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One of the puzzling aspects of sporadic Alzheimer’s disease (AD) is how it commences. Changes in one key brain peptide, amyloid-beta (Aβ), accompany disease progression, but whether this comprises a trigger or a consequence of AD is still a topic of debate. It is clear however that the cerebral presence of oligomeric Aβ (1–42) is a key factor in early AD-pathogenesis. Furthermore, treatment of rodent brains with oligomeric Aβ (1–42) either in vitro or in vivo, acutely impairs hippocampal synaptic plasticity, creating a link between Aβ-pathology and learning impairments. Here, we show that a once-off inoculation of the brains of healthy adult rats with oligomeric Aβ (1–42) exerts debilitating effects on the long-term viability of the hippocampus, one of the primary targets of AD. Changes are progressive: months after treatment, synaptic plasticity, neuronal firing and spatial learning are impaired and expression of plasticity-related proteins are changed, in the absence of amyloid plaques. Early changes relate to activation of microglia, whereas later changes are associated with a reconstruction of astroglial morphology. These data suggest that a disruption of Aβ homeostasis may suffice to trigger an irreversible cascade, underlying progressive loss of hippocampal function, that parallels the early stages of AD.

Type-2 diabetes (T2D) is a metabolic disorder that is considered a risk factor for Alzheimer's disease (AD). Cognitive impairment can arise due to hypoglycemia associated with T2D, and hyperamylinemia associated with insulin resistance can enhance AD pathology. We explored whether changes occur in the hippocampus in aging (6–12 months old) female V-Lep○b-/- transgenic (tg) mice, comprising an animal model of T2D. We also investigated whether an increase in vulnerability to Aβ (1–42), a known pathological hallmark of AD, is evident. Using magnetic resonance imaging we detected significant decreases in hippocampal brain volume in female tg-mice compared to wild-type (wt) littermates. Long-term potentiation (LTP) was impaired in tg compared to wt mice. Treatment of the hippocampus with Aβ (1–42) elicited a stronger debilitation of LTP in tg compared to wt mice. Treatment with an amylin antagonist (AC187) significantly enhanced LTP in wt and tg mice, and rescued LTP in Aβ (1–42)-treated tg mice. Taken together our data indicate that a T2D-like state results in an increased vulnerability of the hippocampus to the debilitating effects of Aβ (1–42) and that effects are mediated in part by changes in amylin receptor signaling.

Studies in rodent models have revealed that oligomeric beta-amyloid protein [Aβ (1–42)] plays an important role in the pathogenesis of Alzheimer’s disease. Early elevations in hippocampal neuronal excitability caused by Aβ (1–42) have been proposed to be mediated via enhanced activation of GluN2B-containing N-methyl-D-aspartate receptors (NMDAR). To what extent GluN2A or GluN2B-containing NMDAR contribute to Aβ (1–42)-mediated impairments of hippocampal function in advanced rodent age is unclear. Here, we assessed hippocampal long-term potentiation (LTP) and neuronal responses 4–5 weeks after bilateral intracerebral inoculation of 8–15 month old GluN2A+/− or GluN2B+/− transgenic mice with oligomeric Aβ (1–42), or control peptide. Whole-cell patch-clamp recordings in CA1 pyramidal neurons revealed a more positive resting membrane potential and increased total spike time in GluN2A+/−, but not GluN2B+/−-hippocampi following treatment with Aβ (1–42) compared to controls. Action potential 20%-width was increased, and the descending slope was reduced, in Aβ–treated GluN2A+/−, but not GluN2B+/− hippocampi. Sag ratio was increased in Aβ–treated GluN2B+/−-mice. Firing frequency was unchanged in wt, GluN2A+/−, and GluN2B+/−hippocampi after Aβ–treatment. Effects were not significantly different from responses detected under the same conditions in wt littermates, however. LTP that lasted for over 2 h in wt hippocampal slices was significantly reduced in GluN2A+/− and was impaired for 15 min in GluN2B+/−-hippocampi compared to wt littermates. Furthermore, LTP (>2 h) was significantly impaired in Aβ–treated hippocampi of wt littermates compared to wt treated with control peptide. LTP induced in Aβ–treated GluN2A+/− and GluN2B+/−-hippocampi was equivalent to LTP in control peptide-treated transgenic and Aβ–treated wt animals. Taken together, our data indicate that knockdown of GluN2A subunits subtly alters membrane properties of hippocampal neurons and reduces the magnitude of LTP. GluN2B knockdown reduces the early phase of LTP but leaves later phases intact. Aβ (1–42)-treatment slightly exacerbates changes in action potential properties in GluN2A+/−-mice. However, the vulnerability of the aging hippocampus to Aβ–mediated impairments of LTP is not mediated by GluN2A or GluN2B-containing NMDAR.

