Plasticity In CA1 Research Articles

Denervated mouse CA1 pyramidal neurons express homeostatic synaptic plasticity following entorhinal cortex lesion.

Structural, functional, and molecular reorganization of denervated neural networks is often observed in neurological conditions. The loss of input is accompanied by homeostatic synaptic adaptations, which can affect the reorganization process. A major challenge of denervation-induced homeostatic plasticity operating in complex neural networks is the specialization of neuronal inputs. It remains unclear whether neurons respond similarly to the loss of distinct inputs. Here, we used in vitro entorhinal cortex lesion (ECL) and Schaffer collateral lesion (SCL) in mouse organotypic entorhino-hippocampal tissue cultures to study denervation-induced plasticity of CA1 pyramidal neurons. We observed microglia accumulation, presynaptic bouton degeneration, and a reduction in dendritic spine numbers in the denervated layers 3 days after SCL and ECL. Transcriptome analysis of the CA1 region revealed complex changes in differential gene expression following SCL and ECL compared to non-lesioned controls with a specific enrichment of differentially expressed synapse-related genes observed after ECL. Consistent with this finding, denervation-induced homeostatic plasticity of excitatory synapses was observed 3 days after ECL but not after SCL. Chemogenetic silencing of the EC but not CA3 confirmed the pathway-specific induction of homeostatic synaptic plasticity in CA1. Additionally, increased RNA oxidation was observed after SCL and ECL. These results reveal important commonalities and differences between distinct pathway lesions and demonstrate a pathway-specific induction of denervation-induced homeostatic synaptic plasticity.

All-optical physiology resolves a synaptic basis for behavioral timescale plasticity

Learning has been associated with modifications of synaptic and circuit properties, but the precise changes storing information in mammals have remained largely unclear. We combined genetically targeted voltage imaging with targeted optogenetic activation and silencing of pre- and post-synaptic neurons to study the mechanisms underlying hippocampal behavioral timescale plasticity. In mice navigating a virtual-reality environment, targeted optogenetic activation of individual CA1 cells at specific places induced stable representations of these places in the targeted cells. Optical elicitation, recording, and modulation of synaptic transmission in behaving mice revealed that activity in presynaptic CA2/3 cells was required for the induction of plasticity in CA1 and, furthermore, that during induction of these place fields in single CA1 cells, synaptic input from CA2/3 onto these same cells was potentiated. These results reveal synaptic implementation of hippocampal behavioral timescale plasticity and define a methodology to resolve synaptic plasticity during learning and memory in behaving mammals.

Microglial diversity along the hippocampal longitudinal axis impacts synaptic plasticity in adult male mice under homeostatic conditions.

The hippocampus is a plastic brain area that shows functional segregation along its longitudinal axis, reflected by a higher level of long-term potentiation (LTP) in the CA1 region of the dorsal hippocampus (DH) compared to the ventral hippocampus (VH), but the mechanisms underlying this difference remain elusive. Numerous studies have highlighted the importance of microglia-neuronal communication in modulating synaptic transmission and hippocampal plasticity, although its role in physiological contexts is still largely unknown. We characterized in depth the features of microglia in the two hippocampal poles and investigated their contribution to CA1 plasticity under physiological conditions. We unveiled the influence of microglia in differentially modulating the amplitude of LTP in the DH and VH, showing that minocycline or PLX5622 treatment reduced LTP amplitude in the DH, while increasing it in the VH. This was recapitulated in Cx3cr1 knockout mice, indicating that microglia have a key role in setting the conditions for plasticity processes in a region-specific manner, and that the CX3CL1-CX3CR1 pathway is a key element in determining the basal level of CA1 LTP in the two regions. The observed LTP differences at the two poles were associated with transcriptional changes in the expression of genes encoding for Il-1, Tnf-α, Il-6, and Bdnf, essential players of neuronal plasticity. Furthermore, microglia in the CA1 SR region showed an increase in soma and a more extensive arborization, an increased prevalence of immature lysosomes accompanied by an elevation in mRNA expression of phagocytic markers Mertk and Cd68 and a surge in the expression of microglial outward K+ currents in the VH compared to DH, suggesting a distinct basal phenotypic state of microglia across the two hippocampal poles. Overall, we characterized the molecular, morphological, ultrastructural, and functional profile of microglia at the two poles, suggesting that modifications in hippocampal subregions related to different microglial statuses can contribute to dissect the phenotypical aspects of many diseases in which microglia are known to be involved.

