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Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline related to deficits in synaptic transmission and plasticity. We report in APP/PS1 mice, a double transgenic mouse model of AD, that females displayed an early burden of Aβ plaques load in the stratum moleculare of the dentate gyrus (DG) together with prominent neuroinflammatory activation of astrocytes and microglia. Robust deficits in hippocampus-dependent memory tasks were observed in APP/PS1 female mice as early as 3 months of age. We then studied the functional properties of the lateral perforant path (LPP) to DG granule cells. Remarkably DG granule cells displayed higher intrinsic excitability in APP/PS1 female mice. We showed that the long term potentiation of population spike amplitude induced by high frequency stimulation (HFS) at LPP-DG granule cells synapse is impaired in APP/PS1 female mice. HFS induced plasticity of intrinsic excitability in DG granule cells without inducing noticeable modification of synaptic strength. Furthermore, the enhanced intrinsic excitability was potentiated to a greater extent in APP/PS1 as compared to control mice following HFS. Our study shows that changes in the intrinsic excitability of DG granule cells in AD contribute to the dysfunctional transfer of information from the entorhinal cortex to the hippocampus., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Ketamine has been shown to possess lasting antidepressant properties. However, studies of the mechanisms involved in its effects on poststroke depression are nonexistent., Methods: To investigate these mechanisms, Sprague-Dawley rats were treated with a single local dose of ketamine after middle cerebral artery occlusion and chronic unpredicted mild stress. The effects on the hippocampal dentate gyrus were analyzed through assessment of the N-methyl-D-aspartate receptor/calcium/calmodulin-dependent protein kinase II (NMDAR/CaMKII) pathway, synaptic plasticity, and behavioral tests., Results: Ketamine administration rapidly exerted significant and lasting improvements of depressive symptoms. The biochemical analysis showed rapid, selective upregulation and downregulation of the NMDAR2- β and NMDAR2- α subtypes as well as their downstream signaling proteins β -CaMKII and α -phosphorylation in the dentate gyrus, respectively. Furthermore, the colocalization analysis indicated a significant and selectively increased conjunction of β -CaMKII and postsynaptic density protein 95 (PSD95) coupled with a notable decrease in NMDAR2- β association with PSD95 after ketamine treatment. These changes translated into significant and extended synaptic plasticity in the dentate gyrus., Conclusions: These findings not only suggest that ketamine represents a viable candidate for the treatment of poststroke depression but also that ketamine's lasting antidepressant effects might be achieved through modulation of NMDAR/CaMKII-induced synaptic plasticity in key brain regions., Competing Interests: The authors declare that there are no competing interests., (Copyright © 2021 Idriss Ali Abdoulaye et al.)

α-actinin-2 (α-actn-2) is an F-actin-crosslinking protein, localized in dendritic spines. In vitro studies suggested that it is involved in spinogenesis, morphogenesis, actin organization, cell migration and anchoring of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptors in dendritic spines. However, little is known regarding its function in vivo. We examined the levels of α-actn-2 expression within the dentate gyrus (DG) during the development of chronic limbic seizures (epileptogenesis) induced by pilocarpine in rats. In this model, plasticity of the DG glutamatergic granule cells including spine loss, spinogenesis, morphogenesis, neo-synaptogenesis, aberrant migration, and alterations of NMDA receptors have been well characterized. We showed that α-actn-2 immunolabeling was reduced in the inner molecular layer at 1-2 weeks post-status epilepticus (SE), when granule cell spinogenesis and morphogenesis occur. This low level persisted at the chronic stage when new functional synapses are established. This decreased of α-actn-2 protein is concomitant with the recovery of drebrin A (DA), another actin-binding protein, at the chronic stage. Indeed, we demonstrated in cultured cells that in contrast to DA, α-actn-2 did not protect F-actin destabilization and DA inhibited α-actn-2 binding to F-actin. Such alteration could affect the anchoring of NR1 in dendritic spines. Furthermore, we showed that the expression of α-actn-2 and NR1 are co-down-regulated in membrane fractions of pilocarpine animals at chronic stage. Last, we showed that α-actn-2 is expressed in migrating newly born granule cells observed within the hilus of pilocarpine-treated rats. Altogether, our results suggest that α-actn-2 is not critical for the structural integrity and stabilization of granule cell dendritic spines. Instead, its expression is regulated when spinogenesis and morphogenesis occur and within migrating granule cells. Our data also suggest that the balance between α-actn-2 and DA expression levels may modulate NR1 anchoring within dendritic spines., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Neuronal calcium sensor-1 or Frequenin is a calcium sensor widely expressed in the nervous system, with roles in neurotransmission, neurite outgrowth, synaptic plasticity, learning, and motivated behaviours. Neuronal calcium sensor-1 has been implicated in neuropsychiatric disorders including autism spectrum disorder, schizophrenia, and bipolar disorder. However, the role of neuronal calcium sensor-1 in behavioural phenotypes and brain changes relevant to autism spectrum disorder have not been evaluated. We show that neuronal calcium sensor-1 deletion in the mouse leads to a mild deficit in social approach and impaired displaced object recognition without affecting social interactions, behavioural flexibility, spatial reference memory, anxiety-like behaviour, or sensorimotor gating. Morphologically, neuronal calcium sensor-1 deletion leads to increased dendritic arbour complexity in the frontal cortex. At the level of hippocampal synaptic plasticity, neuronal calcium sensor-1 deletion leads to a reduction in long-term potentiation in the dentate gyrus, but not area Cornu Ammonis 1. Metabotropic glutamate receptor-induced long-term depression was unaffected in both dentate and Cornu Ammonis 1. These studies identify roles for neuronal calcium sensor-1 in specific subregions of the brain including a phenotype relevant to neuropsychiatric disorders., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: With the growing use of second-generation antipsychotics for the treatment of a spectrum of psychiatric illnesses in pregnancy, concerns have been raised about the long-term impact of these medications on offspring neurodevelopment. However, preclinical and clinical evidence on the lasting effects of prenatal antipsychotic exposure is still sparse., Methods: Risperidone, a widely used second-generation antipsychotic, and haloperidol, a representative first-generation antipsychotic, were administered to pregnant C57BL/6N mice from embryonic day 6 to 16. Behavioral tests, immunohistochemical staining, Golgi-Cox technique, and western blot were used to determine the effects of prenatal antipsychotic exposure on the plasticity of the dentate gyrus and related behavior in adult male mice., Results: Both prenatal haloperidol- and risperidone-exposed mice showed recognition memory deficits but had no anxiety-related behavior. In addition, both prenatal haloperidol and risperidone exposure impaired the proliferation and maturation of adult-born dentate granule cells. We found that haloperidol exposure decreased dendritic length of dentate granule cells, while risperidone had no effect. However, both drugs inhibited dendrite branching in granule cells. Haloperidol exposure also significantly reduced total spine density in the middle dendritic segment of dentate gyrus. Prenatally risperidone-exposed mice only displayed a loss in thin and mushroom spines of infrapyramidal blade of dentate gyrus. Collectively, prenatal haloperidol exposure exerted more robust negative effects than risperidone., Conclusion: These data provide evidence for the long-term programming effects of early-life exposure to antipsychotics on hippocampal plasticity and behavior.

The dentate gyrus of the hippocampus has been implicated in the pathophysiological basis of neuropsychiatric disorders including schizophrenia. We have identified several mouse models of neuropsychiatric disorders with robust molecular and functional defects in the dentate gyrus. Among them, mice lacking Schnurri-2 (Shn2 or HIVEP2) have been proposed as a model of schizophrenia and intellectual disability. Shn2 knockout mice exhibit behavioral abnormalities resembling symptoms of schizophrenia and HIVEP2-related intellectual disability as well as marked functional alterations in the soma and output synapse of the dentate granule cells (GCs). Although robust abnormalities were also observed in the dendritic spine morphology in the GCs, their functional correlates remain unknown. In the present study, we performed electrophysiological analyses of synaptic transmission at the medial perforant path (MPP) input onto the GCs in Shn2 knockout mice. While the basal synaptic efficacy was preserved, short-term synaptic depression induced by paired-pulse or low-frequency stimulation was reduced in the mutant mice. High-frequency tetanic stimulation induced lasting synaptic potentiation in both wild-type and mutant mice. However, the decaying synaptic potentiation shortly after the tetanic stimulation was significantly reduced in the mutant mice. These results indicate that the Shn2 deficiency attenuates bidirectional short-term synaptic plasticity at the MPP-GC synapse, thereby rendering the synapse more static. Our finding further supports a possible role of the dentate gyrus dysfunction in pathophysiology of schizophrenia and may also provide important information in interpreting morphology changes of the brain synapses in neuropsychiatric disorders.