Abstract Quantitative muscle MRI is increasingly important in the non-invasive evaluation of neuromuscular disorders and their progression. Underlying histopathotological alterations, leading to changes in qMRI parameters are incompletely unraveled. Early microstructural differences of unknown origin reflected by Diffusion MRI in non-fat infiltrated muscles were detected in Pompe patients. This study employed a longitudinal approach with a Pompe disease mouse model to investigate the histopathological basis of these changes. Monthly scans of Pompe (Gaa6neo/6neo) and wildtype mice (age 1–8 months) were conducted using diffusion MRI, T2-mapping, and Dixon-based water-fat imaging on a 7 T scanner. Immunofluorescence studies on quadriceps muscles were analyzed for lysosomal accumulations and autophagic buildup and correlated with MRI outcome measures. Fat fraction and water-T2 did not differ between groups and remained stable over time. In Pompe mice, fractional anisotropy increased, while mean diffusivity (MD) and radial diffusivity (RD) decreased in all observed muscles. Autophagic marker and muscle fibre diameter revealed significant negative correlations with reduced RD and MD, while lysosomal marker did not show any change or correlation. Using qMRI, we showed diffusion changes in muscles of presymptomatic Pompe mice without fat-infiltrated muscles and correlated them to autophagic markers and fibre diameter, indicating diffusion MRI reveals autophagic buildup.

Summary: Visual responses of the primary visual cortex (V1) are altered by sound. Sound-driven behavioral arousal suggests that, in addition to direct inputs from the primary auditory cortex (A1), multiple other sources may shape V1 responses to sound. Here, we show in anesthetized mice that sound (white noise, ≥70dB) drives a biphasic modulation of V1 visually driven gamma-band activity, comprising fast-transient inhibitory and slow, prolonged excitatory (A1-independent) arousal-driven components. An analogous yet quicker modulation of the visual response also occurred earlier in the visual pathway, at the level of the dorsolateral geniculate nucleus (dLGN), where sound transiently inhibited the early phasic visual response and subsequently induced a prolonged increase in tonic spiking activity and gamma rhythmicity. Our results demonstrate that sound-driven modulations of visual activity are not exclusive to V1 and suggest that thalamocortical inputs from the dLGN to V1 contribute to shaping V1 visual response to sound.

Abstract In the weeks immediately after onset of sensory loss, extensive reorganization of both the cortex and hippocampus occurs. Two fundamental characteristics comprise widespread changes in the relative expression of GABA and glutamate receptors and debilitation of hippocampal synaptic plasticity. Here, we explored whether recovery from adaptive changes in the expression of plasticity-related neurotransmitter receptors and hippocampal synaptic plasticity occurs in the time-period of up to 12 months after onset of sensory loss. We compared receptor expression in CBA/J mice that develop hereditary blindness, with CBA/CaOlaHsd mice that have intact vision and no deficits in other sensory modalities throughout adulthood. GluN1-subunit expression was reduced and the GluN2A:GluN2B ratio was persistently altered in cortex and hippocampus. GABA-receptor expression was decreased and metabotropic glutamate receptor expression was altered. Hippocampal synaptic plasticity was persistently compromised in vivo. But although LTP in blind mice was chronically impaired throughout adulthood, a recovery of the early phase of LTP became apparent when the animals reached 12 months of age. These data show that cortical and hippocampal adaptation to early postnatal blindness progresses into advanced adulthood and is a process that compromises hippocampal function. A partial recovery of hippocampal synaptic plasticity emerges in advanced adulthood, however.

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.

Abstract The context-dependence of extinction learning has been well studied and requires the hippocampus. However, the underlying neural mechanisms are still poorly understood. Using memory-driven reinforcement learning and deep neural networks, we developed a model that learns to navigate autonomously in biologically realistic virtual reality environments based on raw camera inputs alone. Neither is context represented explicitly in our model, nor is context change signaled. We find that memory-intact agents learn distinct context representations, and develop ABA renewal, whereas memory-impaired agents do not. These findings reproduce the behavior of control and hippocampal animals, respectively. We therefore propose that the role of the hippocampus in the context-dependence of extinction learning might stem from its function in episodic-like memory and not in context-representation per se. We conclude that context-dependence can emerge from raw visual inputs.

Long-term potentiation (LTP) and long-term depression (LTD) comprise the principal cellular mechanisms that fulfill established criteria for the physiological correlates of learning and memory. Traditionally LTP, that increases synaptic weights, has been ascribed a prominent role in learning and memory whereas LTD, that decreases them, has often been relegated to the category of “counterpart to LTP” that serves to prevent saturation of synapses. In contradiction of these assumptions, studies over the last several years have provided functional evidence for distinct roles of LTD in specific aspects of hippocampus-dependent associative learning and information encoding. Furthermore, evidence of the experience-dependent “pruning” of excitatory synapses, the majority of which are located on dendritic spines, by means of LTD has been provided. In addition, reports exist of the temporal and physical restriction of LTP in dendritic compartments by means of LTD. Here, we discuss the role of LTD and LTP in experience-dependent information encoding based on empirical evidence derived from conjoint behavioral and electrophysiological studies conducted in behaving rodents. We pinpoint the close interrelation between structural modifications of dendritic spines and the occurrence of LTP and LTD. We report on findings that support that whereas LTP serves to acquire the general scheme of a spatial representation, LTD enables retention of content details. We argue that LTD contributes to learning by engaging in a functional interplay with LTP, rather than serving as its simple counterpart, or negator. We propose that similar spatial experiences that share elements of neuronal representations can be modified by means of LTD to enable pattern separation. Therewith, LTD plays a crucial role in the disambiguation of similar spatial representations and the prevention of generalization.