Hippocampal oxytocin is involved in spatial memory and synaptic plasticity deficits following acute high-fat diet intake in juvenile rats.

The hippocampus undergoes maturation during juvenility, a period of increased vulnerability to environmental challenges. We recently found that acute high-fat diet (HFD) impaired hippocampal long-term potentiation (LTP) and hippocampal-dependent spatial memory. We also recently reported that similar HFD exposure affected prefrontal plasticity and social memory through decreased oxytocin levels in the prefrontal cortex. In the present study, we therefore evaluated whether hippocampal oxytocin levels are also affected by juvenile HFD and could mediate deficits of hippocampal LTP and spatial memory. We found that postweaning HFD decreased oxytocin levels in the CA1 of the dorsal hippocampus. Interestingly, systemic injection of high, but not low, dose of oxytocin rescued HFD-induced LTP impairment in CA1. Moreover, deficits in long-term object location memory (OLM) were prevented by systemic injection of both high and low dose of oxytocin as well as by intra-CA1 infusion of oxytocin receptor agonist. Finally, we found that blocking oxytocin receptors in CA1 impaired long-term OLM in control-fed juvenile rats. These results suggest that acute HFD intake lowers oxytocin levels in the CA1 that lead to CA1 plasticity impairment and spatial memory deficits in juveniles. Further, these results provide the first evidence for the regulatory role of oxytocin in spatial memory.

Disrupted presynaptic nectin1-based neuronal adhesion in the entorhinal-hippocampal circuit contributes to early-life stress-induced memory deficits

The cell adhesion molecule nectin3 and its presynaptic partner nectin1 have been linked to early-life stress-related cognitive disorders, but how the nectin1-nectin3 system contributes to stress-induced neuronal, circuit, and cognitive abnormalities remains to be studied. Here we show that in neonatally stressed male mice, temporal order and spatial working memories, which require the medial entorhinal cortex (MEC)-CA1 pathway, as well as the structural integrity of CA1 pyramidal neurons were markedly impaired in adulthood. These cognitive and structural abnormalities in stressed mice were associated with decreased nectin levels in entorhinal and hippocampal subregions, especially reduced nectin1 level in the MEC and nectin3 level in the CA1. Postnatal suppression of nectin1 but not nectin3 level in the MEC impaired spatial memory, whereas conditional inactivation of nectin1 from MEC excitatory neurons reproduced the adverse effects of early-life stress on MEC-dependent memories and neuronal plasticity in CA1. Our data suggest that early-life stress disrupts presynaptic nectin1-mediated interneuronal adhesion in the MEC-CA1 pathway, which may in turn contribute to stress-induced synaptic and cognitive deficits.

Early-stage hippocampal hyperexcitability and impaired synaptic plasticity in the TgF344-AD rat model of Alzheimer's disease.

