Rodent Dentate Gyrus Research Articles

Optimizing GABAA receptor antagonism for the induction of long-term potentiation in the mouse and rat dentate gyrus in vitro.

The reliable induction of long-term potentiation (LTP) in the dentate gyrus (DG) in vitro requires the blockade of the γ-aminobutyric acid A (GABAA) receptor. In these studies we examined the effectiveness of the specific GABAA receptor antagonist bicuculline methiodide (BMI) in facilitating LTP in the DG from hippocampal slices obtained from either C57Bl/6 mice or Sprague-Dawley rats, two species commonly used for electrophysiology. In the C57Bl/6 mice, maximal short-term potentiation and LTP in the DG were produced with a concentration of 5 µM BMI. In contrast, a concentration of 10 μM BMI was required to produce maximal short-term potentiation and LTP in the DG of Sprague-Dawley rats. These results reveal that there are species differences in the optimal amount of BMI required to produce robust and reliable LTP in the rodent DG in vitro and highlight the need to take consideration of the species being used when choosing concentrations of pharmacological agents to employ for electrophysiological use.NEW & NOTEWORTHY In this report we provide specific neurophysiological evidence for concentrations of GABAA antagonist required to study long-term potentiation in the medial perforant pathway of the dentate gyrus. Two commonly used species, Sprague-Dawley rats and C57Bl/6 mice, require different concentrations of bicuculline methiodide to induce optimal short-term and long-term potentiation.

Adult-born neurons add flexibility to hippocampal memories.

Although most neurons are generated embryonically, neurogenesis is maintained at low rates in specific brain areas throughout adulthood, including the dentate gyrus of the mammalian hippocampus. Episodic-like memories encoded in the hippocampus require the dentate gyrus to decorrelate similar experiences by generating distinct neuronal representations from overlapping inputs (pattern separation). Adult-born neurons integrating into the dentate gyrus circuit compete with resident mature cells for neuronal inputs and outputs, and recruit inhibitory circuits to limit hippocampal activity. They display transient hyperexcitability and hyperplasticity during maturation, making them more likely to be recruited by any given experience. Behavioral evidence suggests that adult-born neurons support pattern separation in the rodent dentate gyrus during encoding, and they have been proposed to provide a temporal stamp to memories encoded in close succession. The constant addition of neurons gradually degrades old connections, promoting generalization and ultimately forgetting of remote memories in the hippocampus. This makes space for new memories, preventing saturation and interference. Overall, a small population of adult-born neurons appears to make a unique contribution to hippocampal information encoding and removal. Although several inconsistencies regarding the functional relevance of neurogenesis remain, in this review we argue that immature neurons confer a unique form of transience on the dentate gyrus that complements synaptic plasticity to help animals flexibly adapt to changing environments.

The cortical hem lacks stem cell potential despite expressing SOX9 and HOPX.

The adult dentate gyrus (DG) of rodents hosts a neural stem cell (NSC) niche capable of generating new neurons throughout life. The embryonic origin and molecular mechanisms underlying formation of DG NSCs are still being investigated. We performed a bulk transcriptomic analysis on mouse developing archicortex conditionally deleted for Sox9, a SoxE transcription factor controlling both gliogenesis and NSC formation, and identified Hopx, a recently identified marker of both prospective adult DG NSCs and astrocytic progenitors, as being downregulated. We confirm SOX9 is required for HOPX expression in the embryonic archicortex. In particular, we found that both NSC markers are highly expressed in the cortical hem (CH), while only weakly in the adjacent dentate neuroepithelium (DNE), suggesting a potential CH embryonic origin for DG NSCs. However, we demonstrate both in vitro and in vivo that the embryonic CH, as well as its adult derivatives, lacks stem cell potential. Instead, deletion of Sox9 in the DNE affects both HOPX expression and NSC formation in the adult DG. We conclude that HOPX expression in the CH is involved in astrocytic differentiation downstream of SOX9, which we previously showed regulates DG development by inducing formation of a CH-derived astrocytic scaffold. Altogether, these results suggest that both proteins work in a dose-dependent manner to drive either astrocytic differentiation in CH or NSC formation in DNE.