The perirhinal cortex (PRC), subdivided into areas 35 and 36, belongs to the parahippocampal regions that provide polysensory input to the hippocampus. Efferent and afferent connections along its rostro-caudal axis, and of areas 35 and 36, are extremely diverse. Correspondingly functional tasks in which the PRC participates are manifold. The PRC engages, for example, in sensory information processing, object recognition, and attentional processes. It was previously reported that layer II of the caudal area 35 may be critically involved in the encoding of large-scale objects. In the present study we aimed to disambiguate the roles of the different PRC layers, along with areas 35 and 36, and the rostro-caudal compartments of the PRC, in processing information about objects of different dimensions. Here, we compared effects on information encoding triggered by learning about subtle and discretely visible (microscale) object information and overt, highly visible landmark (macroscale) information. To this end, nuclear expression of the immediate early gene Arc was evaluated using fluorescence in situ hybridization. Increased nuclear Arc expression occurred in layers III and V-VI of the middle and caudal parts of area 35 in response to both novel microscale and macroscale object exposure. By contrast, a significant increase in Arc expression occurred in area 36 only in response to microscale objects. These results indicate that area 36 is specifically involved in the encoding of small and less prominently visible items. In contrast, area 35 engages globally (layer III to VI) in the encoding of object information independent of item dimensions.

Dopamine is a key factor in the enablement of cognition and hippocampal information processing. Its action in the hippocampus is mediated by D1/D5 and D2-like (D2, D3, D4) receptors. While D1/D5-receptors are well recognized as strong modulators of hippocampal synaptic plasticity and information storage, much less is known about the role of D2-like receptors (D2R) in these processes. Here, we explored to what extent D2R contribute to synaptic plasticity and cumulative spatial memory derived from semantic and episodic-like information storage. In freely behaving adult rats, we also assessed to what extent short and long-term forms of synaptic plasticity are influenced by pharmacological activation or blockade of D2R. Antagonism of D2R by means of intracerebral treatment with remoxipride, completely prevented the expression of both short-term (4 h), as well as the expression of short-term depression (STD,

Functional magnetic resonance imaging, as a non-invasive technique, offers unique opportunities to assess brain function and connectivity under a broad range of applications, ranging from passive sensory stimulation to high-level cognitive abilities, in awake animals. This approach is confounded, however, by the fact that physical restraint and loud unpredictable acoustic noise must inevitably accompany fMRI recordings. These factors induce marked stress in rodents, and stress-related elevations of corticosterone levels are known to alter information processing and cognition in the rodent. Here, we propose a habituation strategy that spans specific stages of adaptation to restraint, MRI noise, and confinement stress in awake rats and circumvents the need for surgical head restraint. This habituation protocol results in stress levels during awake fMRI that do not differ from pre-handling levels and enables stable image acquisition with very low motion artifacts. For this, rats were gradually trained over a period of three weeks and eighteen training sessions. Stress levels were assessed by analysis of fecal corticosterone metabolite levels and breathing rates. We observed significant drops in stress levels to below pre-handling levels at the end of the habituation procedure. During fMRI in awake rats, after the conclusion of habituation and using a non-invasive head-fixation device, breathing was stable and head motion artifacts were minimal. A task-based fMRI experiment, using acoustic stimulation, conducted 2 days after the end of habituation, resulted in precise whole brain mapping of BOLD signals in the brain, with clear delineation of the expected auditory-related structures. The active discrimination by the animals of the acoustic stimuli from the backdrop of scanner noise was corroborated by significant increases in BOLD signals in the thalamus and reticular formation. Taken together, these data show that effective habituation to awake fMRI can be achieved by gradual and incremental acclimatization to the experimental conditions. Subsequent BOLD recordings, even during superimposed acoustic stimulation, reflect low stress-levels, low motion and a corresponding high-quality image acquisition. Furthermore, BOLD signals obtained during fMRI indicate that effective habituation facilitates selective attention to sensory stimuli that can in turn support the discrimination of cognitive processes in the absence of stress confounds.

The metabotropic glutamate (mGlu) receptor family consists of group I receptors (mGlu1 and mGlu5) that are positively coupled to phospholipase-C and group II (mGlu2 and mGlu3) and III receptors (mGlu4-8) that are negatively coupled to adenylyl cyclase. Of these, mGlu5 has emerged as a key factor in the induction and maintenance of persistent (>24 h) forms of hippocampal synaptic plasticity. Studies in freely behaving rodents have revealed that mGlu5 plays a pivotal role in the stabilisation of hippocampal long-term potentiation (LTP) and long-term depression (LTD) that are tightly associated with the acquisition and retention of knowledge about spatial experience. In this review article we shall address the state of the art in terms of the role of mGlu5 in forms of hippocampal synaptic plasticity related to experience-dependent information storage and present evidence that normal mGlu5 function is central to these processes.