The transgenic TgF344-AD (TG) rat is emerging as a useful model for investigating age-dependent AD features that include behavioural, electrophysiological and pathological phenotypes of relevance to disease. In this study we investigated changes related to early stages of AD in 9 month old animals. Male and female TG rats and wild-type (WT) littermates undertook longitudinal behavioural testing at 3, 6 & 9 months (n=6-13/sex-genotype combination) and were tested for: (i) hippocampus-dependent rapid place learning in a delayed-matching-to place watermaze (DMP) test, (ii) novel object recognition (NOR) memory, (iii) expression of startle/pre-pulse inhibition; and (iv) open-field locomotor activity. In another cohort of rats at 9 months (n=8 males per genotype), spontaneous and evoked activities were record and measured in hippocampal CA3->CA1 circuit to study synaptic plasticity using in vivo electrophysiology under urethane anaesthesia. Following behavioural or electrophysiology testing brains were collected for post-mortem analyses (n=10 males per genotype). GABAergic and synaptic markers including parvalbumin, GAD67 , GABAA α5, SNAP-25 and PSD95 were measured by Simple Western analysis in the frontal cortex, prefrontal cortex, dorsal and ventral hippocampus. Behaviour: WT rats showed poor DMP performance with no clear genotype effect. Object exploration was low with no significant NOR. We found startle and locomotor sex differences, replicating previous reports. Interestingly, at 9 months, TG rats showed locomotor hypoactivity at the beginning and hyperactivity at the end of the 30-min open-field test, indicating impaired habituation, which may reflect impaired hippocampal contextual memory. Electrophysiology: 9-month-old TG rats showed reduced long-term potentiation with an increased baseline connectivity. A general decrease in power across frequency bands was found in the TG, especially for theta band. Western analysis: TG rats showed reduced levels of parvalbumin with a clear effect of genotype at 9-months. There was no detectable changes in synaptic markers. Impaired locomotor habituation of TG rats suggests abnormal hippocampal function emerges around 9 months, reflected by impaired hippocampal CA1 plasticity. A reduction of parvalbumin was also seen in the TG animals at this age. However, poor memory performance may limit the suitability of the TG model for testing clinically relevant memory deficits.

Rapid synaptic plasticity contributes to a learned conjunctive code of position and choice-related information in the hippocampus

To successfully perform goal-directed navigation, animals must know where they are and what they are doing-e.g., looking for water, bringing food back to the nest, or escaping from a predator. Hippocampal neurons code for these critical variables conjunctively, but little is known about how this "where/what" code is formed or flexibly routed to other brain regions. To address these questions, we performed intracellular whole-cell recordings in mouse CA1 during a cued, two-choice virtual navigation task. We demonstrate that plateau potentials in CA1 pyramidal neurons rapidly strengthen synaptic inputs carrying conjunctive information about position and choice. Plasticity-induced response fields were modulated by cues only in animals previously trained to collect rewards based on available cues. Thus, we reveal that gradual learning is required for the formation of a conjunctive population code, upstream of CA1, while plateau-potential-induced synaptic plasticity in CA1 enables flexible routing of the code to downstream brain regions.

Serine/Threonine Phosphatases in LTP: Two B or Not to Be the Protein Synthesis Blocker-Induced Impairment of Early Phase.

Dephosphorylation of target proteins at serine/threonine residues is one of the most crucial mechanisms regulating their activity and, consequently, the cellular functions. The role of phosphatases in synaptic plasticity, especially in long-term depression or depotentiation, has been reported. We studied serine/threonine phosphatase activity during the protein synthesis blocker (PSB)-induced impairment of long-term potentiation (LTP). Established protein phosphatase 2B (PP2B, calcineurin) inhibitor cyclosporin A prevented the LTP early phase (E-LTP) decline produced by pretreatment of hippocampal slices with cycloheximide or anisomycin. For the first time, we directly measured serine/threonine phosphatase activity during E-LTP, and its significant increase in PSB-treated slices was demonstrated. Nitric oxide (NO) donor SNAP also heightened phosphatase activity in the same manner as PSB, and simultaneous application of anisomycin + SNAP had no synergistic effect. Direct measurement of the NO production in hippocampal slices by the NO-specific fluorescent probe DAF-FM revealed that PSBs strongly stimulate the NO concentration in all studied brain areas: CA1, CA3, and dentate gyrus (DG). Cyclosporin A fully abolished the PSB-induced NO production in the hippocampus, suggesting a close relationship between nNOS and PP2B activity. Surprisingly, cyclosporin A alone impaired short-term plasticity in CA1 by decreasing paired-pulse facilitation, which suggests bi-directionality of the influences of PP2B in the hippocampus. In conclusion, we proposed a minimal model of signaling events that occur during LTP induction in normal conditions and the PSB-treated slices.