A dynamic clamp protocol to artificially modify cell capacitance.

Dynamics of excitable cells and networks depend on the membrane time constant, set by membrane resistance and capacitance. Whereas pharmacological and genetic manipulations of ionic conductances of excitable membranes are routine in electrophysiology, experimental control over capacitance remains a challenge. Here, we present capacitance clamp, an approach that allows electrophysiologists to mimic a modified capacitance in biological neurons via an unconventional application of the dynamic clamp technique. We first demonstrate the feasibility to quantitatively modulate capacitance in a mathematical neuron model and then confirm the functionality of capacitance clamp in in vitro experiments in granule cells of rodent dentate gyrus with up to threefold virtual capacitance changes. Clamping of capacitance thus constitutes a novel technique to probe and decipher mechanisms of neuronal signaling in ways that were so far inaccessible to experimental electrophysiology.

Crossed Entorhino-Dentate Projections Form and Terminate With Correct Layer-Specificity in Organotypic Slice Cultures of the Mouse Hippocampus.

The entorhino-dentate projection, i.e., the perforant pathway, terminates in a highly ordered and laminated fashion in the rodent dentate gyrus (DG): fibers arising from the medial entorhinal cortex (MEC) terminate in the middle molecular layer, whereas fibers arising from the lateral entorhinal cortex (LEC) terminate in the outer molecular layer of the DG. In rats and rabbits, a crossed entorhino-dentate projection exists, which originates from the entorhinal cortex (EC) and terminates in the contralateral DG. In contrast, in mice, such a crossed projection is reportedly absent. Using single and double mouse organotypic entorhino-hippocampal slice cultures, we studied the ipsi- and crossed entorhino-dentate projections. Viral tracing revealed that entorhino-dentate projections terminate with a high degree of lamina-specificity in single as well as in double cultures. Furthermore, in double cultures, entorhinal axons arising from one slice freely intermingled with entorhinal axons originating from the other slice. In single as well as in double cultures, entorhinal axons exhibited a correct topographical projection to the DG: medial entorhinal axons terminated in the middle and lateral entorhinal axons terminated in the outer molecular layer. Finally, entorhinal neurons were virally transduced with Channelrhodopsin2-YFP and stimulated with light, revealing functional connections between the EC and dentate granule cells. We conclude from our findings that entorhino-dentate projections form bilaterally in the mouse hippocampus in vitro and that the mouse DG provides a permissive environment for crossed entorhinal fibers.

Rapid Aging in the Perforant Path Projections to the Rodent Dentate Gyrus.

Why layers II/III of entorhinal cortex (EC) deteriorate in advance of other regions during the earliest stages of Alzheimer's disease is poorly understood. Failure of retrograde trophic support from synapses to cell bodies is a common cause of neuronal atrophy, and we accordingly tested for early-life deterioration in projections of rodent layer II EC neurons. Using electrophysiology and quantitative imaging, changes in EC terminals during young adulthood were evaluated in male rats and mice. Field excitatory postsynaptic potentials, input/output curves, and frequency following capacity by lateral perforant path (LPP) projections from lateral EC to dentate gyrus were unchanged from 3 to 8-10 months of age. In contrast, the unusual presynaptic form of long-term potentiation (LTP) expressed by the LPP was profoundly impaired by 8 months in rats and mice. This impairment was accompanied by a reduction in the spine to terminal endocannabinoid signaling needed for LPP-LTP induction and was offset by an agent that enhances signaling. There was a pronounced age-related increase in synaptophysin within LPP terminals, an effect suggestive of incipient pathology. Relatedly, presynaptic levels of TrkB-receptors mediating retrograde trophic signaling-were reduced in the LPP terminal field. LTP and TrkB content were also reduced in the medial perforant path of 8- to 10-month-old rats. As predicted, performance on an LPP-dependent episodic memory task declined by late adulthood. We propose that memory-related synaptic plasticity in EC projections is unusually sensitive to aging, which predisposes EC neurons to pathogenesis later in life.SIGNIFICANCE STATEMENT Neurons within human superficial entorhinal cortex are particularly vulnerable to effects of aging and Alzheimer's disease, although why this is the case is not understood. Here we report that perforant path projections from layer II entorhinal cortex to the dentate gyrus exhibit rapid aging in rodents, including reduced synaptic plasticity and abnormal protein content by 8-10 months of age. Moreover, there was a substantial decline in the performance of an episodic memory task that depends on entorhinal cortical projections at the same ages. Overall, the results suggest that the loss of plasticity and related trophic signaling predispose the entorhinal neurons to functional decline in relatively young adulthood.

