampus. Our data suggest that melatonin imprints a time cue on mouse hippocampal signaling and gene expression to foster better learning during daytime.

GSK3 activity regulates rhythms in hippocampal clock gene expression and synaptic plasticity.

Hippocampal rhythms in clock gene expression, enzymatic activity, and long-term potentiation (LTP) are thought to underlie day-night differences in memory acquisition and recall. Glycogen synthase kinase 3-beta (GSK3β) is a known regulator of hippocampal function, and inhibitory phosphorylation of GSK3β exhibits region-specific differences over the light-dark cycle. Here, we sought to determine whether phosphorylation of both GSK3α and GSK3β isoforms has an endogenous circadian rhythm in specific areas of the hippocampus and whether chronic inhibition or activation alters the molecular clock and hippocampal plasticity (LTP). Results indicated a significant endogenous circadian rhythm in phosphorylation of GSK3β, but not GSK3α, in hippocampal CA1 extracts from mice housed in constant darkness for at least 2weeks. To examine the importance of this rhythm, genetic and pharmacological strategies were used to disrupt the GSK3 activity rhythm by chronically activating or inhibiting GSK3. Chronic activation of both GSK3 isoforms in transgenic mice (GSK3-KI mice) diminished rhythmic BMAL1 expression. On the other hand, chronic treatment with a GSK3 inhibitor significantly shortened the molecular clock period of organotypic hippocampal PER2::LUC cultures. While WT mice exhibited higher LTP magnitude at night compared to day, the day-night difference in LTP magnitude remained with greater magnitude at both times of day in mice with chronic GSK3 activity. On the other hand, pharmacological GSK3 inhibition impaired day-night differences in LTP by blocking LTP selectively at night. Taken together, these results support the model that circadian rhythmicity of hippocampal GSK3β activation state regulates day/night differences in molecular clock periodicity and a major form of synaptic plasticity (LTP).

Sex Differences in Long-Term Potentiation at Temporoammonic-CA1 Synapses: Potential Implications for Memory Consolidation.

Sex differences in spatial memory have long been observed in humans, non-human primates and rodents, but the underlying cellular and molecular mechanisms responsible for these differences remain obscure. In the present study we found that adolescent male rats outperformed female rats in 7 d and 28 d retention probes, but not in learning trials and immediate probes, in the Morris water maze task. Male rats also had larger long-term potentiation (LTP) at hippocampal temproammonic-CA1 (TA-CA1) synapses, which have been implicated to play a key role in place field and memory consolidation, when protocols designed to elicit late-stage LTP (LLTP) were used. Interestingly, the ratio of evoked AMPA/NMDA currents was found to be smaller at TA-CA1 synapses in male rats compared to female rats. Protein biotinylation experiments showed that male rats expressed more surface GluN1 receptors in hippocampal CA1 stratum lacunosum-moleculare (SLM) than female rats, although GluA1 expression was also slightly higher in male rats. Taken together, our results suggest that differences in the expression of AMPA and NMDA receptors may affect LTP expression at TA-CA1 synapses in adolescent male and female rats, and thus possibly contribute to the observed sex difference in spatial memory.

Theta burst stimulation-induced LTP: Differences and similarities between the dorsal and ventral CA1 hippocampal synapses.

The hippocampal synapses display a conspicuous ability for long-term plasticity, which is thought to contribute to learning and memory. Previous research has shown that long-term potentiation (LTP) greatly differs between the dorsal (DH) and ventral (VH) CA1 hippocampal synapses when induced by high-frequency stimulation. In this study, using rat hippocampal slices and more physiologically relevant activity patterns based on the frequency of the theta rhythm (i.e., theta-burst stimulation, TBS) we found that the DH compared with the VH displayed a higher ability for induction and stability of NMDA receptor-dependent LTP of the field excitatory postsynaptic potential. Nevertheless, the maximal magnitude of LTP was similar in the two hippocampal segments. Blockade of GABAB receptors prevented the LTP induction by the minimal effective TBS and reduced the magnitude of LTP induced by longer TBS. TBS produced a three-fold higher facilitation of the synaptic burst responses in the DH compared with the VH, accompanied by a strong enhancement in the postsynaptic excitation in the DH but mostly depression in the VH. The DH displayed NMDA receptor-dependent and NMDA receptor-independent facilitation, but the facilitation in the VH was only NMDA receptor-dependent. Also, the TBS-associated activity of GABAB receptors was higher in the DH than in the VH. The different response profiles during TBS could underlie the differences in LTP between the two hippocampal segments. L-type voltage-dependent calcium channels (L-VDCC) and the metabotropic glutamate receptor-5 (mGluR5) equally contributed in DH and VH to compound LTP induced by relatively long TBS. We propose that these dorsoventral differences in synaptic plasticity reflect specializations of the intrinsic circuitry of the hippocampus, that are involved in the distinct information processing performed by the two hippocampal segments and could effectively support the contribution of the dorsal and the ventral hippocampal segment to single event memory and to emotional memory respectively. © 2016 Wiley Periodicals, Inc.