Dopamine in the hippocampal dentate gyrus modulates spatial learning via D1-like receptors

Increasing evidence supports that dopamine (DA) plays an important role in the hippocampal function via activation of D1-like receptors (D1Rs). As the entry structure of the hippocampal formation, the hippocampal dentate gyrus (DG) is critically involved in spatial learning and memory. Despite a number of studies investigated how DA influences CA1 plasticity and learning, there are fewer studies examining the influence of DA signaling to the DG. To investigate the roles of DA and D1Rs of the DG in modulation of spatial learning and memory, the spatial learning and memory abilities of rats were measured by Morris water maze (MWM), and then the concentration of DA in the DG region was determined by in vivo brain microdialysis and HPLC. Next, the effects of local microinjection of SCH23390 (an antagonist of D1Rs) on extracellular levels of excitatory amino acids (EAAs), including glutamate (Glu) and aspartate (Asp), were measured in the DG region during MWM test in freely-moving conscious rats. During the place navigation trial of MWM test, the escape latency was decreased with the increase in training days, and DA concentration in the DG was significantly increased. In SCH23390 group rats, the escape latency was increased in place navigation trial and the percentage of time spent in target quadrant and the number of platform crossings were decreased in spatial probe trial during MWM test, compared with vehicle group. Furthermore, in vehicle group rats, the extracellular levels of Glu and Asp in the DG were significantly increased during place navigation trial of MWM test, and these responses were partly inhibited by microinjection of SCH23390. Our results suggest that DA activation of D1Rs in the hippocampal DG promotes spatial learning and memory, in part by modulating the responses of EAAs during spatial learning.

P.2.015 - The differential effects of short-term exposure to high fat diet on hippocampal function during juvenility and adulthood

Environmental and metabolic challenges during early life can have long-term devastating effects on cognitive and emotional functions. We recently showed in two lines of experiments that the juvenile brain is different from that of the adult brain; we showed that stress has opposite effects on prefrontal cortex plasticity and extinction [1]. Specifically, while stress results in impaired long-term potentiation (LTP) and extinction in the adult animal, it resulted in enhanced extinction and LTP in the juveniles. Similarly, exposure to long-term high fat diet (HFD) from juvenility until adulthood was associated with enhanced activation and plasticity in the amygdala and impaired activation and plasticity in the hippocampus, while similar exposure starting at adulthood was not associated with these effects [2]. Both stress and HFD are associated with activation of the hypothalamic-pituitary-adrenal (HPA) axis. Based on these findings we focused on the effects of short- term exposure to HFD on synaptic plasticity in Schaffer Collateral- CA1 pathway and hippocampal-dependent spatial memory in adults [post-natal day (PND 60)] and juveniles (PND 27). Rats were exposed to HFD for 7-10 days and CA1 LTP was examined or spatial recognition. In the spatial paradigm, two different objects were located in opposite corners; each rat was allowed to explore the objects for 5 min, 24h after the sample phase the rat was presented with the same two objects one of the objects was placed at a new location. A discrimination index calculated for each animal was expressed as TN/(TN+TF) (TN = time spent exploring the object in the novel location; TF = time spent exploring the object in the familiar location). In the last part of this work we examined the ability of the glucocorticoid receptor (GR) antagonist (RU486) to reverse the effects of the HFD on LTP in the CA1 pathway and on spatial memory. The main finding of this experiment was that short-term HFD deferentially modulates plasticity in the adult animals as compared to the juveniles. Specifically, in the Schaffer Collateral- CA1 pathway, in contrast to the adult animals where exposure to short-term HFD enhanced the induction of LTP; in the juvenile animals’ exposure to the same duration of HFD inhibited LTP in the CA1. Furthermore, corresponding to these results, short-term HFD enhanced spatial memory in adult animals while it abolished spatial memory in juvenile rats. In addition, after systemic application of GRs antagonist the effects of HFD were no longer observed; the antagonist abolished the induction of LTP in the HFD-fed adults while enhancing induction in HFD-fed juveniles and reversed the HFD effects on spatial memory.The results were presented as mean ± S.E.M. For statistical analysis, independent t-test and ANOVA for repeated measures tests were used as indicated. These results suggest developmental differences in the way short-term HFD affects CA1 plasticity and the spatial memory. These effects are differently modulated by GRs; inhibition of GRs normalized the potentiation in CA1. These effects of HFD may be relevant to the increase prevalence of emotional and behavioral disorders in children exposed to western diet.

Foxp1 in Forebrain Pyramidal Neurons Controls Gene Expression Required for Spatial Learning and Synaptic Plasticity.