Activation of the amygdala is one of the hallmarks of acute stress reactions and a central element of the negative impact of stress on hippocampus-dependent memory and cognition. Stress-induced psychopathologies, such as posttraumatic stress disorder, exhibit a sustained hyperactivity of the amygdala, triggered at least in part by deficits in GABAergic inhibition that lead to shifts in amygdalo-hippocampal interaction. Here, we have utilized lentiviral knock down of neurofascin to reduce GABAergic inhibition specifically at the axon initial segment (AIS) of principal neurons within the basolateral amygdala (BLA) of rats. Metaplastic effects of such a BLA modulation on hippocampal synaptic function were assessed using BLA priming prior to the induction of long-term potentiation (LTP) on dentate gyrus synapses in anesthetized rats in vivo. The knock down of neurofascin in the BLA prevented a priming-induced impairment on LTP maintenance in the dentate gyrus. At the behavioral level, a similar effect was observable, with neurofascin knock down preventing the detrimental impact of acute traumatic stress on hippocampus-dependent spatial memory retrieval in a water maze task. These findings suggest that reducing GABAergic inhibition specifically at the AIS synapses of the BLA alters amygdalo-hippocampal interactions such that it attenuates the adverse impact of acute stress exposure on cognition-related hippocampal functions.

Newborn granule cells are continuously produced in the subgranular zone of dentate gyrus throughout life. Once these cells mature, they integrate into pre-existing circuits modulating hippocampus-dependent memory. Subsequently, mechanisms controlling generation and maturation of newborn cells are essential for proper hippocampal function. Therefore, we have studied the role of aryl hydrocarbon receptor (AhR), a ligand-activated bHLH-PAS transcription factor, in hippocampus-dependent memory and granule neuronal morphology and function using genetic loss-of-function approaches based on constitutive and inducible-nestin AhR -/- mice. The results presented here show that the impaired hippocampus-dependent memory in AhR absence is not due to its effects on neurogenesis but to aberrant dendritic arborization and an increased spine density, albeit with a lower number of mature mushrooms spines in newborn granule cells, a finding that is associated with an immature electrophysiological phenotype. Together, our data strongly suggest that AhR plays a pivotal role in the regulation of hippocampal function, by controlling hippocampal granule neuron morphology and synaptic maturation.

Aberrant epileptic activity is detectable at early disease stages in Alzheimer's disease (AD) patients and in AD mouse models. Here, we investigated in young ArcticAβ mice whether AD-like pathology renders neuronal networks more susceptible to the development of acquired epilepsy induced by unilateral intrahippocampal injection of kainic acid (IHK). In this temporal lobe epilepsy model, IHK induces a status epilepticus followed after two weeks by spontaneous recurrent seizures (SRS). ArcticAβ mice exhibited more severe status epilepticus and early onset of SRS. This hyperexcitable phenotype was characterized in CA1 neurons by decreased synaptic strength, increased kainic acid-induced LTP and reduced frequency of spontaneous inhibitory currents. However, no difference in neurodegeneration, neuroinflammation, axonal reorganization or adult neurogenesis was observed in ArcticAβ mice compared to wild-type littermates following IHK-induced epileptogenesis. Neuropeptide Y (NPY) expression was reduced at baseline and its IHK-induced elevation in mossy fibres and granule cells was attenuated. However, although this alteration might underlie premature seizure onset, neutralization of soluble Aβ species by intracerebroventricular Aβ-specific antibody application mitigated the hyperexcitable phenotype of ArcticAβ mice and prevented early SRS onset. Therefore, the development of seizures at early stages of AD is mediated primarily by Aβ species causing widespread changes in synaptic function., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Following traumatic brain injury (TBI), treatment with rapamycin suppresses mammalian (mechanistic) target of rapamycin (mTOR) activity and specific components of hippocampal synaptic reorganization associated with altered cortical excitability and seizure susceptibility. Reemergence of seizures after cessation of rapamycin treatment suggests, however, an incomplete suppression of epileptogenesis. Hilar inhibitory interneurons regulate dentate granule cell (DGC) activity, and de novo synaptic input from both DGCs and CA3 pyramidal cells after TBI increases their excitability but effects of rapamycin treatment on the injury-induced plasticity of interneurons is only partially described. Using transgenic mice in which enhanced green fluorescent protein (eGFP) is expressed in the somatostatinergic subset of hilar inhibitory interneurons, we tested the effect of daily systemic rapamycin treatment (3 mg/kg) on the excitability of hilar inhibitory interneurons after controlled cortical impact (CCI)-induced focal brain injury. Rapamycin treatment reduced, but did not normalize, the injury-induced increase in excitability of surviving eGFP+ hilar interneurons. The injury-induced increase in response to selective glutamate photostimulation of DGCs was reduced to normal levels after mTOR inhibition, but the postinjury increase in synaptic excitation arising from CA3 pyramidal cell activity was unaffected by rapamycin treatment. The incomplete suppression of synaptic reorganization in inhibitory circuits after brain injury could contribute to hippocampal hyperexcitability and the eventual reemergence of the epileptogenic process upon cessation of mTOR inhibition. Further, the cell-selective effect of mTOR inhibition on synaptic reorganization after CCI suggests possible mechanisms by which rapamycin treatment modifies epileptogenesis in some models but not others.

Synthetic cannabinoids and phytocannabinoids have been shown to suppress seizures both in humans and experimental models of epilepsy. However, they generally have a detrimental effect on memory and memory-related processes. Here we compared the effect of the inhibition of the endocannabinoid (eCB) degradation versus synthetic CB agonist on limbic seizures induced by maximal dentate activation (MDA) acute kindling. Moreover, we investigated the dentate gyrus (DG) granule cell reactivity and synaptic plasticity in naïve and in MDA-kindled anaesthetised rats. We found that both the fatty acid amide hydrolase (FAAH) inhibitor URB597 and the synthetic cannabinoid agonist WIN55,212-2 displayed AM251-sensitive anti-seizure effects. WIN55,212-2, dose-dependently (0.5-2 mg/kg, i.p.) impaired short-term plasticity (STP) and long-term potentiation (LTP) at perforant path-DG synapses in naïve rats. Strikingly, URB597 (1 mg/kg, i.p.) was devoid of any deleterious effects in normal conditions, while it prevented seizure-induced alterations of both STP and LTP. Our evidence indicates that boosting the eCB tone rather than general CB1 activation might represent a potential strategy for the development of a new class of drugs for treatment of both seizures and comorbid memory impairments associated with epilepsy.

Increasing evidence suggests that glycogen synthase kinase-3β (GSK-3β) plays a crucial role in neurodegenerative/psychiatric disorders, while pan-neural knockout of GSK-3β also shows detrimental effects. Currently, the function of GSK-3β in specific type of neurons is elusive. Here, we infused AAV-CaMKII-Cre-2A-eGFP into GSK-3β lox/lox mice to selectively delete the kinase in excitatory neurons of hippocampal dentate gyrus (DG), and studied the effects on cognitive/psychiatric behaviors and the molecular mechanisms. We found that mice with GSK-3β deletion in DG excitatory neurons displayed spatial and fear memory defects with an anti-anxiety behavior. Further studies demonstrated that GSK-3β deletion in DG subset inhibited hippocampal synaptic transmission and reduced levels of GluN1, GluN2A and GluN2B (NMDAR subunits), GluA1 (AMPAR subunit), PSD93 and drebrin (postsynaptic structural proteins), and synaptophysin (presynaptic protein). GSK-3β deletion also suppressed the activity-dependent neural activation and calcium/calmodulin-dependent protein kinase II (CaMKII)/CaMKIV-cAMP response element binding protein (CREB) signaling. Our data suggest that GSK-3β in hippocampal DG excitatory neurons is essential for maintaining synaptic plasticity and memory.