Brain derived neurotropic factor (BDNF) supports neuronal survival, growth, and differentiation and is involved in forms of hippocampus-dependent and independent learning, as well as hippocampus-dependent learning. Extinction learning comprises active inhibition of no-longer relevant learned information, in conjunction with a decreased response of a previously learned behavior. It is highly dependent on context, and evidence exists that it requires hippocampal activation. The participation of BDNF in memory processing is experience-dependent. For example, BDNF has been associated with synaptic plasticity needed for spatial learning, and it is involved in acquisition and extinction learning of fear conditioning. However, little is known about its role in spatial appetitive extinction learning. In this study, we evaluated to what extent BDNF contributes to spatial appetitive extinction learning in the presence (ABA) or absence (AAA) of exposure to the acquisition context. Daily training, of BDNF+/−-mice or their wildtype (WT) littermates, to reach acquisition criterion in a T-maze, resulted in a similar performance outcome. However, extinction learning was delayed in the AAA, and impaired in the ABA-paradigm compared to performance in WT littermates. Trial-by-trial learning analysis indicated differences in the integration of the context into extinction learning by BDNF+/−-mice compared to WT littermates. Taken together, these results support an important role for BDNF in processes that relate to information updating and retrieval that in turn are crucial for effective extinction learning.

Beta-amyloid protein [Aβ(1-42)] plays an important role in the disease progress and pathophysiology of Alzheimer's disease (AD). Membrane properties and neuronal excitability are altered in the hippocampus of transgenic AD mouse models that overexpress amyloid precursor protein. Although gap junction hemichannels have been implicated in the early pathogenesis of AD, to what extent Pannexin channels contribute to Aβ(1-42)-mediated brain changes is not yet known. In this study we, therefore, investigated the involvement of Pannexin1 (Panx1) channels in Aβ-mediated changes of neuronal membrane properties and long-term potentiation (LTP) in an animal model of AD. We conducted whole-cell patch-clamp recordings in CA1 pyramidal neurons 1 week after intracerebroventricular treatments of adult wildtype (wt) and Panx1 knockout (Panx1-ko) mice with either oligomeric Aβ(1-42), or control peptide. Panx1-ko hippocampi treated with control peptide exhibited increased neuronal excitability compared to wt. In addition, action potential (AP) firing frequency was higher in control Panx1-ko slices compared to wt. Aβ-treatment reduced AP firing frequency in both cohorts. But in Aβ-treated wt mice, spike frequency adaptation was significantly enhanced, when compared to control wt and to Aβ-treated Panx1-ko mice. Assessment of hippocampal LTP revealed deficits in Aβ-treated wt compared to control wt. By contrast, Panx1-ko exhibited LTP that was equivalent to LTP in control ko hippocampi. Taken together, our data show that in the absence of Pannexin1, hippocampi are more resistant to the debilitating effects of oligomeric Aβ. Both Aβ-mediated impairments in spike frequency adaptation and in LTP that occur in wt animals, are ameliorated in Panx1-ko mice. These results suggest that Panx1 contributes to early changes in hippocampal neuronal and synaptic function that are triggered by oligomeric Aβ.

Whereas the postrhinal cortex (POR) is a critical center for the integration of egocentric and allocentric spatial information, the perirhinal cortex (PRC) plays an important role in the encoding of objects that supports spatial learning. The POR and PRC send afferents to the hippocampus, a structure that builds complex associative memories from the spatial experience. Hippocampal encoding of item-place experience is accompanied by the nuclear expression of immediate early gene (IEGs). Subfields of the Cornus ammonius and subregions of the hippocampus exhibit differentiated and distinct encoding responses, depending on whether the spatial location and relationships of large highly visible items (macroscale encoding) or small partially concealed items (microscale encoding), is learned. But to what extent the PRC and POR support hippocampal processing of different kinds of item-place representations is unclear. Using fluorescence in situ hybridization (FISH), we examined the effect of macroscale (overt, landmark) and microscale (subtle, discrete) item-place learning on the nuclear expression of the IEG, Arc. We observed an increase in Arc mRNA in the caudal part of PRC area 35 and the caudal part of the POR after macroscale, but not microscale item-place learning. The caudal part of PRC area 36, the rostral and middle parts of PRC areas 35 and 36, as well as the middle part of the POR responded to neither type of item. These results suggest that macroscale items may contain a strong identity component that is processed by specific compartments of the PRC and POR. In contrast small, microscale items are not encoded by the POR or PRC, indicating that item dimensions may play a role in the involvement of these structures in item processing.

During extinction learning (EL), an individual learns that a previously learned behavior no longer fulfills its original purpose, or is no longer relevant. Recent studies have contradicted earlier theories that EL comprises forgetting, or the inhibition of the previously learned behavior, and indicate that EL comprises new associative learning. This suggests that the hippocampus is involved in this process. Empirical evidence is lacking however. Here, we used fluorescence in situ hybridization of somatic immediate early gene (IEG) expression to scrutinize if the hippocampus processes EL. Rodents engaged in context-dependent EL and were also tested for renewal of (the original behavioral response to) a spatial appetitive task in a T-maze. Whereas distal and proximal CA1 subfields processed both EL and renewal, effects in the proximal CA1 were more robust consistent with a role of this subfield in processing context. The lower blade of the dentate gyrus (DG) and the proximal CA3 subfields were particularly involved in renewal. Responses in the distal and proximal CA3 subfields suggest that this hippocampal subregion may also contribute to the evaluation of the reward outcome. Taken together, our findings provide novel and direct evidence for the involvement of distinct hippocampal subfields in context-dependent EL and renewal.