Re-innervation of the Denervated Dentate Gyrus by Sprouting Associational and Commissural Mossy Cell Axons in Organotypic Tissue Cultures of Entorhinal Cortex and Hippocampus.

Collateral sprouting of surviving axons contributes to the synaptic reorganization after brain injury. To study this clinically relevant phenomenon, we used complex organotypic tissue cultures of mouse entorhinal cortex (EC) and hippocampus (H). Single EC-H cultures were generated to analyze associational sprouting, and double EC-H cultures were used to evaluate commissural sprouting of mossy cells in the dentate gyrus (DG) following entorhinal denervation. Entorhinal denervation (transection of the perforant path) was performed at 14 days in vitro (DIV) and associational/commissural sprouting was assessed at 28 DIV. First, associational sprouting was studied in genetically hybrid EC-H cultures of beta-actin-GFPtg and wild-type mice. Using calretinin as a marker, associational axons were found to re-innervate almost the entire entorhinal target zone. Denervation experiments performed with EC-H cultures of Thy1-YFPtg mice, in which mossy cells are YFP-positive, confirmed that the overwhelming majority of sprouting associational calretinin-positive axons are mossy cell axons. Second, we analyzed associational/commissural sprouting by combining wild-type EC-H cultures with calretinin-deficient EC-H cultures. In these cultures, only wild-type mossy cells contain calretinin, and associational and commissural mossy cell collaterals can be distinguished using calretinin as a marker. Nearly the entire DG entorhinal target zone was re-innervated by sprouting of associational and commissural mossy cell axons. Finally, viral labeling of newly formed associational/commissural axons revealed a rapid post-lesional sprouting response. These findings demonstrate extensive and rapid re-innervation of the denervated DG outer molecular layer by associational and commissural mossy cell axons, similar to what has been reported to occur in juvenile rodent DG in vivo.

Maturation Dynamics of the Axon Initial Segment (AIS) of Newborn Dentate Granule Cells in Young Adult C57BL/6J Mice.

Newborn dentate granule cells (DGCs) are generated in the hippocampal dentate gyrus (DG) of rodents through a process called adult hippocampal neurogenesis, which is subjected to tight intrinsic and extrinsic regulation. The use of retroviruses encoding fluorescent proteins has allowed the characterization of the maturation dynamics of newborn DGCs, including their morphological development and the establishment and maturation of their afferent and efferent synaptic connections. However, the study of a crucial cellular compartment of these cells, namely, the axon initial segment (AIS), has remained unexplored to date. The AIS is not only the site of action potential initiation, but it also has a unique molecular identity that makes it one of the master regulators of neural plasticity and excitability. Here we examined the dynamics of AIS formation in newborn DGCs of young female adult C57BL/6J mice in vivo Our data reveal notable changes in AIS length and thickness throughout cell maturation under physiological conditions and show that the most remarkable structural changes coincide with periods of intense morphological and functional remodeling. Moreover, we demonstrate that AIS development can be modulated extrinsically by both neuroprotective (environmental enrichment) and detrimental (lipopolysaccharide from Escherichia coli) stimuli.SIGNIFICANCE STATEMENT The hippocampal dentate gyrus (DG) of rodents generates newborn dentate granule cells (DGCs) throughout life. This process, named adult hippocampal neurogenesis, confers a unique degree of plasticity to the hippocampal circuit, and it is crucial for learning and memory. Here we studied, for the first time, the formation of a key cellular compartment of newborn DGCs, namely, the axon initial segment (AIS) in vivo Our data reveal remarkable AIS structural remodeling throughout the maturation of these cells under physiological conditions. Moreover, AIS development can be modulated extrinsically by both neuroprotective (environmental enrichment) and detrimental (lipopolysaccharide from Escherichia coli) stimuli.

