Stem- and Progenitor Cell Proliferation in the Dentate Gyrus of the Reeler Mouse

Adult hippocampal neurogenesis has been implicated in hippocampus-dependent learning and memory. Furthermore, the decline of neurogenesis accompanying aging could be involved in age-related cognitive deficits. It is believed that the neural stem cell niche comprises a specialized microenvironment regulating stem cell activation and maintenance. However, little is known about the significance of the extracellular matrix in controlling adult stem cells. Reelin is a large glycoprotein of the extracelluar matrix known to be of crucial importance for neuronal migration. Here, we examined the local interrelation between Reelin expressing interneurons and putative hippocampal stem cells and investigated the effects of Reelin deficiency on stem cell and progenitor cell proliferation. Reelin-positive cells are found in close vicinity to putative stem cell processes, which would allow for stem cell regulation by Reelin. We investigated the proliferation of stem cells in the Reelin-deficient reeler hippocampus by Ki67 labeling and found a strong reduction of mitotic cells. A detailed analysis of dividing Type 1, type 2 and type 3 cells indicated that once a stem cell is recruited for proliferation, the progression to the next progenitor stage as well as the number of mitotic cycles is not altered in reeler. Our data point to a role for Reelin in either regulating stem cell quiescence or maintenance.     

proNGF Inhibits Neurogenesis and Induces Glial Activation in Adult Mouse Dentate Gyrus

Recent studies have shown that the precursor of nerve growth factor (proNGF) is highly elevated in aging brains and in the brains of patients with Alzheimer’s Disease. proNGF accumulates in hippocampus which is an important neurogenic region related to learning and memory. However, it remains unclear whether proNGF has an influence on hippocampal neurogenesis. In this study, we demonstrated that the high-affinity receptor of proNGF, p75 neurotrophic factor (p75NTR), was expressed both on cells undergoing mitosis and postmitotic mature cells in mouse hippocampus. proNGF infusion into adult mouse hippocampus significantly reduced the density of BrdU-incorporating cells and the density of BrdU/Doublecortin double positive cells in the subgranular zone of hippocampus, indicating an inhibitory effect of proNGF on hippocampal neurogenesis. proNGF infusion also induced prominent cell apoptosis and activated residential astrocyte and microglia, which might further impair the hippocampal neurogenesis. These results implied that proNGF played a pivotal role in regulating the hippocampal neurogenesis and might account for the memory deficit and cognitive impairment.     

Temporal Changes in Prosaposin Expression in the Rat Dentate Gyrus after Birth

Neurogenesis in the hippocampal dentate gyrus occurs constitutively throughout postnatal life. Adult neurogenesis includes a multistep process that ends with the formation of a postmitotic and functionally integrated new neuron. During adult neurogenesis, various markers are expressed, including GFAP, nestin, Pax6, polysialic acid-neural cell adhesion molecule (PSA-NCAM), neuronal nuclei (NeuN), doublecortin, TUC-4, Tuj-1, and calretinin. Prosaposin is the precursor of saposins A–D; it is found in various organs and can be excreted. Strong prosaposin expression has been demonstrated in the developing brain including the hippocampus, and its neurotrophic activity has been proposed. This study investigated changes in prosaposin in the dentate gyrus of young and adult rats using double immunohistochemistry with antibodies to prosaposin, PSA-NCAM, and NeuN. Prosaposin immunoreactivity was intense in the dentate gyrus at postnatal day 3 (P3) and P7, but decreased gradually after P14. In the dentate gyrus at P28, immature PSA-NCAM-positive neurons localized exclusively in the subgranular zone were prosaposin-negative, whereas mature Neu-N-positive neurons were positive for prosaposin. Furthermore, these prosaposin-negative immature neurons were saposin B-positive, suggesting that the neurons take up and degrade prosaposin. In situ hybridization assays showed that prosaposin in the adult dentate gyrus is dominantly the Pro+9 type, a secreted type of prosaposin. These results imply that prosaposin secreted from mature neurons stimulates proliferation and maturation of immature neurons in the dentate gyrus.     