Gender differences in spatial learning, synaptic activity, and long-term potentiation in the hippocampus in rats: molecular mechanisms.

In tests of spatial ability, males outperform females both in rats and in humans. The mechanism underlying this gender differential learning ability and memory in spatial tasks remains unknown. Long-term potentiation (LTP) in the hippocampus is considered the basis for spatial learning and memory. The aims of this work were (a) to assess spatial learning and memory in male and female rats in the radial and Morris mazes; (b) to assess whether basal synaptic activity and LTP in the hippocampus are different in male and female rats; and (c) to identify the molecular mechanisms responsible for the gender differences in LTP. We analyzed in young male and female rats (a) performance in spatial tasks in the radial and Morris water mazes; (b) basal synaptic activity in hippocampal slices; and (c) LTP and some mechanisms modulating its magnitude. The results reported allow us to conclude that female rats show larger AMPA receptor-mediate synaptic responses under basal conditions, likely due to enhanced phosphorylation of GluR2 in Ser880 and increased amounts of GluR2-containing AMPA receptors in postsynaptic densities. In contrast, the magnitude of tetanus-induced LTP was lower in females than in males. This is due to reduced activation of soluble guanylate cyclase and the formation of cGMP, leading to lower activation of cGMP-dependent protein kinase and phosphorylation of GluR1 in Ser845, which results in lower insertion of AMPA receptors in the synaptic membrane and a lower magnitude of LTP. These mechanisms may contribute to the reduced performance of females in the radial and Morris water mazes.

Aging alters long-term potentiation–related gene networks and impairs synaptic protein synthesis in the rat hippocampus

During aging, memory retention and persistence of long-term potentiation (LTP) are impaired, suggesting an aging-related deterioration in mechanisms regulating information storage. Late-phase LTP requires synthesis of proteins at synapses as well as integrated regulation of gene networks. Because aging diminishes the persistence of LTP, primarily by affecting the transition between early and late phases, we assessed whether this was reflected in perturbation of gene networks. Using DNA microarray analysis, we compared LTP-associated gene expression in young (5 months), middle-aged (15 months), and old (22 months) male Sprague–Dawley rats. As expected, we found no significant difference in LTP measured 20 minutes postinduction; however, we found that overall more genes were regulated in the young group. Bioinformatics predicted not only dysregulation of activator protein-1 and nuclear factor kB transcription factor activity and epigenetic modifications but also dysregulation of protein synthesis. Notably, we confirmed an age-related impairment in metabotropic and ionotropic receptor–mediated synaptic protein synthesis. Together, these results demonstrate that LTP-specific gene expression is altered with aging and suggest that dysregulation of synaptic protein synthesis also contributes to the age-dependent reduction in LTP persistence.

The influence of high frequency, repetitive transcranial magnetic stimulation on long-term potentiation in the hippocampus and on spatial learning and memory after global cerebral ischemia

Objective To investigate the effects of repeated high frequency transcranial magnetic stimulation (rTMS) on spatial learning and memory function,and on long-term potentiation (LTP) after global cerebral ischemia and reperfusion,and to explore the mechanisms involved.Methods Eighty-three male Wistar rats were studied.Five were tested to determine their average motor threshold (Tm).The others were divided into a normal control group,a cerebral ischemia and reperfusion model group and an rTMS group.Cerebral ischemia was induced with the four vessel occlusion method for 10 minutes.The rTMS treatment protocol (10 Hz stimulation for 5 s at the resting threshold,twice a day) was applied over a 2-week period from day 3 post-operation.The Morris water maze test was performed to observe spatial learning and memory at post-operation day 2 and day 4.The field excitatory postsynaptic potentials,population spike and the magnitude of long-term potentiation (LTP) induced by theta burst electric stimulation were recorded from the perforant path to the dentate gyrus (PP-DG).Results At post-operation day 3,rats in the untreated cerebral ischemia and reperfusion model group exhibited a significant decrease in the magnitude of the PP-DG LTP as compared to the normal group.No significant difference in LTP was found between the model group and the rTMS group.After the 2 weeks of treatment the LTP levels in the rTMS treated group were significantly higher than in the two untreated groups.In the Morris water maze testing,the average escape latency in the rTMS group was significantly shorter than that of the cerebral ischemia and reperfusion model group (which was not treated).In the probe trials,the time in the original quadrant of the platform and the time of crossing the platform were both significantly less for the rTMS-treated rats than for those not treated.Conclusions High frequency rTMS can improve spatial learning and memory after global cerebral ischemia and reperfusion by enhancing the LTP induced in the hippocampus.High frequency rTMS might exert this beneficial effect by modulating the function of intermediate neurons in the hippocampal neuronal network and by promoting neurotransmitter release. Key words: Transcranial magnetic stimulation; Cerebral ischemia; Spatial learning; Memory; Long-term potentiation