The hippocampus is reciprocally connected with the entorhinal cortex. Although several studies emphasized a role for the entorhinal cortex in mesial temporal lobe epilepsy (MTLE), it remains uncertain whether its synaptic connections with the hippocampus are altered. To address this question, we traced hippocampo-entorhinal and entorhino-hippocampal projections, assessed their connectivity with the respective target cells and examined functional alterations in a mouse model for MTLE. We show that hippocampal afferents to the dorsal entorhinal cortex are lost in the epileptic hippocampus. Conversely, entorhino-dentate projections via the medial perforant path (MPP) are preserved, but appear substantially altered on the synaptic level. Confocal imaging and 3D-reconstruction revealed that new putative contacts are established between MPP fibers and dentate granule cells (DGCs). Immunohistochemical identification of pre- and postsynaptic elements indicated that these contacts are functionally mature synapses. On the ultrastructural level, pre- and postsynaptic compartments of MPP synapses were strongly enlarged. The length and complexity of postsynaptic densities were also increased pointing to long-term potentiation-related morphogenesis. Finally, whole-cell recordings of DGCs revealed an enhancement of evoked excitatory postsynaptic currents. In conclusion, the synaptic rearrangement of excitatory inputs to DGCs from the medial entorhinal cortex may contribute to the epileptogenic circuitry in MTLE., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The nucleus basalis magnocellularis (NBM) is a major source of cholinergic projections to the neocortex that is vulnerable to degeneration in Alzheimer's disease. Despite numerous anatomical, pharmacological, behavioral, and physiological investigations of NBM, there is no in vivo study of its effects on short- or long-term synaptic plasticity. Hence, this study was devoted to the assessment of the effects of bilateral lesion of the NBM on synaptic plasticity in the dentate gyrus of the hippocampus using electrophysiological techniques. For this purpose, twenty-five male Wistar rats were randomly allocated into the three Control, Sham, and NBM-lesioned groups. Lesion was made via bilateral injections of 5µg/µl ibotenic acid. After twenty-one days, the input-output functions, paired-pulse facilitation/inhibition, and long-term potentiation (LTP) were evaluated in the dentate gyrus while the perforant pathway was stimulated. NBM lesion was found to attenuate the basal synaptic responsiveness, paired-pulse responses, and LTP in the rats' dentate gyrus, indicating that lesions of this cholinergic nucleus affects both short- and long-term neural plasticity in the dentate gyrus although NBM does not send direct cholinergic projections to the hippocampus., (Copyright © 2016. Published by Elsevier B.V.)

The dentate gyrus (DG) of the hippocampus is known to be more resistant to the effects of various external factors than other hippocampal areas. This study investigated the neuroprotective effects of moderate treadmill exercise on early-phase long-term potentiation (E-LTP) and its molecular signaling pathways in the DG of amyloid β rat model of sporadic Alzheimer's disease (AD). Animals were preconditioned to run on treadmill for 4 weeks and concurrently received ICV infusion of Aβ₁₋₄₂ peptides (250 pmol/day) during the third and fourth weeks of exercise training. We utilized in vivo electrophysiological recordings to assess the effect of exercise and/or AD pathology on basal synaptic transmission and E-LTP magnitude of the perforant pathway synapses in urethane-anesthetized rats. Immunoblotting analysis was used to quantify changes in the levels of learning and memory-related key signaling molecules. The AD-impaired basal synaptic transmission and suppression of E-LTP in the DG were prevented by prior moderate treadmill exercise. In addition, exercise normalized the basal levels of memory and E-LTP-related signaling molecules including Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), calcineurin (PP2B), and brain-derived neurotrophic factor (BDNF). Exercise also prevented the reduction of phosphorylated CaMKII and aberrant increase of PP2B seen after E-LTP induction in amyloid-infused rats. Our data suggests that by restoring the balance of kinase-phosphatase, 4 weeks of moderate treadmill exercise prevents DG synaptic deficits and deleterious alterations in signaling pathways associated with AD.

Background: Chronic stress has been found to suppress adult neurogenesis, but it remains unclear whether it may affect the maturation process of adult-born neurons. Here, we examined the influence of chronic social defeat stress on the morphological and electrophysiological properties of adult-born dentate granule cells at different developmental stages., Methods: Adult C57BL/6 mice were subjected to 10 days of chronic social defeat stress followed by a social interaction test 24 hours after the last defeat. Defeated mice were segregated into susceptible and unsusceptible subpopulations based on a measure of social interaction test. Combining electrophysiology with retrovirus-mediated birth-dating and labeling, we examined the impact of chronic social defeat stress on temporal regulation of synaptic plasticity of adult-born dentate granule cells along their maturation., Results: Chronic social defeat stress decreases the survival and dendritic complexity of adult-born dentate granule cells. While chronic social defeat stress doesn't alter the intrinsic electrophysiological properties and synaptic transmission of surviving adult-born dentate granule cells, it promotes the developmental switch in synaptic N-methyl-D-aspartate receptors from predominant GluN2B- to GluN2A-containing receptors, which transform the immature synapse of adult-born dentate granule cells from one that exhibits enhanced long-term potentiation to one that has normal levels of long-term potentiation. Furthermore, chronic social defeat stress increases the level of endogenous repressor element-1 silencing transcription factor mRNA in adult-born dentate granule cells, and knockdown of the repressor element-1 silencing transcription factor in adult-born dentate granule cells rescues chronic social defeat stress-induced morphological deficits and accelerated developmental switch in synaptic N-methyl-D-aspartate receptor subunit composition., Conclusions: These results uncover a previously unsuspected role of chronic social defeat stress in regulating adult neurogenesis and suggest that chronic social defeat stress can affect synaptic maturation process of adult-born dentate granule cells., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

Lead (Pb) is a neurotoxic metal that is widely distributed in the environment. In experimental animals, chronic exposure to this neurotoxicant resulted in impaired synaptic plasticity and cognitive function. In this study, we examined the protective effects of vitamin C (ascorbic acid) against Pb exposure-induced impairment of long-term potentiation (LTP). Forty-four adult male Wistar rats were divided into six groups and subjected to the following treatments for three months: (1) vehicle (distilled water); (2) Pb; (3) ascorbic acid; (4) Pb+ascorbic acid; (5) Pb (two months) followed by ascorbic acid; and (6) ascorbic acid (one month) followed by Pb. After treatment, the population spike (PS) amplitude and slope of excitatory postsynaptic potentials (EPSP) were measured in the dentate gyrus(DG) of rats in vivo. Following these measurements, blood samples were collected for the following biochemical assays: malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidant status (TOS). There was a significant increase in plasma MDA and TOS in the Pb-intoxicated group compared to the control group. There was a significant increase in TAC levels in the ascorbic acid group. Our results also show that Pb exposure caused a decrease in the EPSP slope and PS amplitude when compared with the control group, whereas vitamin C increased these parameters. Co-administration of Pb with vitamin C inhibited the effects of Pb. These findings suggested that Pb exposure caused impairment in LTP, that may have been mediated through oxidative damage. Vitamin C ameliorated the Pb-induced impairment of synaptic plasticity in the DG via antioxidant activity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Patients with temporal lobe epilepsy often display cognitive comorbidity with recurrent seizures. However, the cellular mechanisms underlying the impairment of neuronal information processing remain poorly understood in temporal lobe epilepsy. Within the hippocampal formation neuronal networks undergo major reorganization, including the sprouting of mossy fibers in the dentate gyrus; they establish aberrant recurrent synapses between dentate granule cells and operate via postsynaptic kainate receptors. In this report, we tested the hypothesis that this aberrant local circuit alters information processing of perforant path inputs constituting the major excitatory afferent pathway from entorhinal cortex to dentate granule cells., Methods: Experiments were performed in dentate granule cells from control rats and rats with temporal lobe epilepsy induced by pilocarpine hydrochloride treatment. Neurons were recorded in patch clamp in whole cell configuration in hippocampal slices., Results: Our present data revealed that an aberrant readout of synaptic inputs by kainate receptors triggered a long-lasting impairment of the perforant path input-output operation in epileptic dentate granule cells. We demonstrated that this is due to the aberrant activity-dependent potentiation of the persistent sodium current altering intrinsic firing properties of dentate granule cells., Interpretation: We propose that this aberrant activity-dependent intrinsic plasticity, which lastingly impairs the information processing of cortical inputs in dentate gyrus, may participate in hippocampal-related cognitive deficits, such as those reported in patients with epilepsy., (© 2015 American Neurological Association.)