Genetic perturbations of the transcription factor Forkhead Box P1 (FOXP1) are causative for severe forms of autism spectrum disorder that are often comorbid with intellectual disability. Recent work has begun to reveal an important role for FoxP1 in brain development, but the brain-region-specific contributions of Foxp1 to autism and intellectual disability phenotypes have yet to be determined fully. Here, we describe Foxp1 conditional knock-out (Foxp1cKO) male and female mice with loss of Foxp1 in the pyramidal neurons of the neocortex and the CA1/CA2 subfields of the hippocampus. Foxp1cKO mice exhibit behavioral phenotypes that are of potential relevance to autism spectrum disorder, including hyperactivity, increased anxiety, communication impairments, and decreased sociability. In addition, Foxp1cKO mice have gross deficits in learning and memory tasks of relevance to intellectual disability. Using a genome-wide approach, we identified differentially expressed genes in the hippocampus of Foxp1cKO mice associated with synaptic function and development. Furthermore, using magnetic resonance imaging, we uncovered a significant reduction in the volumes of both the entire hippocampus as well as individual hippocampal subfields of Foxp1cKO mice. Finally, we observed reduced maintenance of LTP in area CA1 of the hippocampus in these mutant mice. Together, these data suggest that proper expression of Foxp1 in the pyramidal neurons of the forebrain is important for regulating gene expression pathways that contribute to specific behaviors reminiscent of those seen in autism and intellectual disability. In particular, Foxp1 regulation of gene expression appears to be crucial for normal hippocampal development, CA1 plasticity, and spatial learning.SIGNIFICANCE STATEMENT Loss-of-function mutations in the transcription factor Forkhead Box P1 (FOXP1) lead to autism spectrum disorder and intellectual disability. Understanding the potential brain-region-specific contributions of FOXP1 to disease-relevant phenotypes could be a critical first step in the management of patients with these mutations. Here, we report that Foxp1 conditional knock-out (Foxp1cKO) mice with loss of Foxp1 in the neocortex and hippocampus display autism and intellectual-disability-relevant behaviors. We also show that these phenotypes correlate with changes in both the genomic and physiological profiles of the hippocampus in Foxp1cKO mice. Our work demonstrates that brain-region-specific FOXP1 expression may relate to distinct, clinically relevant phenotypes.

Membrane-associated guanylate kinase dynamics reveal regional and developmental specificity of synapse stability.

The membrane-associated guanylate kinase (MAGUK) family of synaptic scaffolding proteins anchor glutamate receptors at CNS synapses. MAGUK removal via RNAi-mediated knockdown in the CA1 hippocampal region in immature animals causes rapid and lasting reductions in glutamatergic transmission. In mature animals, the same manipulation has little acute effect. The hippocampal dentate gyrus, a region with ongoing adult neurogenesis, is sensitive to MAGUK loss in mature animals, behaving like an immature CA1. Over long time courses, removal of MAGUKs in CA1 causes reductions in glutamatergic transmission, indicating that synapses in mature animals require MAGUKs for anchoring glutamate receptors, but are much more stable. These results demonstrate regional and developmental control of synapse stability and suggest the existence of a sensitive period of heightened hippocampal plasticity in CA1 of pre-adolescent rodents, and in dentate gyrus throughout maturity. Fast excitatory transmission in the brain requires localization of glutamate receptors to synapses. The membrane-associated guanylate kinase (MAGUK) family of synaptic scaffolding proteins is critical for localization of glutamate receptors to synapses. Although the MAGUKs are well-studied in reduced preparations and young animals, few data exist on their role in adult animals. Here, we present a detailed developmental study of the role of the MAGUKs during rat development. We first confirmed by knockdown experiments that MAGUKs are essential for glutamatergic transmission in young animals and cultured slices, and an increase in postsynaptic density protein 95 (PSD-95) by overexpression caused correlated increases in glutamatergic transmission. We found that CA1 synapses in adults, in contrast, were largely unaffected by overexpression of MAGUKs, and although adult CA1 synapses required MAGUKs to the same degree as synapses in young animals, this was only apparent over long time scales of knockdown. We additionally showed that overexpression of MAGUKs is likely to function to accelerate the developmental strengthening of excitatory transmission. Finally, we showed that adult dentate gyrus appears similar to immature CA1, demonstrating regional and developmental control of MAGUK dynamics. Together, these results demonstrate a period of juvenile instability at CA1 synapses, followed by a period of adult stability in which synapses are acutely unaffected by changes in MAGUK abundance.