Neonatal ketamine exposure-induced cognitive dysfunction persists into adulthood in rats

Objective To determine ff cognitive dysfunction induced by neonatal ketamine anesthesia can persist into adulthood.Methods Thirty 7-day-old SD rats of both sexes were randomly divided into 3 groups.Control group received normal saline 0.2 ml intraperitoneally (IP) (group C),while ketamine groups 1 and 2 received ketamine 25 and 50 mg/kg IP respectively (groups K1,K2 ).Morris water maze test was performed and hippocampal long-term potentiation (LTP) recorded when the rats were 2.5 months old.Results LTP was significantly lower in groups K1 and K2 than in group C.There was no significant difference in LTP between groups K1 and K2.The escape latency and swimming time were comparable among the 3 groups.Conclusion Neonatal ketamine anesthesia can decrease the cognitive function in adult rats.There is no significant difference between light and deep ketamine anesthesia. Key words: Ketamine; Cognition disorders; Infant, newborn; Adult

Vestibular stimulation enhances hippocampal long-term potentiation via activation of cholinergic septohippocampal cells

Vestibular stimulation induced acetylcholine release in the hippocampus, and acetylcholine is known to facilitate long-term potentiation (LTP) in the hippocampus. Thus, we hypothesize that vestibular stimulation enhances LTP in CA1 in freely behaving rats, and this enhancement depends on the activation of septohippocampal cholinergic neurons. Field excitatory postsynaptic potentials were recorded in CA1 area of behaving rats following stimulation of the basal dendritic afferents. LTP was induced by a single stimulation train (100 pulses at 200Hz) during passive whole-body rotation or during awake-immobility. LTP induced during rotation was significantly larger than that induced during immobility. Pretreatment with cholinergic antagonist atropine sulfate (50mg/kg i.p.) abolished the facilitation of LTP during rotation as compared to immobility. Selective lesion of cholinergic cells in the medial septum (MS) with 192 IgG-saporin (0.49μg in 1.4μl) also abolished the difference in LTP induced during rotation and immobility, which was found in sham-lesion rats. 192 IgG-saporin lesioned rats, as compared to sham-lesion rats, revealed a depletion of MS cells immunopositive to choline acetyltransferase and paling of acetylcholinesterase staining in the hippocampus, without significant change in the number of parvalbumin-immunopositive cells. We conclude that enhancement of LTP during vestibular stimulation is mediated by the activation of cholinergic septohippocampal cells. This is the first direct evidence that vestibular stimulation facilitates hippocampal synaptic plasticity via a cholinergic input.

Pull-Push Neuromodulation of LTP and LTD Enables Bidirectional Experience-Induced Synaptic Scaling in Visual Cortex

Neuromodulatory input, acting on G protein-coupled receptors, is essential for the induction of experience-dependent cortical plasticity. Here we report that G-coupled receptors in layer II/III of visual cortex control the polarity of synaptic plasticity through a pull-push regulation of LTP and LTD. In slices, receptors coupled to Gs promote LTP while suppressing LTD; conversely, receptors coupled to Gq11 promote LTD and suppress LTP. In vivo, the selective stimulation of Gs- or Gq11-coupled receptors brings the cortex into LTP-only or LTD-only states, which allows the potentiation or depression of targeted synapses with visual stimulation. The pull-push regulation of LTP/LTD occurs via direct control of the synaptic plasticity machinery and it is independent of changes in NMDAR activation or neuronal excitability. We propose these simple rules governing the pull-push control of LTP/LTD form a general metaplasticity mechanism that may contribute to neuromodulation of plasticity in other cortical circuits.