The endocannabinoid ligand 2-arachidonoylglycerol (2-AG) is inactivated primarily by monoacylglycerol lipase (MAGL). We have shown recently that chronic treatments with MAGL inhibitor JZL184 produce antidepressant- and anxiolytic-like effects in a chronic unpredictable stress (CUS) model of depression in mice. However, the underlying mechanisms remain poorly understood. Adult hippocampal neurogenesis has been implicated in animal models of anxiety and depression and behavioral effects of antidepressants. We tested whether CUS and chronic JZL184 treatments affected adult neurogenesis and synaptic plasticity in the dentate gyrus (DG) of mouse hippocampus. We report that CUS induced depressive-like behaviors and decreased the number of bromodeoxyuridine-labeled neural progenitor cells and doublecortin-positive immature neurons in the DG, while chronic JZL184 treatments prevented these behavioral and cellular deficits. We also investigated the effects of CUS and chronic JZL184 on a form long-term potentiation (LTP) in the DG known to be neurogenesis-dependent. CUS impaired LTP induction, whereas chronic JZL184 treatments restored LTP in CUS-exposed mice. These results suggest that enhanced adult neurogenesis and long-term synaptic plasticity in the DG of the hippocampus might contribute to antidepressant- and anxiolytic-like behavioral effects of JZL184., (© 2014 Wiley Periodicals, Inc.)

A common feature of neurological diseases is the loss of central neurons, which leads to deafferentation of connected brain regions. In turn, the remodeling of denervated neuronal networks is considered to play an important role for the postlesional recovery, but has also been linked to maladaptive plasticity resulting in disease-related complications such as memory dysfunction or epilepsy. Recent work has indicated that Protease-Activated Receptor 1 (PAR1), which can be activated by thrombin that enters the brain under pathological conditions, alters synaptic plasticity and neuronal excitability. However, the role of PAR1 in lesion-induced synaptic plasticity remains incompletely understood. Here, we used entorhinal denervation of organotypic hippocampal slice cultures to study the effects of PAR1 on denervation-induced homeostatic synaptic plasticity. Our results disclose that PAR1 activation counters the ability of denervated dentate granule cells to increase their excitatory synaptic strength in a compensatory, i.e., homeostatic manner. Furthermore, we demonstrate that this PAR1 effect is rescued by pharmacological inhibition of N-methyl-d-aspartate receptors (NMDA-R). Thus, NMDA-R inhibitors may restore the ability of denervated neurons to express homeostatic synaptic plasticity under conditions of increased PAR1-activity, which may contribute to their beneficial effects seen in the context of neurological diseases., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Huntington's disease (HD) is a progressive and fatal neurodegenerative disorder caused by a polyglutamine expansion in the gene encoding the protein huntingtin. The disease progresses over decades, but often patients develop cognitive impairments that precede the onset of the classical motor symptoms. Similar to the disease progression in humans, the yeast artificial chromosome (YAC) 128 HD mouse model also exhibits cognitive dysfunction that precedes the onset of the neuropathological and motor impairments characteristic of HD. Thus, the purpose of this study was to evaluate whether short- and long-term synaptic plasticity in the hippocampus, two related biological models of learning and memory processes, were altered in YAC128 mice in early stages of disease progression. We show that the YAC128 hippocampal dentate gyrus (DG) displays marked reductions in paired-pulse depression both at 3 and 6 months of age. In addition, significantly enhanced post-tetanic and short-term potentiation are apparent in YAC128 mice after high-frequency stimulation at this time. Early and late forms of long-term plasticity were not altered at this stage. Together these findings indicate that there may be elevated neurotransmitter release in response to synaptic stimulation in YAC128 mice during the initial phase of disease progression. These abnormalities in short-term plasticity detected at this stage in YAC128 HD transgenic mice indicate that aberrant information processing at the level of the synapses may contribute, at least in part, to the early onset of cognitive deficits that are characteristic of this devastating neurodegenerative disorder., (Copyright © 2014 Elsevier B.V. All rights reserved.)

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., (© 2013.)

In the last decade, early-onset of affective illness has been recognized as a major public health problem. However, clinical studies indicate that although children experience the symptoms of anxiety and depression in much the same way as adults, they display and react to those symptoms differently (Bostic et al., 2005). Recently, we have demonstrated that similar differences in symptoms are found also between adult and juvenile rats (Jacobson-Pick and Richter-Levin, 2010). Especially the hippocampus is believed to be vulnerable to stress-related illness, as this brain region has a high density of corticoid receptors. The hippocampus is known to finalize its development, and particularly that of GABA-related functions, into adolescence (Bergmann et al., 1991; Harris et al., 1992; Nurse and Lacaille, 1999; Lopez-Tellez et al., 2004; Jacobson-Pick et al., 2008) and may thus be differentially sensitive to environmental challenges in childhood and in adulthood. In this study we explored the differences in activity and plasticity of the dentate gyrus between pre-pubertal and adult rats in vivo. Furthermore, we have examined the impact of exposure to stress either during pre-puberty or in adulthood on dentate gyrus electrophysiology. In both male and female rats, marked differences were found for intrinsic excitability and local circuit activity between pre-pubertal and adult animals. Exposure to forced swim stress resulted in significant alterations of dentate gyrus activity and plasticity in male rats with differences between adult and pre-pubertal animals. Stress had far less impact on females' dentate electrophysiology. The results are in agreement with the differences in behavioral response to stress between pre-pubertal and adult rats, and with reported differences for the sensitivity of male and female rats in performing hippocampus-dependent tasks under stress, such as the active avoidance task., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

The adult brain is highly plastic and tends to undergo substantial reorganization after injury to compensate for the lesion effects. It has been shown that such reorganization mainly relies on anatomical and biochemical modifications of the remaining cells which give rise to a network rewiring without reinstating the original morphology of the damaged region. However, few studies have analyzed the neurorepair potential of a neurogenic structure. Thus, the aim of this work was to analyze if the DG could restore its original morphology after a lesion and to establish if the structural reorganization is accompanied by behavioral and electrophysiological recovery. Using a subepileptogenic injection of kainic acid (KA), we induced a focal lesion in the DG and assessed in time (1) the loss and recovery of dependent and non dependent DG cognitive functions, (2) the anatomical reorganization of the DG using a stereological probe and immunohistochemical markers for different neuronal maturation stages and, (3) synaptic plasticity as assessed through the induction of in vivo long-term potentiation (LTP) in the mossy fiber pathway (CA3-DG). Our results show that a DG focal lesion with KA leads to a well delimited region of neuronal loss, disorganization of the structure, the loss of associated mnemonic functions and the impairment to elicit LTP. However, behavioral and synaptic plasticity expression occurs in a time dependent fashion and occurs along the morphological restoration of the DG. These results provide novel information on neural plasticity events associated to functional reorganization after damage.