Dopamine D2-like receptors (D2R) play an important role in the regulation of hippocampal neuronal excitability and contribute to the regulation of synaptic plasticity, the encoding of hippocampus-dependent memories and the regulation of affective state. In line with this, D2R are targeted in the treatment of psychosis and affective disorders. It has been proposed that the dorso-ventral axis of the hippocampus can be functionally delineated into the dorsal pole that predominantly processes spatial information and the ventral pole that mainly addresses hippocampal processing of emotional and affective state. Although dopaminergic control of hippocampal information processing has been the focus of a multitude of studies, very little is known about the precise distribution of D2R both within anatomically defined sublayers of the hippocampus and along its dorsoventral axis, that could in turn yield insights as to the functional significance of this receptor in supporting hippocampal processing of spatial and affective information. Here, we used an immunohistochemical approach to precisely scrutinize the protein expression of D2R both within the cellular and dendritic layers of the hippocampal subfields, and along the dorso-ventral hippocampal axis. In general, we detected significantly higher levels of protein expression of D2R in the ventral, compared to the dorsal poles with regard to the CA1, CA2, CA3 and dentate gyrus (DG) regions. Effects were very consistent: the molecular layer, granule cell layer and polymorphic layer of the DG exhibited higher D2R levels in the ventral compared to dorsal hippocampus. D2R levels were also significantly higher in the ventral Stratum oriens, Stratum radiatum, and Stratum lacunosum-moleculare layers of the CA1 and CA3 regions. The apical dendrites of the ventral CA2 region also exhibited higher D2R expression compared to the dorsal pole. Taken together, our study suggests that the higher D2R expression levels of the ventral hippocampus may contribute to reported gradients in the degree of expression of synaptic plasticity along the dorso-ventral hippocampal axis, and may support behavioral information processing by the ventral hippocampus.

Psychosis is a clinical state that encompasses a range of abnormal conditions, including distortions in sensory information processing and the resultant delusional thinking, emotional discordance and cognitive impairments. Upon developing this condition, the rate at which cognitive and behavioral deteriorations progress steadily increases suggesting an active contribution of the first psychotic event to the progression of structural and functional abnormalities and disease establishment in diagnosed patients. Changes in GABAergic and glutamatergic function, or expression, in the hippocampus have been proposed as a key factor in the pathophysiology of psychosis. However, little is known as to the time-point of onset of putative changes, to what extent they are progressive, and their relation to disease stabilization. Here, we characterized the expression and distribution patterns of groups I and II metabotropic glutamate (mGlu) receptors and GABA receptors 1 week and 3 months after systemic treatment with an N-methyl-D-aspartate receptor (NMDAR) antagonist (MK801) that is used to model a psychosis-like state in adult rats. We found an early alteration in the expression of mGlu1, mGlu2/3, and GABAB receptors across the hippocampal dorsoventral and transverse axes. This expanded to include an up-regulation of mGlu5 levels across the entire CA1 region and a reduction in GABAB expression, as well as GAD67-positive interneurons particularly in the dorsal hippocampus that appeared 3 months after treatment. Our findings indicate that a reduction of excitability may occur in the hippocampus soon after first-episode psychosis. This changes, over time, into increased excitability. These hippocampus-specific alterations are likely to contribute to the pathophysiology and stabilization of psychosis.

The group I metabotropic glutamate (mGlu) receptor subtypes, mGlu1 and mGlu5, strongly regulate hippocampal synaptic plasticity. Both harbor PSD-95/discs-large/ZO-1 (PDZ) motifs at their extreme carboxyl terminals, which allow interaction with the PDZ domain of Tamalin, regulate the cell surface expression of group I mGlu receptors, and may modulate their coupling to signaling proteins. We investigated the functional role of this interaction in hippocampal long-term depression (LTD). Acute intracerebral treatment of adult rats with a cell-permeable PDZ-blocking peptide (pep-mGluR-STL), designed to competitively inhibit the interaction between Tamalin and group 1 mGlu receptors, prevented expression of LTD in the hippocampal CA1 region without affecting long-term potentiation (LTP) or basal synaptic transmission. Pep-mGluR-STL prevented facilitation by the group I mGlu receptor agonist, (S)-3,5-Dihydroxyphenylglycine (DHPG), and the mGlu5 agonist, (R,S)-2-chloro-5-Hydroxyphenylglycine (CHPG), of short-term depression (STD) into LTD, suggesting that Tamalin preferentially acts by mediating signaling through mGlu5. These data support that Tamalin is essential for the persistent expression of LTD and that it subserves the effective signaling of group 1 mGlu receptors.

A hallmark of glioblastoma multiforme (GBM) is neoangiogenesis, mediated by the overexpression of vascular endothelial growth factor (VEGF). Anti-VEGF antibodies, like bevacizumab, prolong progression-free survival in GBM, however, this treatment has been reported to be associated with a decline in neurocognitive function. Therefore, this study focused on the effects of bevacizumab on neuronal function and plasticity. We analyzed neuronal membrane properties and synaptic plasticity in rat hippocampal slices, as well as spine dynamics in dissociated hippocampal neurons, to examine the impact of bevacizumab on hippocampal function and viability. VEGF inhibition resulted in profound impairments in hippocampal synaptic plasticity as well as reductions in dendritic spine number and length. Physiological properties of hippocampal neurons were also affected. These effects of VEGF blockade on hippocampal function may play a role in compromising memory and information processing and thus, may contribute to neurocognitive dysfunction in GBM patients treated with bevacizumab.