Short- and Long-term Exposure to Low and High Dose Running Produce Differential Effects on Hippocampal Neurogenesis

Continuous running wheel (RW) exercise increases adult hippocampal neurogenesis in the dentate gyrus (DG) of rodents. Evidence suggests that greater amounts of RW exercise does not always equate to more adult-generated neurons in hippocampus. It can also be argued that continuous access to a RW results in exercise levels not representative of human exercise patterns. This study tested if RW paradigms that more closely represent human exercise patterns (e.g. shorter bouts, alternating daily exercise) alter neurogenesis. Neurogenesis was measured by examining the survival and fate of bromodeoxyuridine (BrdU)-labeled proliferating cells in the DG of male Sprague–Dawley rats after acute (14 days) or chronic (30 days) RW access. Rats were assigned to experimental groups based on the number of hours that they had access to a RW over two days: 0 h, 4 h, 8 h, 24 h, and 48 h. After acute RW access, rats that had unlimited access to the RW on alternating days (24 h) had a stronger neurogenic response compared to those rats that ran modest distances (4 h, 8 h) or not at all (0 h). In contrast, following chronic RW access, rats that ran a moderate amount (4 h, 8 h) had significantly more surviving cells compared to 0 h, 24 h, and 48 h. Linear regression analysis established a negative relationship between running distance and surviving BrdU+ cells in the chronic RW access cohort (R2 = 0.40). These data demonstrate that in rats moderate amounts of RW exercise are superior to continuous daily RW exercise paradigms at promoting hippocampal neurogenesis in the long-term.

TrkB dependent adult hippocampal progenitor differentiation mediates sustained ketamine antidepressant response

Adult neurogenesis persists in the rodent dentate gyrus and is stimulated by chronic treatment with conventional antidepressants through BDNF/TrkB signaling. Ketamine in low doses produces both rapid and sustained antidepressant effects in patients. Previous studies have shed light on post-transcriptional synaptic NMDAR mediated mechanisms underlying the acute effect, but how ketamine acts at the cellular level to sustain this anti-depressive function for prolonged periods remains unclear. Here we report that ketamine accelerates differentiation of doublecortin-positive adult hippocampal neural progenitors into functionally mature neurons. This process requires TrkB-dependent ERK pathway activation. Genetic ablation of TrkB in neural stem/progenitor cells, or pharmacologic disruption of ERK signaling, or inhibition of adult neurogenesis, each blocks the ketamine-induced behavioral responses. Conversely, enhanced ERK activity via Nf1 gene deletion extends the response and rescues both neurogenic and behavioral deficits in mice lacking TrkB. Thus, TrkB-dependent neuronal differentiation is involved in the sustained antidepressant effects of ketamine.

Distinct dendritic morphology across the blades of the rodent dentate gyrus.

The dentate gyrus (DG) is a hippocampal region that has long been characterized as a critical mediator of enduring memory formation and retrieval. As such, there is a wealth of studies investigating this area. Most of these studies have either treated the DG as a homogeneous structure, or examined differences in neurons along the septal-temporal axis. Recent data, however, have indicated that a functional distinction exists between the suprapyramidal and infrapyramidal blades of the DG, with the former showing more robust responses during spatial tasks. To date, few anatomical studies have addressed this functional gradient in rats, and no study has done so in the mouse. To address this, we investigated dendritic morphology and spine density in hippocampal granule cells of rats and mice using the Golgi-Cox technique. We find that granule cells from the suprapyramidal blade of the DG contain greater dendritic material in the region receiving spatial information from the medial perforant path. This provides a potential anatomical substrate for the asymmetric response of the DG to spatial input. Synapse 70:277-282, 2016. © 2016 Wiley Periodicals, Inc.

BDNF-induced LTP is associated with rapid Arc/Arg3.1-dependent enhancement in adult hippocampal neurogenesis.