Chronic diabetes mellitus initiates apoptosis and negatively affects synaptic plasticity in the hippocampus with ensuing impairments of learning and memory. Berberine, an isoquinoline alkaloid, exhibits anti-diabetic, antioxidant and nootropic effects. This study was conducted to evaluate the effect of berberine on hippocampal CA1 neuronal apoptosis, synaptic plasticity and learning and memory of streptozotocin (STZ)-diabetic rats. Long-term potentiation (LTP) in perforant path-dentate gyrus synapses was recorded for assessment of synaptic plasticity and field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude. PS amplitude and fEPSP significantly decreased in diabetic group versus control, and chronic berberine treatment (100mg/kg/day, p.o.) restored PS amplitude and fEPSP and ameliorated learning and memory impairment and attenuated apoptosis of pyramidal neurons in the CA1 area, as determined by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling method. In summary, chronic berberine treatment of STZ-diabetic rats significantly ameliorates learning and memory impairment and part of its beneficial effect could be attributed to improvement of synaptic dysfunction and anti-apoptotic property., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Synaptic glutamate signaling in brain is highly complex and includes multiple interacting receptors, modulating cotransmitters and distinct regional dynamics. Medial temporal lobe (MTL) memory structures receive excitatory inputs from neocortical sensory and associational projections: afferents from neocortex pass to parahippocampal cortex, then to layers II/III of entorhinal cortex, and then onto hippocampal subfields. Principles of Hebbian plasticity govern synaptic encoding of memory signals, and homeostatic plasticity processes influence the activity of the memory system as a whole. Hippocampal imaging studies in schizophrenia have identified 2 alterations in MTL--increases in baseline blood perfusion and decreases in task-related activation. These observations along with converging postsynaptic hippocampal protein changes suggest that homeostatic plasticity mechanisms might be altered in schizophrenia hippocampus. If hippocampal pattern separation is diminished due to partial dentate gyrus failure (resulting in 'spurious associations') and also if pattern completion is accelerated and increasingly inaccurate due to increased CA3 associational activity, then it is conceivable that associations could be false and, especially if driven by anxiety or stress, could generate psychotic content, with the mistaken associations being laid down in memory, despite their psychotic content, especially delusions and thought disorder.

The recent discovery of a large latent population of precursor cells in the dentate gyrus of adult mice led us to investigate whether activation of this population is regulated by synaptic activity, thereby explaining the observation that environmental signals can affect neurogenesis. Using a variety of stimulation protocols, we found that only a long-term potentiation (LTP)-inducing protocol activated the latent precursor pool, leading to increased neurogenesis in the dentate gyrus. LTP induced by high-frequency stimulation (HFS) of the perforant pathway in vivo produced a two-fold increase in the number of neurospheres cultured from the stimulated hippocampus, compared with the unstimulated hippocampus. No increase in neurosphere number or neurogenesis was observed when the HFS failed to induce LTP. These results show that LTP can activate latent neural precursor cells in the adult mouse dentate gyrus, thereby providing a direct mechanism for regulating activity-driven neurogenesis. In the future, it may be possible to utilize such learning- or stimulation-induced neurogenesis to overcome disorders characterized by neuronal loss.

Recurrent seizures can induce mossy fiber sprouting (MFS), of the hippocampal dentate gyrus, and synaptic reorganization in mature brain. This changes local circuits and provides a structural basis for epileptogenesis in the hippocampus. However, the mechanisms of MFS and synaptic reorganization still remain unclear. Neural-cadherin (N-cadherin), a calcium adhesion molecule, plays an important role in neurite outgrowth, pathfinding, and synaptic specificity of early central nervous system development. It is unknown whether N-cadherin is involved in MFS after seizures in mature brain. To further examine the correlation between MFS and N-cadherin expression, we separately labeled MFS and N-cadherin with Timm staining and antibody in adult rats after status epilepticus (SE). Timm staining revealed that MFS is observed in the inner molecular layer of dentate gyrus of rats 2 and 4 weeks after SE. The observed MFS migrated from the hilus to the granule cell layer, gradually extending axons into the inner molecular layer to form an intense band. Immunohistochemical staining of N-cadherin revealed that the upregulated expression of N-cadherin was concentrated in the position of mossy fiber axonal sprouts of rats 1-4 weeks after SE, and that it was earlier than MFS. The spatial and temporal distribution consistence of N-cadherin and Timm staining supported the correlation that exists between N-cadherin expression and the process of aberrant MFS. This result suggests that N-cadherin may be involved in the pathfinding and synaptic specificity of MFS in mature brain after seizures, and can play an important role in the targeted growth of mossy fibers.

Chronic lead exposure causes a variety of impairments in learning and memory and cognitive function. Synaptic plasticity in hippocampus is an extensively studied cellular model of learning and memory, which includes long-term potentiation (LTP) and long-term depression (LTD) in two forms. Depotentiation (DP) is another form of synaptic plasticity. Previous studies show that chronic lead exposure can damage the induction of LTP/LTD in hippocampal CA1 and dentate gyrus (DG) areas. In the present study, we investigated the repair and protection on lead-caused synaptic plasticity impairment by galantamine, using field potential recording on chronic lead exposure rats. The results showed that chronic lead exposure impaired LTP/DP induction in DG area of the hippocampus, and galantamine caused a significant increase on the amplitudes of LTP/DP of lead-exposed rats, but only a small increase in non-exposed group. These results suggest that galantamine could reverse the lead-induced impairments of synaptic plasticity in rats and might be an effective medicine to cure the cognitive deficits induced by lead., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Febrile seizure (FS) is common in childhood and can impair cognitive function. The potential to exhibit plasticity at many synapses appears to be modulated by prior synaptic activity. This intriguing higher-order form of plasticity has been termed metaplasticity. Plasticity and metaplasticity have been considered to be one of the most important neurological fundaments of learning and memory. In the present study, field potential recording was carried out to detect the effects of FS on plasticity and metaplasticity in the lateral perforant path of rat hippocampus. Brain slices from rat pups of FS model were prepared and superfused. The recording electrodes were placed within the outer molecular layer for recording of lateral perforant path field excitatory postsynaptic potentials (fEPSP). Stimulation of the lateral perforant path and the dentate hilar region was carried out by placing bipolar stimulating electrodes within the outer molecular layer and hilus, respectively. The results showed that long term potentiation (LTP) of control and FS rats didn't show significant difference after 100 Hz conditioning stimulation. Subjected to 10 Hz priming stimulation applied to lateral perforant path or dentate hilar region 40 min prior to 100 Hz conditioning, the LTP of control group was inhibited, while the LTP of FS rats remained constant. Normalized fEPSP slope 1 h after tetanization of control group was 1.10 ± 0.26 and 1.15 ± 0.14 after homosynaptic and antidromic priming stimulation respectively. On the contrast, FS group didn't show any depression of LTP after homosynaptic and antidromic priming stimulation, normalized fEPSP slope 1 h after tetanization being 1.35 ± 0.2 and 1.47 ± 0.19, respectively. These results suggest that FS would impair lateral perforant path metaplasticity without affecting LTP. These findings represent an intriguing phenomenon of FS-caused brain damage and imply the injury of excitatory status in different pathways.