BDNF Depresses Excitability of Parvalbumin-Positive Interneurons through an M-Like Current in Rat Dentate Gyrus

In addition to their classical roles in neuronal growth, survival and differentiation, neurotrophins are also rapid regulators of excitability, synaptic transmission and activity-dependent synaptic plasticity. We have recently shown that mature BDNF (Brain Derived Neurotrophic Factor), but not proBDNF, modulates the excitability of interneurons in dentate gyrus within minutes. Here, we used brain slice patch-clamp recordings to study the mechanisms through which BDNF modulates the firing of interneurons in rat dentate gyrus by binding to TrkB receptors. Bath application of BDNF (15 ng/ml) under current-clamp decreased the firing frequency (by 80%) and input resistance, blocking the delayed firing observed at near-threshold voltage ranges, with no changes in resting membrane potential or action potential waveform. Using TEA (tetraethylammonium), or XE991(a Kv7/KCNQ channel antagonist), the effect of BDNF was abolished, whereas application of retigabine (a Kv7/KCNQ channel opener) mimicked the effect of BDNF, suggesting that the M-current could be implicated in the modulation of the firing. In voltage-clamp experiments, BDNF increased the M-like current amplitude with no change in holding current. This effect was again blocked by XE991 and mimicked by retigabine, the latter accompanied with a change in holding current. In agreement with the electrophysiology, parvalbumin-positive interneurons co-expressed TrkB receptors and Kv7.2/KCNQ2 channels. In conclusion, BDNF depresses the excitability of interneurons by activating an M-like current and possibly blocking Kv1 channels, thereby controlling interneuron resting membrane potential and excitability.     

Chronic Fluoxetine Induces the Enlargement of Perforant Path-Granule Cell Synapses in the Mouse Dentate Gyrus

A selective serotonin reuptake inhibitor is the most commonly prescribed antidepressant for the treatment of major depression. However, the mechanisms underlying the actions of selective serotonin reuptake inhibitors are not fully understood. In the dentate gyrus, chronic fluoxetine treatment induces increased excitability of mature granule cells (GCs) as well as neurogenesis. The major input to the dentate gyrus is the perforant path axons (boutons) from the entorhinal cortex (layer II). Through voltage-sensitive dye imaging, we found that the excitatory neurotransmission of the perforant path synapse onto the GCs in the middle molecular layer of the mouse dentate gyrus (perforant path-GC synapse) is enhanced after chronic fluoxetine treatment (15 mg/kg/day, 14 days). Therefore, we further examined whether chronic fluoxetine treatment affects the morphology of the perforant path-GC synapse, using FIB/SEM (focused ion beam/scanning electron microscopy). A three-dimensional reconstruction of dendritic spines revealed the appearance of extremely large-sized spines after chronic fluoxetine treatment. The large-sized spines had a postsynaptic density with a large volume. However, chronic fluoxetine treatment did not affect spine density. The presynaptic boutons that were in contact with the large-sized spines were large in volume, and the volumes of the mitochondria and synaptic vesicles inside the boutons were correlated with the size of the boutons. Thus, the large-sized perforant path-GC synapse induced by chronic fluoxetine treatment contains synaptic components that correlate with the synapse size and that may be involved in enhanced glutamatergic neurotransmission.     

CP-154,526 Modifies CREB Phosphorylation and Thioredoxin-1 Expression in the Dentate Gyrus following Morphine-Induced Conditioned Place Preference

Corticotropin-releasing factor (CRF) acts as neuro-regulator of the behavioral and emotional integration of environmental and endogenous stimuli associated with drug dependence. Thioredoxin-1 (Trx-1) is a functional protein controlling the redox status of several proteins, which is involved in addictive processes. In the present study, we have evaluated the role of CRF1 receptor (CRF1R) in the rewarding properties of morphine by using the conditioned place preference (CPP) paradigm. We also investigate the effects of the CRF1R antagonist, CP-154,526, on the morphine CPP-induced activation of CRF neurons, CREB phosphorylation and Trx expression in paraventricular nucleus (PVN) and dentate gyrus (DG) of the mice brain. CP-154,526 abolished the acquisition of morphine CPP and the increase of CRF/pCREB positive neurons in PVN. Moreover, this CRF1R antagonist prevented morphine-induced CRF-immunoreactive fibers in DG, as well as the increase in pCREB expression in both the PVN and DG. In addition, morphine exposure induced an increase in Trx-1 expression in DG without any alterations in PVN. We also observed that the majority of pCREB positive neurons in DG co-expressed Trx-1, suggesting that Trx-1 could activate CREB in the DG, a brain region involved in memory consolidation. Altogether, these results support the idea that CRF1R antagonist blocked Trx-1 expression and pCREB/Trx-1 co-localization, indicating a critical role of CRF, through CRF1R, in molecular changes involved in morphine associated behaviors.     