Spatial encoding in the hippocampus is based on a range of different input sources. To generate spatial representations, reliable sensory cues from the external environment are integrated with idiothetic cues, derived from self-movement, that enable path integration and directional perception. In this study, we examined to what extent idiothetic cues significantly contribute to spatial representations and navigation: we recorded place cells while rodents navigated towards two visually identical chambers in 180° orientation via two different paths in darkness and in the absence of reliable auditory or olfactory cues. Our goal was to generate a conflict between local visual and direction-specific information, and then to assess which strategy was prioritized in different learning phases. We observed that, in the absence of distal cues, place fields are initially controlled by local visual cues that override idiothetic cues, but that with multiple exposures to the paradigm, spaced at intervals of days, idiothetic cues become increasingly implemented in generating an accurate spatial representation. Taken together, these data support that, in the absence of distal cues, local visual cues are prioritized in the generation of context-specific spatial representations through place cells, whereby idiothetic cues are deemed unreliable. With cumulative exposures to the environments, the animal learns to attend to subtle idiothetic cues to resolve the conflict between visual and direction-specific information.

Interneurons are critical for proper neural network function and can activate Ca2+ signaling in astrocytes. However, the impact of the interneuron-astrocyte signaling into neuronal network operation remains unknown. Using the simplest hippocampal Astrocyte-Neuron network, i.e., GABAergic interneuron, pyramidal neuron, single CA3-CA1 glutamatergic synapse, and astrocytes, we found that interneuron-astrocyte signaling dynamically affected excitatory neurotransmission in an activity- and time-dependent manner, and determined the sign (inhibition vs potentiation) of the GABA-mediated effects. While synaptic inhibition was mediated by GABAA receptors, potentiation involved astrocyte GABAB receptors, astrocytic glutamate release, and presynaptic metabotropic glutamate receptors. Using conditional astrocyte-specific GABAB receptor (Gabbr1) knockout mice, we confirmed the glial source of the interneuron-induced potentiation, and demonstrated the involvement of astrocytes in hippocampal theta and gamma oscillations in vivo. Therefore, astrocytes decode interneuron activity and transform inhibitory into excitatory signals, contributing to the emergence of novel network properties resulting from the interneuron-astrocyte interplay.

The glutamatergic N-methyl-D-aspartate receptor (NMDAR) is critically involved in many forms of hippocampus-dependent memory that may be enabled by synaptic plasticity. Behavioral studies with NMDAR antagonists and NMDAR subunit (GluN2) mutants revealed distinct contributions from GluN2A- and GluN2B-containing NMDARs to rapidly and slowly acquired memory performance. Furthermore, studies of synaptic plasticity, in genetically modified mice in vitro, suggest that GluN2A and GluN2B may contribute in different ways to the induction and longevity of synaptic plasticity. In contrast to the hippocampal slice preparation, in behaving mice, the afferent frequencies that induce synaptic plasticity are very restricted and specific. In fact, it is the stimulus pattern, and not variations in afferent frequency that determine the longevity of long-term potentiation (LTP). Here, we explored the contribution of GluN2A and GluN2B to LTP of differing magnitudes and persistencies in freely behaving mice. We applied differing high-frequency stimulation (HFS) patterns at 100 Hz to the hippocampal CA1 region, to induce NMDAR-dependent LTP in wild-type (WT) mice, that endured for 24h (late (L)-LTP). In GluN2A-KO mice, E-LTP (HFS, 50 pulses) was significantly reduced in magnitude and duration, whereas LTP (HFS, 2 x 50 pulses) and L-LTP (HFS, 4 x 50 pulses) were unaffected compared to responses in WT animals. By contrast, pharmacological antagonism of GluN2B in WT had no effect on E-LTP but significantly prevented LTP. E- LTP and LTP were significantly impaired by GluN2B antagonism in GluN2A-KO mice. These data indicate that the pattern of afferent stimulation is decisive for the recruitment of distinct GluN2A and GluN2B signaling pathways that in turn determine the persistency of hippocampal LTP. Whereas brief bursts of patterned stimulation preferentially recruit GluN2A and lead to weak and short-lived forms of LTP, prolonged, more intense, afferent activation recruits GluN2B and leads to robust and persistent LTP. These unique signal-response properties of GluN2A and GluN2B enable qualitative differentiation of information encoding in hippocampal synapses.

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 (>24h) 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 spatial experience effectively occurs and the neuromodulator dopamine plays a key role in motivation-based learning. Prior research on the regulation by dopamine receptors of long-term synaptic plasticity in CA1 and dentate gyrus 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 these receptors in persistent (>24h) 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 dopamine 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.