Patients with traumatic brain injury (TBI) exhibit impaired cognitive capability that is exacerbated with methylprednisolone (MP). Since long-term potentiation (LTP) is a leading cellular model underlying learning, we hypothesize that MP disturbs the electrophysiological character in the hippocampus by decreasing the number of interneurons post-traumatically in the dentate gyrus (DG) and cornu ammonis3 (CA3) regions, resulting in learning deficits. To test this hypothesis, we investigated the alterations of learning abilities and correlated the alternation with hippocampal synaptic plasticity in rats receiving lateral fluid percussion injury (FPI) and being treated with MP. We found that MP aggravates the spatial learning deficiency and changes in the excitability of the DG and cornu ammonis1 (CA1) areas in rats subjected to FPI. The functional and electrophysiological deficits are associated with a decrease in the number of parvalbumin-immunoreactive (PV-IR) and cholecystokinin-immunoreactive (CCK-IR) GABAergic cells. The data suggest that MP therapy may decrease the number of DG interneurons in post-traumatic hippocampus, resulting in the aggravated deficits of learning ability induced by TBI., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Long-term potentiation (LTP) and neurogenesis in the dentate gyrus (DG) are correlated forms of hippocampal plasticity which share, under physiological conditions, common regulatory mechanisms. In Alzheimer's disease (AD), their alterations are potentially associated with the early cellular pathology and cognitive decline. We analyzed DG LTP and neurogenesis in B6.152H mice, an amyloid precursor protein and presenilin 2 double-transgenic mouse model of amyloidosis and observed that DG LTP was strongly enhanced before and after amyloid plaque formation. Whereas proliferation of DG neuronal progenitor cells was unchanged, survival of newborn neurons was strongly decreased already before plaque formation. As similar alteration of neurogenesis was observed in PS2APP mice without changes in DG LTP (Richards et al. 2003), this study suggests that enhanced synaptic plasticity did not rescue impaired neurogenesis, and supports decreased survival of newborn neurons as an early event associated with AD detectable even before plaque formation., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Early life stress increases the risk for developing stress-related pathologies later in life. Recent studies in rats suggest that mild early life stress, rather than being overall unfavorable, may program the hippocampus such that it is optimally adapted to a stressful context later in life. Here, we tested whether this principle of "adaptive programming" also holds under severely adverse early life conditions, i.e., 24 h of maternal deprivation (MD), a model for maternal neglect. In young adult male rats subjected to MD on postnatal day 3, we observed reduced levels of adult hippocampal neurogenesis as measured by cell proliferation, cell survival, and neuronal differentiation. Also, mature dentate granule cells showed a change in their dendritic morphology that was most noticeable in the proximal part of the dendritic tree. Lasting structural changes due to MD were paralleled by impaired water maze acquisition but did not affect long-term potentiation in the dentate gyrus. Importantly, in the presence of high levels of the stress hormone corticosterone, even long-term potentiation in the dentate gyrus of MD animals was facilitated. In addition to this, contextual learning in a high-stress environment was enhanced in MD rats. These morphological, electrophysiological, and behavioral observations show that even a severely adverse early life environment does not evolve into overall impaired hippocampal functionality later in life. Rather, adversity early in life can prepare the organism to perform optimally under conditions associated with high corticosteroid levels in adulthood.

Valproic acid (VPA) is widely used clinically, as an anticonvulsant and mood stabilizer but is, however, also known to block cell proliferation through its ability to inhibit histone deacetylase enzymes. There have been a number of reports of cognitive impairments in patients taking VPA. In this investigation we examined the relationship between cognition and changes in cell proliferation within the hippocampus, a brain region where continued formation of new neurons is associated with learning and memory. Treatment of rats by i.p. injection of VPA, reduced cell proliferation in the sub granular zone of the dentate gyrus within the hippocampus. This was linked to a significant impairment in their ability to perform a hippocampus-dependent spatial memory test (novel object location). In addition, drug treatment caused a significant reduction in brain-derived neurotrophic factor (BDNF) and Notch 1 but not doublecortin levels within the hippocampus. These results support the idea that VPA may cause cognitive impairment and provide a possible mechanism for this by reducing neurogenesis within the hippocampus., (Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.)

Altered granule cell>>CA3 pyramidal cell synaptic connectivity may contribute to the development of limbic epilepsy. To explore this possibility, granule cell giant mossy fiber bouton plasticity was examined in the kindling and pilocarpine models of epilepsy using green fluorescent protein-expressing transgenic mice. These studies revealed significant increases in the frequency of giant boutons with satellite boutons 2 days and 1 month after pilocarpine status epilepticus, and increases in giant bouton area at 1 month. Similar increases in giant bouton area were observed shortly after kindling. Finally, both models exhibited plasticity of mossy fiber giant bouton filopodia, which contact GABAergic interneurons mediating feedforward inhibition of CA3 pyramids. In the kindling model, however, all changes were fleeting, having resolved by 1 month after the last evoked seizure. Together, these findings demonstrate striking structural plasticity of granule cell mossy fiber synaptic terminal structure in two distinct models of adult limbic epileptogenesis. We suggest that these plasticities modify local connectivities between individual mossy fiber terminals and their targets, inhibitory interneurons, and CA3 pyramidal cells potentially altering the balance of excitation and inhibition during the development of epilepsy., (Copyright 2009 Wiley-Liss, Inc.)

Early stressful adverse situations may increase the vulnerability to cognitive deficits and psychiatric disorders, such as depression. Maternal separation (MS) has been used as an animal model to study changes in neurochemistry and behavior associated with exposure to early-life stress. This study investigated the effects of neonatal stress (MS) on the expression of synaptic plasticity markers in the hippocampus and a purported relationship to cognitive processes. Spatial learning (Morris water maze) significantly increased the expression of total levels of the neural cell adhesion molecule (NCAM), as well as its three major isoforms (NCAM-120, -140, and -180) both in the control and MS groups. Interestingly, these increases in NCAM expression after learning were lower in MS animals when compared with control rats. MS induced a significant decrease in total levels of NCAM, and specifically, in the NCAM-140 isoform expression. In the hippocampus of MS rats there was a significant decrease in brain-derived neurotrophic factor and synaptophysin mRNA densities. Cell proliferation, measured as BrdU-positive cells, was also decreased in the dentate gyrus of MS rats. Altogether these results suggest that MS can alter normal brain development, providing a potential mechanism by which early environmental stressors may influence vulnerability to show cognitive impairments later in life.

Transient prenatal vitamin D deficiency is considered a neurodevelopmental animal model in schizophrenia research. Vitamin D deficiency in female rats causes morphological, cellular and molecular changes in the brain and alters behaviour and nerve growth factors expression in their offspring. Prenatal depleted animals showed a significant impairment of latent inhibition, a feature often associated with schizophrenia and of hole board habituation. Interestingly, memory consolidation of brightness discrimination was improved. Possible functional effects of altered brain development that results from prenatal vitamin D deficiency were characterized by investigation of potentiation phenomena in the hippocampus in freely moving rats. Transient prenatal vitamin D deficiency induced an enhancement of long-term potentiation (LTP) using either weak tetanic or strong tetanic stimulation, whereas the response to test stimuli was not changed. The classic neuroleptic drug haloperidol (Hal) and the atypical neuroleptic risperidone (Ris) in doses, which normalized behavioural disturbances in prenatal vitamin D-deficient animals without any side effects on the normal behaviour decreased the enhanced LTP in the experimental group to control level. Interestingly, the effect of the substances was different in experimental and control rats. The LTP was enhanced in control animals by the low doses of the drugs effective in our behavioural experiments. It can be suggested, that changes in brain development induced by prenatal vitamin D deficiency lead to specific functional alterations in hippocampal synaptic plasticity. LTP is considered a cellular correlate of learning and memory. The better retention performance in brightness discrimination seems in accordance with enhanced potentiation level.

To investigate the influence of forepaw sensorimotor deprivation on memory and synaptic plasticity, Sprague-Dawley rats were divided into two groups: a sham-operated group and a group deprived of forepaw sensorimotor function by microsurgical operation at postnatal day 13 (PN13). Behavioral and electrophysiological studies were performed at PN25, PN35, PN45, and PN60. Open field test was used to assess the spontaneous locomotor activity. Morris water maze was used to evaluate spatial reference learning and memory. The long-term potentiation (LTP) in the medial perforant path--dentate gyrus (MPP-DG) pathway was examined with hippocampal slices. We found that forepaw sensorimotor deprivation did not affect spontaneous activity of the rats. However, spatial reference learning and memory were significantly impaired in their early life (PN25, PN35, and PN45). In accordance with the behavior results, LTP in MPP-DG pathway was significantly suppressed in their early life. These data demonstrated that forepaw sensorimotor deprivation led to the impairments on spatial memory via inducing pronounced deficits in the MPP-DG pathway to exhibit LTP, one of the major cellular mechanisms underlying learning and memory.