Cyclosporine A Reduces Dendritic Outgrowth of Neuroblasts in the Subgranular Zone of the Dentate Gyrus in C57BL/6 Mice

In the present study, we observed the effects of cyclosporine A (CsA), an efficient immunosuppressant, on cell proliferation and neuroblast differentiation in the subgranular zone of the dentate gyrus (SZDG) in normal C57BL/6 mice using Ki67 and doublecortin (DCX) immunohistochemical staining, respectively. At 8 weeks of age, vehicle (physiological saline) or CsA was daily administered (40 mg/kg, i.p.) for 1 week. Animals were sacrificed at 2 weeks after last administration. CsA treatment did not show any influences in neurons, astrocytes and microglia based on immunohistochemistry for its markers, respectively. However, in the CsA-treated group, Fluoro-Jade B, a marker for neurodegeneration, positive cells were found in the SZDG, not in the vehicle-treated group. In the vehicle-treated group, Ki67 immunoreactive (⁺) nuclei were clustered in the SZDG, whereas in the CsA-treated group Ki67⁺ nuclei were scattered in the SZDG, showing no difference in cell numbers. Numbers of DCX⁺ neuroblasts with well-developed processes (tertiary dendrites) were much lower in the CsA-treated group than those in the vehicle-treated group; however, numbers of DCX⁺ neuroblasts with secondary dendrites were similar in both the groups. These results suggest that CsA significantly reduces dendritic outgrowth and complexity from neuroblasts in the SZDG without any affecting in neurons, astrocytes and microglia in normal mice.     

脑源性神经生长因子对齿状回miR-132表达及抑制性电流的影响

目的:探讨脑源性神经生长因子(BDNF)对海马mi R-132的表达及齿状回颗粒细胞抑制性突触后电流(sIPSCs)的影响,明确BDNF对颞叶内侧癫痫(MTLE)发病机制的作用。方法:选取哈医大一院神经外科2008年4月-2010年10月手术治疗的MTLE患者12例海马组织。RT-pcr技术检测BDNF孵育后mir-132表达,脑片膜片钳技术检测BDNF对sIPSCs的影响。结果:BDNF升高了颞叶癫痫海马mi RNA-132的表达(P0.01),减弱了颗粒细胞sIPSCs的频率和幅度(P0.01)。结论:BDNF升高了海马mir-132的表达,减弱颗粒细胞sIPSCs的频率和幅度,可能对MTLE的发展有促进作用。     

Pyridoxine Enhances Cell Proliferation and Neuroblast Differentiation by Upregulating the GABAergic System in the Mouse Dentate Gyrus

We investigated the effects of pyridoxine (vitamin B₆) on cell death, cell proliferation, neuroblast differentiation, and the GABAergic system in the mouse dentate gyrus. We administered pyridoxine (350 mg/kg intraperitoneally) to 8 week old mice twice a day for 14 days and sacrificed them at 10 weeks of age. Pyridoxine treatment did not induce neuronal death or activate microglia in the dentate gyrus, while glial fibrillary acidic protein (GFAP)-positive cells were significantly increased in the subgranular zone of the dentate gyrus. The increase in GFAP-positive cells was confirmed to be due to proliferating cells based on double immunofluorescence staining. GFAP-positive cells, which were also labeled with Ki67, a marker for cell proliferation, and doublecortin, a marker for neuroblast differentiation, were significantly increased in the pyridoxine-treated group compared to those in the vehicle-treated group. Pyridoxine treatment also increased the protein levels of glutamic acid decarboxylase (GAD) 67, an enzyme for GABA synthesis, and pyridoxal 5′-phosphate (PNP) oxidase, an enzyme for pyridoxal phosphate synthesis, in the dentate gyrus. These results suggest that pyridoxine treatment distinctly increases cell proliferation, neuroblast differentiation, and upregulated the GABAergic system, as revealed by the increases of GAD67 and PNP oxidase in the mouse dentate gyrus.     