Neuromodulation by means of the catecholaminergic system is a key component of motivation-driven learning and behaviorally modulated hippocampal synaptic plasticity. In particular, dopamine acting on D1/D5 receptors and noradrenaline acting on beta-adrenergic receptors exert a very potent regulation of forms of hippocampal synaptic plasticity that last for very long-periods of time (>24h), and occur in conjunction with novel spatial learning. Antagonism of these receptors not only prevents long-term potentiation (LTP) and long-term depression (LTD), but prevents the memory of the spatial event that, under normal circumstances, leads to the perpetuation of these plasticity forms. Spatial learning behavior that normally comes easily to rats, such as object-place learning and spatial reference learning, becomes increasingly impaired with aging. Middle-aged animals display aging-related deficits of specific, but not all, components of spatial learning, and one possibility is that this initial manifestation of decrements in learning ability that become manifest in middle-age relate to changes in motivation, attention and/or the regulation by neuromodulatory systems of these behavioral states.Here, we compared the regulation by dopaminergic D1/D5 and beta-adrenergic receptors of persistent LTP in young (2-4 month old) and middle-aged (8-14 month old) rats. We observed in young rats, that weak potentiation that typically lasts for ca. 2h could be strengthened into persistent (>24h) LTP by pharmacological activation of either D1/D5 or beta-adrenergic receptors. By contrast, no such facilitation occurred in middle-aged rats. This difference was not related to an ostensible learning deficit: a facilitation of weak potentiation into LTP by spatial learning was possible both in young and middle-aged rats. It was also not directly linked to deficits in LTP: strong afferent stimulation resulted in equivalent LTP in both age groups. We postulate that this change in catecholaminergic control of synaptic plasticity that emerges with aging, does not relate to a learning deficit per se, rather it derives from an increase in behavioural thresholds for novelty and motivation that emerge with increasing age that impact, in turn, on learning efficacy.

The firing patterns of cerebellar Purkinje cells (PCs), as the sole output of the cerebellar cortex, determine and tune motor behavior. PC firing is modulated by various inputs from different brain regions and by cell-types including granule cells (GCs), climbing fibers and inhibitory interneurons. To understand how signal integration in PCs occurs and how subtle changes in the modulation of PC firing lead to adjustment of motor behaviors, it is important to precisely record PC firing in vivo and to control modulatory pathways in a spatio-temporal manner. Combining optogenetic and multi-electrode approaches, we established a new method to integrate light-guides into a multi-electrode system. With this method we are able to variably position the light-guide in defined regions relative to the recording electrode with micrometer precision. We show that PC firing can be precisely monitored and modulated by light-activation of channelrhodopsin-2 (ChR2) expressed in PCs, GCs and interneurons. Thus, this method is ideally suited to investigate the spatio/temporal modulation of PCs in anesthetized and in behaving mice.

Pannexin 1 (Panx1) represents a class of vertebrate membrane channels, bearing significant sequence homology with the invertebrate gap junction proteins, the innexins and more distant similarities in the membrane topologies and pharmacological sensitivities with gap junction proteins of the connexin family. In the nervous system, cooperation among pannexin channels, adenosine receptors, and K(ATP) channels modulating neuronal excitability via ATP and adenosine has been recognized, but little is known about the significance in vivo. However, the localization of Panx1 at postsynaptic sites in hippocampal neurons and astrocytes in close proximity together with the fundamental role of ATP and adenosine for CNS metabolism and cell signaling underscore the potential relevance of this channel to synaptic plasticity and higher brain functions. Here, we report increased excitability and potently enhanced early and persistent LTP responses in the CA1 region of acute slice preparations from adult Panx1(-/-) mice. Adenosine application and N-methyl-D-aspartate receptor (NMDAR)-blocking normalized this phenotype, suggesting that absence of Panx1 causes chronic extracellular ATP/adenosine depletion, thus facilitating postsynaptic NMDAR activation. Compensatory transcriptional up-regulation of metabotropic glutamate receptor 4 (grm4) accompanies these adaptive changes. The physiological modification, promoted by loss of Panx1, led to distinct behavioral alterations, enhancing anxiety and impairing object recognition and spatial learning in Panx1(-/-) mice. We conclude that ATP release through Panx1 channels plays a critical role in maintaining synaptic strength and plasticity in CA1 neurons of the adult hippocampus. This result provides the rationale for in-depth analysis of Panx1 function and adenosine based therapies in CNS disorders.

We previously showed that the serum- and glucocorticoid-inducible kinase 3 (SGK3) increases the AMPA-type glutamate receptor GluA1 protein in the plasma membrane. The activation of AMPA receptors by NMDA-type glutamate receptors eventually leads to postsynaptic neuronal plasticity. Here, we show that SGK3 mRNA is upregulated in the hippocampus of new-born wild type Wistar rats after NMDA receptor activation. We further demonstrate in the Xenopus oocyte expression system that delivery of GluA1 protein to the plasma membrane depends on the small GTPase RAB11. This RAB-dependent GluA1 trafficking requires phosphorylation and activation of phosphoinositol-3-phosphate-5-kinase (PIKfyve) and the generation of PI(3,5)P(2). In line with this mechanism we could show PIKfyve mRNA expression in the hippocampus of wild type C57/BL6 mice and phosphorylation of PIKfyve by SGK3. Incubation of hippocampal slices with the PIKfyve inhibitor YM201636 revealed reduced CA1 basal synaptic activity. Furthermore, treatment of primary hippocampal neurons with YM201636 altered the GluA1 expression pattern towards reduced synaptic expression of GluA1. Our findings demonstrate for the first time an involvement of PIKfyve and PI(3,5)P(2) in NMDA receptor-triggered synaptic GluA1 trafficking. This new regulatory pathway of GluA1 may contribute to synaptic plasticity and memory.