Previous studies indicated that diabetes mellitus leads to impairments in hippocampal synaptic plasticity and defects in learning and memory. Although diabetes affects synaptic transmission in the hippocampus through both pre- and post-synaptic influences, it is not clear if the defects are pre- or post-synaptic or both; and whether these are prevented by running. The aim of this study was to evaluate the effects of treadmill running on short-term plasticity in inhibitory interneurons in the dentate gyrus of STZ-induced diabetic rats. Experimental groups were the control-rest group, the control-exercise group, the diabetes-rest group and the diabetes-exercise group (n=6 for each experimental group). The exercise program was moderate exercise consisting of treadmill running at 17 m/min and 0-degree inclination for 40 min/day, 7 days/week, for 12 weeks. The paired pulse paradigm was used to stimulate the perforant pathway and field excitatory post-synaptic potentials (fEPSP) were recorded in dentate gyrus (DG). In the diabetic-rest group paired pulse facilitation was significantly increased comparing to the control-rest group. However, there were no differences between responses of the control-exercise and diabetes-exercise groups compared to the control-rest group. The present results suggest that the pre-synaptic component of synaptic plasticity in the dentate gyrus is affected under diabetic conditions and that treadmill running prevents this effect. The data support the possibility that alterations in transmission may account, in part, for learning and memory deficits induced in diabetes, and that treadmill running is helpful in alleviating the neural complications of diabetes mellitus.

Experiences during brain development may influence the pathogenesis of developmental disorders. Thus, social isolation (SI) rearing after weaning is a useful animal model for studying the pathological mechanisms of such psychiatric diseases. In this study, we examined the effect of SI on neurogenesis in the hippocampal dentate gyrus (DG) relating to memory and emotion-related behaviors. When newly divided cells were labeled with 5-bromo-2'-deoxyuridine (BrdU) before SI, the number of BrdU-positive cells and the rate of differentiation into neurons were significantly decreased after 4-week SI compared with those in group-housed mice. Repeated treatment of fluoxetine prevented the SI-induced impairment of survival of newly divided cells and ameliorated spatial memory impairment and part of aggression in SI mice. Furthermore, we investigated the changes in gene expression in the DG of SI mice by using DNA microarray and real-time PCR. We finally found that SI reduced the expression of development-related genes Nurr1 and Npas4. These findings suggest that communication in juvenile is important in the survival and differentiation of newly divided cells, which may be associated with memory and aggression, and raise the possibility that the reduced expression of Nurr1 and/or Npas4 may contribute to the impairment of neurogenesis and memory and aggression induced by SI.

Synthetic corticosteroids, such as dexamethasone, are frequently administered to pregnant women at risk for preterm delivery. Endogenous corticosteroids are essential for normal development, but exposure to therapeutic doses at critical developmental stages may have adverse effects on the central nervous system. Major concern has arisen about long-term effects of corticosteroid treatment on brain plasticity, particularly in the hippocampus. Therefore, we analyzed the molecular, cellular, and behavioral effects of prenatal dexamethasone treatment on the adult hippocampus. Pregnant mice were treated at embryonic day 15.5 with a single dose of dexamethasone or saline. Adult offspring was analyzed for hippocampal neuron loss, cell proliferation, and NMDA receptor subunit expression. Hippocampal function was assessed in the Morris water maze and synaptic plasticity in the CA1 field by determining frequency dependence of LTP and LTD in hippocampal slices. Prenatal dexamethasone treatment decreased hippocampal cell proliferation in the dentate gyrus. Treated mice showed reduced LTD, impaired spatial learning, and a marked reduction in lifespan. Our data show long-term adverse effects of prenatal dexamethasone treatment on hippocampal function in mice and suggest accelerated aging. These findings indicate that it is important to be restrictive with corticosteroid administration during fetal development because of the lifelong consequences.

The adult hippocampal dentate gyrus (DG) is a site of continuing neurogenesis. This process is influenced by a variety of physiological and experiential stimuli including total sleep deprivation (TSD). In humans, sleep fragmentation (SF) is a more common sleep condition than TSD. SF is associated with several prevalent diseases. We assessed a hypothesis that SF would suppress adult neurogenesis in the DG of the adult rat. An intermittent treadmill system was used; the treadmill was on for 3 s and off for 30 s (SF). For sleep fragmentation control (SFC), the treadmill was on for 15 min and off for 150 min. SF was conducted for three durations: 1, 4 and 7 days. To label proliferating cells, the thymidine analog, 5-bromo-2-deoxyuridine (BrdU), was injected 2 h prior to the end of each experiment. Expression of the intrinsic proliferative marker, Ki67, was also studied. SF rats exhibited an increased number of non-rapid eye movement (NREM) sleep bouts with no change in the percent of time spent in this stage. The numbers of both BrdU-positive cells and Ki67-positive cells were reduced by approximately 70% (P<0.05) in the SF groups after 4 and 7 days of experimental conditions whereas no differences were observed after 1 day. In a second experiment, we found that the percentage of new cells expressing a neuronal phenotype 3 weeks after BrdU administration was lower in the SF in comparison with the SFC group for all three durations of SF. We also examined the effects of SF on proliferation in adrenalectomized (ADX) animals, with basal corticosterone replacement. ADX SF animals exhibited a 55% reduction in the number of BrdU-positive cells when compared with ADX SFC. Thus, elevated glucocorticoids do not account for most of the reduction in cell proliferation induced by the SF procedure, although a small contribution of stress is not excluded. The results show that sustained SF induced marked reduction in hippocampal neurogenesis.

Long-term neuroplastic changes to dentate granule cells have been reported after seizures and were shown to contribute to recurrent excitatory circuitry. These changes include increased numbers of newborn granule cells, sprouted mossy fibers, granule cell layer dispersion, increased hilar ectopic granule cells and formation of hilar basal dendrites on granule cells. The goal of the current study was to determine the acute progression of neuroplastic changes involving newly generated granule cells after pilocarpine-induced seizures. Doublecortin (DCX) immunocytochemical preparations were used to examine the newly generated granule cells 1-5 days after seizures were induced. The results showed that there are rapid neuroplastic changes to the DCX-labeled cells. At 1 day after seizures were induced, there were significant increases in the percentage of DCX-labeled cells with hilar basal dendrites and in the progenitor cell population. At 2 days after seizures were induced, an increase in the thickness of the layer of DCX-labeled cells occurred. At 3 days after seizures were induced, the number of DCX-labeled cells was significantly increased. At 4 days after seizures were induced, developing synapses were observed on DCX-labeled hilar basal dendrites. Thus, newly generated granule cells in the adult dentate gyrus display neuroplastic changes by 1 day after pilocarpine-induced seizures and further changes occur to this population of cells in the subsequent 4 days. The presence of synapses, albeit developing ones, on hilar basal dendrites during this period indicates that newly generated granule cells become rapidly incorporated into dentate gyrus circuitry following seizures.

Hippocampal structural plasticity induced by entorhinal cortex (EC) lesions has been studied extensively in the rat, but little comparable research has been conducted in primates. In the current study we assessed the long-term effects of bilateral aspiration lesions of the EC on multiple markers of circuit organization in the hippocampal dentate gyrus of young adult monkeys (Macaca fascicularis). Alternate histological sections were processed for the visualization of somatostatin and vesicular acetylcholine transporter (VAChT) immunoreactivity and acetylcholinesterase histochemistry (AChE). The markers revealed the distinct laminar organization of dentate gyrus circuitry for stereology-based morphometric quantification. Consistent with findings in rats, the volume of the somatostatin-immunopositive outer molecular layer (OML), innervated by projections from the EC, was decreased by 42% relative to control values. The inner molecular layer (IML) displayed a corresponding volumetric expansion in response to denervation of the OML as measured by AChE staining, but not when visualized for quantification by VAChT immunoreactivity. Nonetheless, stereological estimation revealed a 36% increase in the total length of VAChT-positive cholinergic fibers in the IML after EC damage, along with no change in the OML. Together, these findings suggest that despite substantial species differences in the organization of hippocampal circuitry, the capacity for reactive plasticity following EC damage, previously documented in rats, is at least partly conserved in the primate dentate gyrus.