Effects of Cu,Zn-Superoxide Dismutase on Cell Proliferation and Neuroblast Differentiation in the Mouse Dentate Gyrus

Oxidative stress is one of the most important factors in reducing adult hippocampal neurogenesis in the adult brain. In this study, we observed the effects of Cu,Zn-superoxide dismutase (SOD1) on lipid peroxidation, cell proliferation, and neuroblast differentiation in the mouse dentate gyrus using malondialdehyde (MDA), Ki67, and doublecortin (DCX), respectively. We constructed an expression vector, PEP-1, fused PEP-1 with SOD1, and generated PEP-1-SOD1 fusion protein. We administered PEP-1 and 100 or 500 μg PEP-1-SOD1 intraperitoneally once a day for 3 weeks and sacrificed at 30 min after the last administrations. PEP-1 administration did not change the MDA levels compared to those in the vehicle-treated group, while PEP-1-SOD1 treatment significantly reduced MDA levels compared to the vehicle-treated group. In the PEP-1-treated group, the number of Ki67-positive nuclei was similar to that in the vehicle-treated group. In the 100 μg PEP-1-SOD1-treated group, the number of Ki67-positive nuclei was slightly decreased; however, in the 500 μg PEP-1-SOD1-treated group, Ki67-positive nuclei were decreased to 78.5% of the vehicle-treated group. The number of DCX-positive neuroblasts in the PEP-1-treated group was similar to that in the vehicle-treated group. However, the arborization of DCX-positive neuroblasts was significantly decreased in both the 100 and 500 μg PEP-1-SOD1-treated groups compared to that in the vehicle-treated group. The number of DCX-positive neuroblasts with tertiary dendrites was markedly decreased in the 500 μg PEP-1-SOD1-treated group. These results suggest that a SOD1 supplement to healthy mice may not be necessary to modulate cell proliferation and neuroblast differentiation in the dentate gyrus.     

The Determination of Spindle Polarity in Early Mitotic Stages of the Dividing Grasshopper Neuroblasts

Although the spindle body of the grasshopper neuroblasts at the early mitotic stages does not have any mechanical linkage to the surrounding cell cortex, a spindle axis is inevitably oriented in parallel with the original division axis. The present study analyzes how the definite orientation of spindle axis along the cap cell (CC)-ganglion cell (GC) axis of the neuroblast is maintained during these stages by use of the microdissection technique and electron microscopy. After removing a microneedle from the cell, metaphase spindles approximately 90°. rotated were able to return autonomously to the original axis. After the middle anaphase, however, the rotated spindle could not return at all. The electron microscopic observations revealed a characteristic behavior of an electron dense layer (EDL) in the CC-side cortex during neuroblast mitosis. The EDL first appeared at very late prophase and became most conspicuous at metaphase. It became discontinuous by the beginning of middle anaphase and then completely disappeared at middle anaphase. So long as an EDL existed in the CC-side polar cortex, 90° rotated spindle bodies were able to return autonomously to the original axis. After the disappearance of the EDL, the autonomous return of the rotated spindle no longer occurred. From these circumstantial evidence, it is conceivable that the orientation of the spindle body along the CC-GC axis is maintained by the interaction between the EDL and the spindle pole.     

Visualization by High Resolution Immunoelectron Microscopy of the Transient Receptor Potential Vanilloid-1 at Inhibitory Synapses of the Mouse Dentate Gyrus

We have recently shown that the transient receptor potential vanilloid type 1 (TRPV1), a non-selective cation channel in the peripheral and central nervous system, is localized at postsynaptic sites of the excitatory perforant path synapses in the hippocampal dentate molecular layer (ML). In the present work, we have studied the distribution of TRPV1 at inhibitory synapses in the ML. With this aim, a preembedding immunogold method for high resolution electron microscopy was applied to mouse hippocampus. About 30% of the inhibitory synapses in the ML are TRPV1 immunopositive, which is mostly localized perisynaptically (∼60% of total immunoparticles) at postsynaptic dendritic membranes receiving symmetric synapses in the inner 1/3 of the layer. This TRPV1 pattern distribution is not observed in the ML of TRPV1 knock-out mice. These findings extend the knowledge of the subcellular localization of TRPV1 to inhibitory synapses of the dentate molecular layer where the channel, in addition to excitatory synapses, is present.     