Dopamine receptor activity participates in hippocampal synaptic plasticity associated with novel object recognition

Physiological and behavioral evidence supports that dopamine (DA) receptor signaling influences hippocampal function. While several recent studies examined how DA influences CA1 plasticity and learning, there are fewer studies investigating the influence of DA signaling to the dentate gyrus. The dentate gyrus receives convergent cortical input through the perforant path fiber tracts and has been conceptualized to detect novelty in spatial memory tasks. To test whether DA-receptor activity influences novelty-detection, we used a novel object recognition (NOR) task where mice remember previously presented objects as an indication of learning. Although DA innervation arises from other sources and the main DA signaling may be from those sources, our molecular approaches verified that midbrain dopaminergic fibers also sparsely innervate the dentate gyrus. During the NOR task, wild-type mice spent significantly more time investigating novel objects rather than previously observed objects. Dentate granule cells in slices cut from those mice showed an increased AMPA/NMDA-receptor current ratio indicative of potentiated synaptic transmission. Post-training injection of a D1-like receptor antagonist not only effectively blocked the preference for the novel objects, but also prevented the increased AMPA/NMDA ratio. Consistent with that finding, neither NOR learning nor the increase in the AMPA/NMDA ratio were observed in DA-receptor KO mice under the same experimental conditions. The results indicate that DA-receptor signaling contributes to the successful completion of the NOR task and to the associated synaptic plasticity of the dentate gyrus that likely contributes to the learning.

Dopamine D1/D5, But not D2/D3, Receptor Dependency of Synaptic Plasticity at Hippocampal Mossy Fiber Synapses that Is Enabled by Patterned Afferent Stimulation, or Spatial Learning.

Although the mossy fiber (MF) synapses of the hippocampal CA3 region display quite distinct properties in terms of the molecular mechanisms that underlie synaptic plasticity, they nonetheless exhibit persistent (>24 h) synaptic plasticity that is akin to that observed at the Schaffer collateral (SCH)-CA1 and perforant path (PP)-dentate gyrus (DG) synapses of freely behaving rats. In addition, they also respond to novel spatial learning with very enduring forms of long-term potentiation (LTP) and long-term depression (LTD). These latter forms of synaptic plasticity are directly related to the learning behavior: novel exploration of generalized changes in space facilitates the expression of LTP at MF-CA3 synapses, whereas exploration of novel configurations of large environmental features facilitates the expression of LTD. In the absence of spatial novelty, synaptic plasticity is not expressed. Motivation is a potent determinant of whether learning about the spatial experience effectively occurs and the neuromodulator dopamine (DA) plays a key role in motivation-based learning. Prior research on the regulation by DA receptors of long-term synaptic plasticity in CA1 and DG synapses in vivo suggests that whereas D2/D3 receptors may modulate a general predisposition toward expressing plasticity, D1/D5 receptors may directly regulate the direction of change in synaptic strength that occurs during learning. Although the CA3 region is believed to play a pivotal role in many forms of learning, the role of dopamine receptors in persistent (>24 h) forms of synaptic plasticity at MF-CA3 synapses is unknown. Here, we report that whereas pharmacological antagonism of D2/D3 receptors had no impact on LTP or LTD, antagonism of D1/D5 receptors significantly impaired LTP and LTD that were induced by solely by means of patterned afferent stimulation, or LTP/LTD that are typically enhanced by the conjunction of afferent stimulation and novel spatial learning. These data indicate an important role for DA acting on D1/D5 receptors in the support of long-lasting and learning-related forms of synaptic plasticity at MF-CA3 synapses and provide further evidence for an important neuromodulatory role for this receptor in experience-dependent synaptic encoding in the hippocampal subfields.