The objective of this work is to check whether the input from the mossy cells to the inner molecular layer is necessary for the integration and maturation of the newly generated granule cells of the dentate gyrus (DG) in mice, and if after status epilepticus the sprouting of the mossy fibers can substitute for this projection. Newly generated cells were labeled by administration of 5-bromo-deoxyuridine either before or after pilocarpine administration. The neuronal loss in the hippocampus after administration of pilocarpine combined with scopolamine and diazepam seemed restricted to the hilar mossy cells. The maturation of the granule cells was studied using immunohistochemistry for calretinin and NeuN in combination with detection of 5-bromo-deoxyuridine. The sprouting of the mossy fibers was detected using Timm staining for zinc-rich boutons. In normal conditions, granule cells took about 2 weeks to lose the immature marker calretinin. After the loss of the mossy cells, newly generated granule cells remained expressing calretinin for more than a month, until the sprouting of the mossy fibers substituted for the projection of the mossy cells in the inner molecular layer of the DG. Therefore, a proper pattern of connectivity is necessary for the normal development and integration of newly generated granule cells in the adult brain. In a changed environment they cannot adapt transforming in other cell types; simply they are unable to mature. The sprouting of the mossy fibers, although aberrant and a probable source of epileptic activity, may be important for the correct physiology of the granule cells, restoring a likeness of normality in their connective environment. The survival of granule cells incorporated as mature neurons was increased after pilocarpine when compared with normal conditions. Thus, it is likely that the reorganization of the circuitry after the loss of the mossy cells facilitates the survival and incorporation of the newly generated granule cells., ((c) 2007 Wiley-Liss, Inc.)

Neurogenesis in the adult mammalian hippocampus resulting in long-term persistence of new neurons with features of capacity for functional activation is recognized. Many stimuli are capable of increasing the rate of neurogenesis, including seizure activity. Whether these insults result in an increased number of new functionally active neurons over and above the baseline rate of neurogenesis is not known. The rapid electrical amygdala kindling (REAK) model of seizures isolates the effects of seizures alone in the absence of neuronal death and the resulting seizures induce expression of c-Fos in the vast majority of dentate gyrus (DG) granule cells. C57BL/6 mice were exposed to REAK then injected with bromodeoxyuridine (BrDU) to label dividing cells, then re-exposed to REAK after a delay period to allow detection of functional activation in new neurons by measurement c-Fos expression in response to seizures. Adult subgranular zone cells migrated into the DG granule cell layer (GCL), assumed a neuronal phenotype and demonstrated seizure-dependent responsiveness. Larger absolute numbers of new neurons demonstrating seizure-dependent activation were found in the GCL of previously kindled mice. Seizures are capable of increasing the number of new neurons with the capacity for functional activation laid down in the postseizure period and incorporated into seizure-activated circuitry.

Abnormal subgranular zone (SGZ) neurogenesis is proposed to contribute to Alzheimer's disease (AD)-related decreases in hippocampal function. Our goal was to examine hippocampal neurogenesis in the PDAPP mouse, a model of AD with age-dependent accumulation of amyloid-beta(42) (Abeta(42))-containing plaques that is well studied with regard to AD therapies. A secondary goal was to determine whether altered neurogenesis in the PDAPP mouse is associated with abnormal maturation or number of mature cells. A tertiary goal was to provide insight into why hippocampal neurogenesis appears to be increased in AD post-mortem tissue and decreased in most AD mouse models. We report an age-dependent decrease in SGZ proliferation in homozygous PDAPP mice. At 1 year of age, PDAPP mice also had new dentate gyrus granule neurons with abnormal maturation and fewer dying cells relative to control mice. In contrast to decreased SGZ cell birth, PDAPP mice had increased birth of immature neurons in the outer portion of the granule cell layer (oGCL), providing insight into why some studies link AD with increased neurogenesis. However, these ectopic oGCL cells were still rare compared with SGZ proliferating cells, emphasizing that the primary characteristic of PDAPP mice is decreased neurogenesis. The decrease in SGZ neurogenesis was not associated with an age-dependent loss of dentate granule neurons. The altered neurogenesis in the PDAPP mouse may contribute to the age-related cognitive deficits reported in this model of AD and may be a useful adjunct target for assessing the impact of AD therapies., (J. Comp. Neurol. 495:70-83, 2006. (c) 2006 Wiley-Liss, Inc.)

The hippocampal dentate gyrus in adult animals is known to contain neural progenitors that proliferate and differentiate into neurons in response to brain injury. Little has been observed, however, on regeneration of the granule cell layer of the dentate gyrus that has been directly injured. Using trimethyltin (TMT)-treated mice as an in vivo model, we evaluated the ability of this layer to regenerate after injury. The administration of TMT induced neuronal death in the dentate gyrus selectively 2 days later, with recovery of granule neurons on day 14 and thereafter. At an early stage (days 2-5) after the damage by TMT treatment, 5-bromo-2'-deoxyuridine (BrdU) incorporation into at least two different types of cells was facilitated in the dentate gyrus: BrdU-positive/neuronal nuclear antigen (NeuN)-negative cells were found predominantly in the subgranular zone and granule cell layer, whereas BrdU-positive/NeuN-positive cells were numerous in the dentate molecular layer and hilus. In addition, expression of proliferating cell nuclear antigen, nestin, NeuroD3, and doublecortin, which are markers for proliferating cells and neural progenitors/neuronal precursors, was extremely enhanced in the dentate gyrus at the early stage after treatment. Double staining revealed that BrdU was colocalized with nestin and doublecortin in the subgranular zone. Behavioral analysis revealed that TMT-induced cognition impairment was ameliorated by day 14 after the treatment. Taken together, our data indicate that the hippocampal dentate gyrus itself is capable of regenerating the neuronal cell layer through rapid enhancement of neurogenesis after injury.

Purpose: We describe the use of a clinically relevant pharmacological intervention that alters the clinical history of status epilepticus (SE)-induced spontaneous recurrent seizures (SRS) in the pilocarpine model and the possible plastic changes underlying such an effect., Methods: Two hours after pilocarpine-induced SE (320-350 mg/kg, i.p.), rats received scopolamine 1-2 mg/kg i.p. or saline, every 6 h for 3 days. After that, osmotic minipumps were implanted for continuous delivery of scopolamine or saline for an additional 14 days. Animals were video-monitored for 12 h/week during the following 3-month period for the occurrence of SRS and, thereafter, were perfused, processed, and coronal brain sections were stained for acetylcholinesterase (AChE) and for the presence of supragranular mossy fibers (Timm)., Results: Treatment with scopolamine led to significantly fewer SRS. Staining for AChE in the dentate gyrus was significantly more intense in naïve animals. The scopolamine group had the least intense AChE staining of all groups. However, regression analysis of the AChE staining for this group did not correlate with the presence or absence of SRS, or the latency or frequency of SRS. Supragranular mossy fiber sprouting developed in all animals experiencing pilocarpine-induced SE, irrespective of whether or not they were treated with scopolamine., Conclusions: Pilocarpine-induced SE in the presence of scopolamine might produce animals that, despite mossy fiber sprouting, were not seen to exhibit spontaneous seizures. In addition, our data suggest that the encountered changes in the AChE staining in the dentate gyrus that followed treatment with scopolamine do not help to explain its disease-modifying effects.

It is known that evoked seizures can increase neurogenesis in the dentate gyrus in adult rats. Whether spontaneous seizures occurring after status epilepticus (SE) also results in alterations in neurogenesis is not known. Here, we measured neurogenesis in rats with and without spontaneous seizures following SE. Lithium-pilocarpine was used to induce seizures in postnatal (P) day 20 rats. Spontaneous seizure frequency was assessed 2 months using video monitoring. Rats then received bromodeoxyuridine to label dividing DNA and were sacrificed 24 h later. Animals with spontaneous seizures (n = 9) had a modest increase in neurogenesis compared to animals with SE (n = 6) and no spontaneous seizures and control rats (n = 10). These findings demonstrate that the hippocampus is capable of generating new neurons weeks following SE and further that recurrent seizures enhance the production of new neurons. These alterations in neurogenesis may contribute to ongoing pathological changes week and months following SE.