Content and Concentration of Taurine,Hypotaurine, and Zinc in the Retina,the Hippocampus,and the Dentate Gyrus of the Rat at Various Postnatal Days

Taurine and zinc possess neurotrophic and neuroprotective properties, and they have been demonstrated to interact in the central nervous system (CNS). The aim of this work was to determine taurine, hypotaurine, and zinc levels during postnatal development and any possible significant correlation between them in selective areas of the CNS with differential taurine level regulation and intrinsic capacity to proliferate. Taurine and hypotaurine content (nM/region) and concentration (nM/mg protein) and total zinc levels were determined in the retina, hippocampus, and dentate gyrus of the rat at postnatal days 5, 10, 15, 20, 30, and 50. Taurine and hypotaurine increased during development in the retina without significant correlation between them. In the hippocampus there was a progressive decrease, and in the dentate gyrus there was an initial increase and a posterior decrease of taurine and hypotaurine levels. Correlation between the two amino acids was observed at P10, P15, and P50 for the hippocampus and at P15, P30, and P50 for the dentate gyrus. The variations in total zinc levels followed a biphasic behavior, with an early decrease and later increase. Significant and positive correlation of zinc and taurine was only observed in the hippocampus at P30 and P50 and negative in the dentate gyrus at P30. No significant correlation was obtained for the retina. The maintenance of taurine levels in specific CNS areas does not seem to be related to the availability of the precursor, hypotaurine, which might have a role by itself. There are critical postnatal periods during which there is a preservation of taurine, hypotaurine, or zinc levels. It seems that these requirements could be related to zinc-taurine interactions.     

Effects of Scopolamine and Melatonin Cotreatment on Cognition,Neuronal Damage,and Neurogenesis in the Mouse Dentate Gyrus

It has been demonstrated that melatonin plays important roles in memory improvement and promotes neurogenesis in experimental animals. We examined effects of melatonin on cognitive deficits, neuronal damage, cell proliferation, neuroblast differentiation and neuronal maturation in the mouse dentate gyrus after cotreatment of scopolamine (anticholinergic agent) and melatonin. Scopolamine (1 mg/kg) and melatonin (10 mg/kg) were intraperitoneally injected for 2 and/or 4 weeks to 8-week-old mice. Scopolamine treatment induced significant cognitive deficits 2 and 4 weeks after scopolamine treatment, however, cotreatment of scopolamine and melatonin significantly improved spatial learning and short-term memory impairments. Two and 4 weeks after scopolamine treatment, neurons were not damaged/dead in the dentate gyrus, in addition, no neuronal damage/death was shown after cotreatment of scopolamine and melatonin. Ki67 (a marker for cell proliferation)- and doublecortin (a marker for neuroblast differentiation)-positive cells were significantly decreased in the dentate gyrus 2 and 4 weeks after scopolamine treatment, however, cotreatment of scopolamine and melatonin significantly increased Ki67- and doublecortin-positive cells compared with scopolamine-treated group. However, double immunofluorescence for NeuN/BrdU, which indicates newly-generated mature neurons, did not show double-labeled cells (adult neurogenesis) in the dentate gyrus 2 and 4 weeks after cotreatment of scopolamine and melatonin. Our results suggest that melatonin treatment recovers scopolamine-induced spatial learning and short-term memory impairments and restores or increases scopolamine-induced decrease of cell proliferation and neuroblast differentiation, but does not lead to adult neurogenesis (maturation of neurons) in the mouse dentate gyrus following scopolamine treatment.     

Late Maturation of Adult-Born Neurons in the Temporal Dentate Gyrus

Hippocampal function varies along its septotemporal axis, with the septal (dorsal) pole more frequently involved in spatial learning and memory and the temporal (ventral) pole playing a greater role in emotional behaviors. One feature that varies across these subregions is adult neurogenesis. New neurons are more numerous in the septal hippocampus but are more active in the temporal hippocampus during water maze training. However, many other aspects of adult neurogenesis remain unexplored in the context of septal versus temporal subregions. In addition, the dentate gyrus contains another functionally important anatomical division along the transverse axis, with the suprapyramidal blade showing greater experience-related activity than the infrapyramidal blade. Here we ask whether new neurons differ in their rates of survival and maturation along the septotemporal and transverse axes. We found that neurogenesis is initially higher in the infrapyramidal than suprapyramidal blade, but these cells are less likely to survive, resulting in similar densities of neurons in the two blades by four weeks. Across the septotemporal axis, neurogenesis was higher in septal than temporal pole, while the survival rate of new neurons did not differ. Maturation was assessed by immunostaining for the neuronal marker, NeuN, which increases in expression level with maturation, and for the immediate-early gene, Arc, which suggests a neuron is capable of undergoing activity-dependent synaptic plasticity. Maturation occurred approximately 1–2 weeks earlier in the septal pole than in the temporal pole. This suggests that septal neurons may contribute to function sooner; however, the prolonged maturation of new temporal neurons may endow them with a longer window of plasticity during which their functions could be distinct from those of the mature granule cell population. These data point to subregional differences in new neuron maturation and suggest that changes in neurogenesis could alter different hippocampus-dependent behaviors with different time courses.     