Adult neurogenesis in the hippocampus is a remarkable phenomenon involved in various aspects of learning and memory as well as disease pathophysiology. Brain-derived neurotrophic factor (BDNF) represents a major player in the regulation of this unique form of neuroplasticity, yet the mechanisms underlying its pro-neurogenic actions remain unclear. Here, we examined the effects associated with brief (25 min), unilateral infusion of BDNF in the rat dentate gyrus. Acute BDNF infusion induced long-term potentiation (LTP) of medial perforant path-evoked synaptic transmission and, concomitantly, enhanced hippocampal neurogenesis bilaterally, reflected by increased dentate gyrus BrdU + cell numbers. Importantly, inhibition of activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) translation through local, unilateral infusion of anti-sense oligodeoxynucleotides (ArcAS) prior to BDNF infusion blocked both BDNF-LTP induction and the associated pro-neurogenic effects. Notably, basal rates of proliferation and newborn cell survival were unaltered in homozygous Arc/Arg3.1 knockout mice. Taken together these findings link the pro-neurogenic effects of acute BDNF infusion to induction of Arc/Arg3.1-dependent LTP in the adult rodent dentate gyrus.

Human neural stem cells promote proliferation of endogenous neural stem cells and enhance angiogenesis in ischemic rat brain.

Transplantation of human neural stem cells into the dentate gyrus or ventricle of rodents has been reportedly to enhance neurogenesis. In this study, we examined endogenous stem cell proliferation and angiogenesis in the ischemic rat brain after the transplantation of human neural stem cells. Focal cerebral ischemia in the rat brain was induced by middle cerebral artery occlusion. Human neural stem cells were transplanted into the subventricular zone. The behavioral performance of human neural stem cells-treated ischemic rats was significantly improved and cerebral infarct volumes were reduced compared to those in untreated animals. Numerous transplanted human neural stem cells were alive and preferentially localized to the ipsilateral ischemic hemisphere. Furthermore, 5-bromo-2′-deoxyuridine-labeled endogenous neural stem cells were observed in the subventricular zone and hippocampus, where they differentiated into cells immunoreactive for the neural markers doublecortin, neuronal nuclear antigen NeuN, and astrocyte marker glial fibrillary acidic protein in human neural stem cells-treated rats, but not in the untreated ischemic animals. The number of 5-bromo-2′-deoxyuridine-positive ⁄ anti-von Willebrand factor-positive proliferating endothelial cells was higher in the ischemic boundary zone of human neural stem cells-treated rats than in controls. Finally, transplantation of human neural stem cells in the brains of rats with focal cerebral ischemia promoted the proliferation of endogenous neural stem cells and their differentiation into mature neural-like cells, and enhanced angiogenesis. This study provides valuable insights into the effect of human neural stem cell transplantation on focal cerebral ischemia, which can be applied to the development of an effective therapy for stroke.

Two-Stage Translational Control of Dentate Gyrus LTP Consolidation Is Mediated by Sustained BDNF-TrkB Signaling to MNK

BDNF signaling contributes to protein-synthesis-dependent synaptic plasticity, but the dynamics of TrkB signaling and mechanisms of translation have not been defined. Here, we show that long-term potentiation (LTP) consolidation in the dentate gyrus of live rodents requires sustained (hours) BDNF-TrkB signaling. Surprisingly, this sustained activation maintains an otherwise labile signaling pathway from TrkB to MAP-kinase-interacting kinase (MNK). MNK activity promotes eIF4F translation initiation complex formation and protein synthesis in mechanistically distinct early and late stages. In early-stage translation, MNK triggers release of the CYFIP1/FMRP repressor complex from the 5'-mRNA cap. Inlate-stage translation, MNK regulates the canonical translational repressor 4E-BP2 in a synapse-compartment-specific manner. This late stage is coupled to MNK-dependent enhanced dendritic mRNA translation. We conclude that LTP consolidation in the dentate gyrus is mediated by sustained BDNF signaling to MNK and MNK-dependent regulation of translation in two functionally and mechanistically distinct stages.