Synaptic plasticity supports slow gamma phase-locking in CA1 place cells during environmental novelty

Information processing and transfer between brain structures have been proposed to engage the phase-locking of neuronal firing to gamma oscillations during certain cognitive functions, including learning and memory. The cellular mechanism behind this precise temporal organisation of action potentials might rely on changes in synaptic strength. Kitanishi et al. (Kitanishi T, Ujita S, Fallahnezhad M, Kitanishi N, Ikegaya Y, Tashiro A. Neuron, 86:1265–76, 2015) tested this hypothesis by blocking synaptic plasticity dependent on the GluR1 subunit of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor using a virus-mediated local genetic manipulation in a restricted population of CA1 principal cells. Multi-tetrode-based unit recording from these genetically-modified principal cells showed that environmental novelty was associated with an impaired phase-locking to slow gamma oscillations and a slower emergence of precise spatial firing compared to control cells. This pattern of deficits suggests that CA3-driven slow gamma oscillations might induce GluR1-dependent synaptic plasticity in CA1. This cellular mechanism would in turn participate in the rapid emergence of precise place fields in CA1 during novel experiences, and in the transfer of this information to downstream neurons in a temporally-organised manner.

Differential contribution of hippocampal subfields to components of associative taste learning.

The ability to associate the consumption of a taste with its positive or negative consequences is fundamental to survival and influences the behavior of species ranging from invertebrate to human. As a result, for both research and clinical reasons, there has been a great effort to understand the neuronal circuits, as well as the cellular and molecular mechanisms, underlying taste learning. From a neuroanatomical perspective, the contributions of the cortex and amygdala are well documented; however, the literature is riddled with conflicting results regarding the role of the hippocampus in different facets of taste learning. Here, we use conditional genetics in mice to block NMDA receptor-dependent plasticity individually in each of the three major hippocampal subfields, CA1, CA3, and the dentate gyrus, via deletion of the NR1 subunit. Across the CA1, CA3, and dentate gyrus NR1 knock-out lines, we uncover a pattern of differential deficits that establish the dispensability of hippocampal plasticity in incidental taste learning, the requirement of CA1 plasticity for associative taste learning, and a specific requirement for plasticity in the dentate gyrus when there is a long temporal gap between the taste and its outcome. Together, these data establish that the hippocampus is involved in associative taste learning and suggest an episodic component to this type of memory.

Effects of prolyl-hydroxylase inhibition and chronic intermittent hypoxia on synaptic transmission and plasticity in the rat CA1 and dentate gyrus

Chronic intermittent hypoxia (CIH) is an underlying component of obstructive sleep apnoea and has been shown to have deleterious and damaging effects on central neurons and to impair synaptic plasticity in the CA1 region of the rat hippocampus. CIH has previously been shown to impair synaptic plasticity and working memory. CIH is a potent inducer of hypoxia inducible factor (HIF), a key regulator in a cell's adaptation to hypoxia that plays an important role in the fate of neurons during ischemia. Levels of HIF-1α are regulated by the activity of a group of enzymes called HIF-prolyl 4-hydroxylases (PHDs) and these have become potential pharmacological targets for preconditioning against ischemia. However little is known about the effects of prolyl hydroxylase inhibition and CIH on synaptic transmission and plasticity in sub-regions of the hippocampus. Male Wistar rats were treated for 7-days with either saline, CIH or PHD inhibition (dimethyloxaloylglycine, DMOG; 50mg/kg, i.p.). At the end of treatment all three groups showed no change in synaptic excitability using paired pulse paradigms. However long-term potentiation (LTP) was impaired in the CA1 region of the hippocampus in both CIH and DMOG treated animals. LTP induced in the dentate gyrus was not significantly affected by either CIH or DMOG treatment. We also investigated the effect of 7-day CIH and DMOG treatment on the recovery of synaptic transmission following an acute 30min hypoxic insult. CIH treated animals showed an improved rate of recovery of synaptic transmission following re-oxygenation in both the CA1 and the dentate gyrus. These results suggest that LTP induction in the CA1 region is more sensitive to both CIH and DMOG treatments than the dentate gyrus.