Age-Related Changes of Elements and Relationships Among Elements in Human Hippocampus, Dentate Gyrus, and Fornix

To elucidate compositional changes of the limbic system with aging, the authors investigated age-related changes of elements in the hippocampus, dentate gyrus, and fornix and the relationships among elements by direct chemical analysis. After ordinary dissections at Nara Medical University were finished, the hippocampi, dentate gyri, and fornices were resected from identical cerebra of the subjects which consisted of 23 men and 23 women, ranging in age from 70 to 101 years. After ashing with nitric acid and perchloric acid, element contents were determined by inductively coupled plasma-atomic emission spectrometry. The average contents of P, Zn, and Na were significantly less in both the hippocampi and dentate gyri compared with the fornices. It was found that the Ca and Mg contents increased significantly in the hippocampus with aging; the P content increased significantly in the dentate gyrus with aging, whereas the Na content decreased in the dentate gyrus with aging; and the Mg content increased significantly in the fornix with aging. Regarding the relationships among elements, a significant direct correlation between Ca and Fe contents and an extremely significant inverse correlation between P and Zn contents were found in both the hippocampi and dentate gyri. In addition, a significant direct correlation between P and Mg contents was found in both the hippocampi and fornices. Pearson's correlation was used to examine whether there were elements with significant correlation among the hippocampus, dentate gyrus, fornix, and mammillary body. Significant correlations were found in five elements of Ca, P, Mg, Zn, and Fe except for S and Na among the hippocampus, dentate gyrus, and mammillary body with one exception. Regarding the fornix, significant correlations were found in two elements of P and Fe between the fornix and hippocampus, dentate gyrus, or mammillary body.     

Presynaptic Changes in Long-Term Potentiation: Elevated Synaptosomal Calcium Concentration and Basal Phosphoinositide Turnover in Dentate Gyrus

In this report, two changes that occur in the presynaptic terminal following induction of long-term potentiation in the dentate gyrus are examined, and the results demonstrate that the same changes are stimulated by the putative retrograde messenger arachidonic acid. First, there is an increase in the concentration of intracellular calcium in synaptosomes prepared from potentiated tissue compared with control tissue. This effect on intracellular calcium concentration was mimicked in control tissue by treatment of synaptosomes with either arachidonic acid or inositol 1,4,5-trisphosphate in a dose-dependent but nonadditive manner. Second, there is an increase in phosphoinositide turnover in synaptosomes prepared from potentiated tissue compared with control tissue, and this change can also be mimicked in control tissue by exposure of synaptosomes to arachidonic acid. These findings are consistent with the hypothesis that the increase in glutamate release associated with long-term potentiation may be stimulated by arachidonic acid, as a result of an increase in intrasynaptosomal calcium concentration, perhaps occurring as a result of arachidonate-stimulated phosphoinositide metabolism.     

Differential Involvement of the Dentate Gyrus in Adaptive Forgetting in the Rat

How does the brain discriminate essential information aimed to be stored permanently from information required only temporarily, and that needs to be cleared away for not saturating our precious memory space? Reference Memory (RM) refers to the long-term storage of invariable information whereas Working Memory (WM) depends on the short-term storage of trial-unique information. Previous work has revealed that WM tasks are very sensitive to proactive interference. In order to prevent such interference, irrelevant old memories must be forgotten to give new ones the opportunity to be stabilized. However, unlike memory, physiological processes underlying this adaptive form of forgetting are still poorly understood. Here, we precisely ask what specific brain structure(s) could be responsible for such process to occur. To answer this question, we trained rats in a radial maze using three paradigms, a RM task and two WM tasks involving or not the processing of interference but strictly identical in terms of locomotion or motivation. We showed that an inhibition of the expression of Zif268 and c-Fos, two indirect markers of neuronal activity and synaptic plasticity, was observed in the dentate gyrus of the dorsal hippocampus when processing such interfering previously stored information. Conversely, we showed that inactivating the dentate gyrus impairs both RM and WM, but improves the processing of interference. Altogether, these results strongly suggest for the first time that the dentate gyrus could be a key structure involved in adaptive forgetting.