Distribution and neurochemical features of neuronal nitric oxide synthase-expressing interneurons in the rat dentate gyrus

Neuronal nitric oxide synthase (nNOS)-expressing interneurons are abundant in the dentate gyrus (DG) of rodents. In the present study, we immunohistochemically analyzed nNOS-positive cells in the rat DG by focusing on their GABAergicity, laminar distribution, and co-localization with calcium-binding proteins and neuropeptides. Experiments were conducted in adult male Sprague Dawley rats. Within the DG, nNOS-positive cells were found to reside in all three layers of DG; percentages of distribution in the molecular layer, granule cell layer and the hilus are 25.4%, 9.4% and 65.2%, respectively. Almost every nNOS-positive cell expressed glutamic acid decarboxylase 67 (GAD67) or glutamic acid decarboxylase 65 (GAD65). In the molecular layer, nearly two-thirds of GAD67-positive cells expressed nNOS. Percentages of nNOS-positive interneurons that expressed cholecystokinin, vasoactive intestinal polypeptide, parvalbumin, somatostatin, neuropeptide Y, and calretinin were approximately 0.8%, 1.8%, 9.2%, 10.3%, 13.8%, and 24.4%, respectively. In the molecular layer, the number of nNOS-positive cells far exceeded the sum total of cells positive for both nNOS and any of the above mentioned calcium-binding proteins or neuropeptides, indicating that a large proportion of nNOS-positive interneurons seldom express calcium-binding proteins or neuropeptides in this area. We conclude that nNOS expressing cells are an important neurochemically defined type of GABAergic interneuron in the rat DG showing a specific laminar-dependent distribution and expressing calcium-binding proteins and neuropeptides at different frequencies. In the molecular layer, most nNOS-positive interneurons do not express calcium-binding proteins or neuropeptides; they could be the missing pieces in the GABAergic interneuron jigsaw puzzle of this DG layer.

Neurofibromin Modulates Adult Hippocampal Neurogenesis and Behavioral Effects of Antidepressants

Neurogenesis persists in the rodent dentate gyrus (DG) throughout adulthood but declines with age and stress. Neural progenitor cells (NPCs) residing in the subgranular zone of the DG are regulated by an array of growth factors and respond to the microenvironment, adjusting their proliferation level to determine the rate of neurogenesis. Here we report that genetic deletion of neurofibromin (Nf1), a tumor suppressor with RAS-GAP activity, in adult NPCs enhanced DG proliferation and increased generation of new neurons in mice. Nf1 loss-associated neurogenesis had the functional effect of enhancing behavioral responses to subchronic antidepressants and, over time, led to spontaneous antidepressive-like behaviors. Thus, our findings establish an important role for the Nf1-Ras pathway in regulating adult hippocampal neurogenesis, and demonstrate that activation of adult NPCs is sufficient to modulate depression- and anxiety-like behaviors.

Macrophage migration inhibitory factor is critically involved in basal and fluoxetine-stimulated adult hippocampal cell proliferation and in anxiety, depression, and memory-related behaviors

Intensive research is devoted to unravel the neurobiological mechanisms mediating adult hippocampal neurogenesis, its regulation by antidepressants, and its behavioral consequences. Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is expressed in the CNS, where its function is unknown. Here, we show, for the first time, the relevance of MIF expression for adult hippocampal neurogenesis. We identify MIF expression in neurogenic cells (in stem cells, cells undergoing proliferation, and in newly proliferated cells undergoing maturation) in the subgranular zone of the rodent dentate gyrus. A causal function for MIF in cell proliferation was shown using genetic (MIF gene deletion) and pharmacological (treatment with the MIF antagonist Iso-1) approaches. Behaviorally, genetic deletion of MIF resulted in increased anxiety- and depression-like behaviors, as well as of impaired hippocampus-dependent memory. Together, our studies provide evidence supporting a pivotal function for MIF in both basal and antidepressant-stimulated adult hippocampal cell proliferation. Moreover, loss of MIF results in a behavioral phenotype that, to a large extent, corresponds with alterations predicted to arise from reduced hippocampal neurogenesis. These findings underscore MIF as a potentially relevant molecular target for the development of treatments linked to deficits in neurogenesis, as well as to problems related to anxiety, depression, and cognition.