Synaptic Plasticity in the Hippocampus of a APP/PS1 Mouse Model of Alzheimer's Disease Is Impaired in Old but Not Young Mice

BackgroundAlzheimer disease (AD) is a neurodegenerative disorder for which there is no cure. We have investigated synaptic plasticity in area CA1 in a novel AD mouse model (APPPS1-21) which expresses the Swedish mutation of APP and the L166P mutation of human PS-1. This model shows initial plaque formation at 2 months in the neocortex and 4 months in the hippocampus and displays β−amyloid-associated pathologies and learning impairments.Methodology/Principal FindingsWe tested long-term potentiation (LTP) and short term potentiation (paired-pulse facilitation, PPF) of synaptic transmission in vivo in area CA1 of the hippocampus. There was no difference in LTP or PPF at 4–5 months of age in APPPS1-21 mice compared to littermate controls. At 6 months of age there was also no difference in LTP but APPPS1-21 mice showed slightly increased PPF (p<0.03). In 8 months old mice, LTP was greatly impaired in APPPS-21 animals (p<0.0001) while PPF was not changed. At 15 months of age, APPPS1-21 mice showed again impaired LTP compared to littermate controls (p<0.005), and PPF was also significantly reduced at 80 ms (p<0.005) and 160 ms (p<0.01) interstimulus interval. Immunohistological analysis showed only modest amyloid deposition in the hippocampus at 4 and 6 months with a robust increase up to 15 months of age.ConclusionsOur results suggest that increased formation and aggregation of beta amyloid with aging is responsible for the impaired LTP with aging in this mouse model, while the transient increase of PPF at 6 months of age is caused by some other mechanism.

Effects of Saccharin Intake on Hippocampal and Cortical Plasticity in Juvenile and Adolescent Rats

The sensory system is developed and optimized by experiences given in the early phase of life in association with other regions of the nervous system. To date, many studies have revealed that deprivation of specific sensory experiences can modify the structure and function of the central nervous system; however, the effects of sensory overload remains unclear. Here we studied the effect of overloading the taste sense in the early period of life on the synaptic plasticity of rat hippocampus and somatosensory cortex. We prepared male and female Sprague Dawley rats with ad libitum access to a 0.1% saccharin solution for 2 hrs per day for three weeks after weaning on postnatal day 22. Saccharin consumption was slightly increased in males compared with females; however, saccharin intake did not affect chow intake or weight gain either in male or in female rats. We examined the effect of saccharin-intake on long term potentiation (LTP) formation in hippocampal Schaffer collateral pathway and somatosensory cortex layer IV - II/III pathways in the 6-week old saccharin-fed rats. There was no significant difference in LTP formation in the hippocampus between the control group and saccharin-treated group in both male and female rats. Also in the somatosensory cortex, we did not see a significant difference in LTP among the groups. Therefore, we conclude that saccharin-intake during 3~6 weeks may not affect the development of physiological function of the cortical and hippocampal synapses in rats.

Dissociation of synaptic dysfunction and behavior in a tauopathy mouse model (PrP-MAPT) of Alzheimer's disease

One major pathophysiological features of Alzheimer's disease (AD) is the accumulation neurofibrillary tangles originating from aggregation of hyperphosphorylated tau. Tau binds to and stabilizes microtubules (MTs) which, in turn, provide structural support and a scaffold for shuttling of essential proteins between the cell body and axon. MT function is governed by a dynamic equilibrium of phosphorylation and dephosphorylation mechanisms; however, aberrant hyperphosphorylation of tau results in its dissociation from MTs, resulting in MT instability and tau aggregation, both of which may independently lead to neurotoxicity. Here, we used PrP-MAPT mice that over-express normal human fetal tau (3R/0N isoform) to better understand the temporal relationship between tau accumulation with synaptic and behavioral deficits. We initiated the electrophysiology studies in the hippocampus_a region critical for memory formation. Field potential recordings were obtained from the lateral perforant path of the dentate gyrus of either wild-type (WT) or heterozygous (Het) mice aged 2, 4 or 10 months, and assessments included basal transmission and long-term potentiation (LTP). At 2 months of age, no difference in the magnitude of LTP between genotypes was observed but a subtle impairment in basal transmission was detected in the Het's even at this early age. By 4 months of age, differences in LTP (WT: 178.2±6.4%, n=6; Het: 148.1±11.9%, n=9) and basal synaptic transmission were observed. Notably, 4 month Het LTP data revealed a large variation in the magnitude of potentiation in that some slices had WT LTP magnitudes while others showed deficits. This duality suggests that at 4 months, Het mice may reside on a threshold between normal and abnormal function. Consistent with this hypothesis, assessment of 9-10 month old mice revealed a further decline in LTP magnitudes (WT: 171.9±7.7%, n=7; Het: 136.7±6.2%, n=8). Behavioral studies were conducted in parallel to ascertain whether these synaptic deficits correlated with age-related cognitive impairments measured in the Morris water maze, a hippocampal-dependent cognitive assay. Surprisingly, no difference between WT and Het animals was found at any age in MWM performance. These results suggest that overexpression of normal tau protein negatively influences hippocampal synaptic properties, but retain sufficient capacity for performing a hippocampal-dependent behavioral test.