Dopamine regulates intrinsic excitability thereby gating successful induction of spike timing-dependent plasticity in CA1 of the hippocampus

Long-term potentiation (LTP) and long-term depression (LTD) are generally assumed to be cellular correlates for learning and memory. Different types of LTP induction protocols differing in severity of stimulation can be distinguished in CA1 of the hippocampus. To better understand signaling mechanisms and involvement of neuromodulators such as dopamine (DA) in synaptic plasticity, less severe and more physiological low frequency induction protocols should be used. In the study which is reviewed here, critical determinants of spike timing-dependent plasticity (STDP) at hippocampal CA3-CA1 synapses were investigated. We found that DA via D1 receptor signaling, but not adrenergic signaling activated by the β-adrenergic agonist isoproterenol, is important for successful expression of STDP at CA3-CA1 synapses. The DA effect on STDP is paralleled by changes in spike firing properties, thereby changing intrinsic excitability of postsynaptic CA1 neurons, and gating STDP. Whereas β-adrenergic signaling also leads to a similar (but not identical) regulation of firing pattern, it does not enable STDP. In this focused review we will discuss the current literature on dopaminergic modulation of LTP in CA1, with a special focus on timing dependent (t-)LTP, and we will suggest possible reasons for the selective gating of STDP by DA [but not noradrenaline (NA)] in CA1.

Different patterns of amygdala priming differentially affect dentate gyrus plasticity and corticosterone, but not CA1 plasticity

Stress-induced activation of the amygdala is involved in the modulation of memory processes in the hippocampus. However, stress effects on amygdala and memory remain complex. The activation of the basolateral amygdala (BLA) was found to modulate plasticity in other brain areas, including the hippocampus. We previously demonstrated a differential effect of BLA priming on long-term potentiation (LTP) in the CA1 and the dentate gyrus (DG). While BLA priming suppressed LTP in CA1, it was found to enhance it in the DG. However, since the amygdala itself is amenable to experience-induced plasticity it is thus conceivable that when activity within the amygdala is modified this will have impact on the way the amygdala modulates activity and plasticity in other brain areas. In the current study, we examined the effects of different patterns of BLA activation on the modulation of LTP in the DG and CA1, as well as on serum corticosterone (CORT). In CA1, BLA-priming impaired LTP induction as was reported before. In contrast, in the DG, varying BLA stimulation intensity and frequency resulted in differential effects on LTP, ranging from no effect to strong impairment or enhancement. Varying BLA stimulation patterns resulted in also differential alterations in Serum CORT, leading to higher CORT levels being positively correlated with LTP magnitude in DG but not in CA1. The results support the notion of a differential role for the DG in aspects of memory, and add to this view the possibility that DG-associated aspects of memory will be enhanced under more emotional or stressful conditions. It is interesting to think of BLA patterns of activation and the differential levels of circulating CORT as two arms of the emotional and stress response that attempt to synchronize brain activity to best meet the challenge. It is foreseeable to think of abnormal such synchronization under extreme conditions, which would lead to the development of maladaptive behavior.

Gene expression in the hippocampus: Regionally specific effects of aging and caloric restriction

We measured changes in gene expression, induced by aging and caloric restriction (CR), in three hippocampal subregions. When analysis included all regions, aging was associated with expression of genes linked to mitochondrial dysfunction, inflammation, and stress responses, and in some cases, expression was reversed by CR. An age-related increase in ubiquintination was observed, including increased expression of ubiquitin conjugating enzyme genes and cytosolic ubiquitin immunoreactivity. CR decreased cytosolic ubiquitin and upregulated deubiquitinating genes. Region specific analyses indicated that CA1 was more susceptible to aging stress, exhibiting a greater number of altered genes relative to CA3 and the dentate gyrus (DG), and an enrichment of genes related to the immune response and apoptosis. CA3 and the DG were more responsive to CR, exhibiting marked changes in the total number of genes across diet conditions, reversal of age-related changes in p53 signaling, glucocorticoid receptor signaling, and enrichment of genes related to cell survival and neurotrophic signaling. Finally, CR differentially influenced genes for synaptic plasticity in CA1 and CA3. It is concluded that regional disparity in response to aging and CR relates to differences in vulnerability to stressors, the availability of neurotrophic, and cell survival mechanisms, and differences in cell function.