Antidepressants increase neural progenitor cells in the human hippocampus

Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) increase neurogenesis in the dentate gyrus (DG) of rodents and nonhuman primates. We determined whether SSRIs or TCAs increase neural progenitor (NPCs) and dividing cells in the human DG in major depressive disorder (MDD).Whole frozen hippocampi from untreated subjects with MDD (N = 5), antidepressant-treated MDD (MDDT, N = 7), and controls (C, N = 7) were fixed, sectioned and immunostained for NPCs and dividing cell markers (nestin and Ki-67 respectively), NeuN and GFAP, in single and double labeling. NPC and dividing cell numbers in the DG were estimated by stereology. Clinical data were obtained by psychological autopsy and toxicological and neuropathological examination performed in all subjects.NPCs decreased with age (p = 0.034). Females had more NPCs than males (p = 0.023). Correcting for age and sex, MDDT receiving SSRIs had more NPCs than untreated MDD (p ≤ 0.001) and controls (p ≤ 0.001), NPCs were not different in SSRIs- and TCAs-treated MDDT (p = 0.169). Dividing cell number, unaffected by age or sex, was greater in MDDT receiving TCAs than in untreated MDD (p ≤ 0.001), SSRI-treated MDD (p = 0.001) and controls (p ≤ 0.001). The NPCs and dividing cells increase in MDDT was localized to the rostral DG. MDDT had a larger DG volume compared with untreated MDD or controls (p = 0.009).Antidepressants increase neural progenitor cell number in the anterior human dentate gyrus. Whether this finding is critical or necessary for the antidepressants effect remains to be determined.

Induction of Neurogenesis in the Adult Dentate Gyrus by Cortical Spreading Depression

Spreading depression (SD) is an epiphenomenon of neurological disorders, like stroke or traumatic brain injury. These diseases have been associated with an increased neurogenesis in the adult rodent dentate gyrus. Such proliferative activity can also be induced by conditions that--like SD--coincide with a disturbed neuronal excitability, eg, epilepsy. Thus we hypothesized that SD might likewise influence hippocampal neurogenesis and potentially act as mediator of injury-induced neurogenesis. Repetitive cortical SD were induced by epidural application of 3 mol/L KCl. At different time points thereafter dentate gyrus neurogenesis was investigated by means of intraperitoneal bromodeoxyuridine injections and immunocytochemistry. Spatial learning and memory was tested in a Morris water maze. Cortical SD significantly increased proliferative activity in the ipsilateral subgranular zone on days 2 and 4. We detected about 280% more newborn cells in the dentate gyrus of rats that received bromodeoxyuridine during the first week after SD and were allowed to recover for 6 weeks. Most of these cells expressed the mature neuronal marker NeuN. The mitogenic action of SD was suppressed by systemic administration of the NMDA receptor antagonist MK-801. Behavioral performance of SD animals in the Morris water maze did not improve significantly. From our data we postulate that the increased dentate gyrus neurogenesis observed after brain injury may at least partly be mediated by SD-like epiphenomena. Furthermore they indicate that even a strongly enhanced dentate gyrus neurogenesis may occur without significant improvements in hippocampus-dependent spatial learning and memory.

Mechanisms and functional significance of aberrant seizure‐induced hippocampal neurogenesis

Studies of experimental mesial temporal lobe epilepsy (mTLE) indicate that prolonged seizures in the adult not only damage the hippocampal formation but also dramatically stimulate neurogenesis. Endogenous neural progenitor cells (NPCs) located in the adult rodent dentate gyrus and striatal subventricular zone are stimulated by experimental status epilepticus (SE) to generate increased numbers of dentate granule cells (DGCs) and olfactory interneurons, respectively (Bengzon et al., 1997; Parent et al., 1997, 2002; Scott et al., 1998). In this review, we discuss current knowledge regarding the consequences of seizure activity on NPC proliferation, focusing on the hippocampus, and on the migration and integration of adult-born hippocampal neurons. We also describe the effects of seizure-induced neurogenesis on hippocampal network function and the potential relevance of aberrant neurogenesis to human mTLE.