The integration of episodic sequences in the hippocampus is believed to occur during theta rhythm episodes, when cortico-hippocampal dialog results in reconfiguration of neuronal assemblies. As the visual cortex (VC) is a major source of sensory information to the hippocampus, information processing in the cortex may affect hippocampal network oscillations, facilitating the induction of synaptic modifications. We investigated to what degree the field activity in the primary VC, elicited by sensory or electrical stimulation, correlates with hippocampal oscillatory and synaptic responsiveness, in freely behaving adult rats. We found that the spectral power of theta rhythm (4-10Hz) in the dentate gyrus (DG), increases in parallel with high-frequency oscillations in layer 2/3 of the VC and that this correlation depends on the degree of exploratory activity. When we mimic robust thalamocortical activity by theta-burst application to dorsal lateral geniculate nucleus, a hippocampal theta increase occurs, followed by a persistent potentiation of the DG granule field population spike. Furthermore, the potentiation of DG neuronal excitability tightly correlates with the concurrently occurring VC plasticity. The concurrent enhancement of VC and DG activity is also combined with a highly negative synchronization between hippocampal and cortical low frequency oscillations. Exploration of familiar environment decreases the degree of this synchrony. Our data propose that novel visual information can induce high-power fluctuations in intrinsic excitability for both VC and hippocampus, potent enough to induce experience-dependent modulation of cortico-hippocampal connections. This interaction may comprise one of the endogenous triggers for long-term synaptic plasticity in the hippocampus.

BACKGROUND:Theta rhythm in the hippocampal formation is a main feature of exploratory behaviour and is believed to enable the encoding of new spatial information and the modification of synaptic weights. Cyclic changes of dentate gyrus excitability during theta rhythm are related to its function, but whether theta epochs per se are able to alter network properties of dentate gyrus for long time-periods is still poorly understood. METHODOLOGY/PRINCIPAL FINDINGS:We used low-frequency stimulation protocols that amplify the power of endogenous theta oscillations, in order to estimate the plasticity effect of endogenous theta oscillations on a population level. We found that stimulation-induced augmentation of the theta rhythm is linked to a subsequent increase of neuronal excitability and decrease of the synaptic response. This EPSP-to-Spike uncoupling is related to an increased postsynaptic spiking on the positive phases of theta frequency oscillations. Parallel increase of the field EPSP slope and the population spike occurs only after concurrent pre- and postsynaptic activation. Furthermore, we observed that long-term potentiation (>24 h) occurs in the dentate gyrus of freely behaving adult rats after phasic activity of entorhinal afferents in the theta-frequency range. This plasticity is proportional to the field bursting activity of granule cells during the stimulation, and may comprise a key step in spatial information transfer. Long-term potentiation of the synaptic component occurs only when the afferent stimulus precedes the evoked population burst, and is input-specific. CONCLUSIONS/SIGNIFICANCE:Our data confirm the role of the dentate gyrus in filtering information to the subsequent network during the activated state of the hippocampus.

Hippocampal synaptic plasticity and learning are strongly regulated by metabotropic glutamate receptors (mGluRs) and particularly by mGluR5. Here, we investigated the mechanisms underlying mGluR5-modulation of these phenomena. Prolonged pharmacological blockade of mGluR5 with MPEP produced a profound impairment of spatial memory. Effects were associated with 1) a reduction of mGluR1a-expression in the dentate gyrus; 2) impaired dentate gyrus LTP; 3) enhanced CA1-LTP and 4) suppressed theta (5-10 Hz) and gamma (30-100 Hz) oscillations in the dentate gyrus. Allosteric potentiation of mGluR1 after mGluR5 blockade significantly ameliorated dentate gyrus LTP, as well as suppression of gamma oscillatory activity. CA3-lesioning prevented MPEP effects on CA1-LTP, suggesting that plasticity levels in CA1 are driven by mGluR5-dependent synaptic and network activity in the dentate gyrus. These data support the hypothesis that prolonged mGluR5-inactivation causes altered hippocampal LTP levels and network activity, which is mediated in part by impaired mGluR1-expression in the dentate gyrus. The consequence is impairment of long-term learning.

A role for oscillatory activity in hippocampal neuronal networks has been proposed in sensory encoding, cognitive functions and synaptic plasticity. In the hippocampus, theta (5–10 Hz) and gamma (30–100 Hz) oscillations may provide a mechanism for temporal encoding of information, and the basis for formation and retrieval of memory traces. Long-term potentiation (LTP) of synaptic transmission, a candidate cellular model of synaptic information storage, is typically induced by high-frequency tetanisation (HFT) of afferent pathways. Taking into account the role of oscillatory activity in the processing of information, dynamic changes may occur in hippocampal network activity in the period during HFT and/or soon after it. These changes in rhythmic activity may determine or, at least, contribute to successful potentiation and, in general, to formation of memory. We have found that short-term potentiation (STP) and LTP as well LTPfailure are characterised with different profiles of changes in theta and gamma frequencies. Potentiation of synaptic transmission was associated with a significant increase in the relative theta power and mean amplitude of theta cycles in the period encompassing 300 seconds after HFT. Where LTP or STP, but not failure of potentiation, occurred, this facilitation of theta was accompanied by transient increases in gamma power and in the mean amplitude of gamma oscillations within a single theta cycle. Our data support that specific, correlated changes in these parameters are associated with successful synaptic potentiation. These findings suggest that changes in theta-gamma activity associated with induction of LTP may enable synaptic information storage in the hippocampus.