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Choline is an essential nutrient under evaluation as a cognitive enhancing treatment for fetal alcohol spectrum disorders (FASD) in clinical trials. As a result, there is increased pressure to identify therapeutic mechanism(s) of action. Choline is not only a precursor for several essential cell membrane components and signaling molecules but also has the potential to directly affect synaptic mechanisms that are believed important for cognitive processes. In the current work, we study how the direct application of choline can affect synaptic transmission in the dentate gyrus (DG) of hippocampal slices obtained from adolescent (postnatal days 21–28) Sprague–Dawley rats (Rattus norvegicus). The acute administration of choline chloride (2 mM) reliably induced a long-term depression (LTD) of field excitatory postsynaptic potentials (fEPSPs) in the DG in vitro. The depression required the involvement of M1 receptors, and the magnitude of the effect was similar in slices obtained from male and female animals. To further study the impact of choline in an animal model of FASD, we examined offspring from dams fed an ethanol-containing diet (35.5% ethanol-derived calories) throughout gestation. In slices from the adolescent animals that experienced prenatal ethanol exposure (PNEE), we found that the choline induced an LTD that uniquely involved the activation of N-methyl-d-aspartate (NMDA) and M1 receptors. This study provides a novel insight into how choline can modulate hippocampal transmission at the level of the synapse and that it can have unique effects following PNEE. NEW & NOTEWORTHY Choline supplementation is a nutraceutical therapy with significant potential for a variety of developmental disorders; however, the mechanisms involved in its therapeutic effects remain poorly understood. Our research shows that choline directly impacts synaptic communication in the brain, inducing a long-term depression of synaptic efficacy in brain slices. The depression is equivalent in male and female animals, involves M1 receptors in control animals, but uniquely involves NMDA receptors in a model of FASD.

BACKGROUND: We have recently shown that alcohol and cannabis can interact prenatally, and in a recent review paper we further identified Parvalbumin-positive (PV) interneurons in the hippocampus as a potential point of convergence for these teratogens. METHODS: A 2 (EtOH, Air) x 2 (THC, Vehicle) design was used to expose pregnant Sprague-Dawley rats to either EtOH or air, in addition to either THC or the inhalant vehicle solution, from gestational days 5–20. Immunohistochemistry was performed to detect parvalbumin-positive interneurons in one male and one female pup from each litter at post-natal day (PND) 70. RESULTS: Significant between-group, and sub-region specific, effects were found in the dorsal CA1 subfield, as well as the ventral DG. In the dorsal CA1 subfield, there was an increase in the number of PV interneurons in both the EtOH and EtOH + THC groups, but only a possible decrease with THC alone. There were fewer changes in interneuron numbers overall in the DG, however, a sex difference was found, and a decrease in the number of PV interneurons in the THC exposed group was observed in the male ventral DG. There was also an increase in cell layer volume between the EtOH + THC group and control group in the DG, and an increase from the control and THC group to the EtOH group in the CA1 region. CONCLUSIONS: Prenatal alcohol and prenatal THC exposure differentially affect parvalbumin interneuron numbers in the hippocampus, indicating that both individual and combined exposure can impact the balance of excitation and inhibition in a structure critically involved in learning and memory processes.

Administration of exercise mimetic drugs could be a novel therapeutic approach to combat comorbid neurodegeneration and metabolic syndromes. Adiponectin is an adipocyte-secreted hormone. In addition to its antidiabetic effect, adiponectin mediates the antidepressant effect of physical exercise associated with adult hippocampal neurogenesis. The antidiabetic effect of the adiponectin receptor agonist AdipoRon has been demonstrated, but its potential pro-cognitive and neurotrophic effects in the hippocampus under diabetic condition are still unclear. This study reported that chronic AdipoRon treatment for 2 weeks improved hippocampal-dependent spatial recognition memory in streptozotocin-induced diabetic mice. Besides, AdipoRon treatment increased progenitor cell proliferation and neuronal differentiation in the hippocampal dentate gyrus (DG) of diabetic mice. Furthermore, AdipoRon treatment significantly increased dendritic complexity, spine density, and N-methyl-D-aspartate receptor-dependent long-term potentiation (LTP) in the dentate region, and increased BDNF levels in the DG of diabetic mice. AdipoRon treatment activated AMPK/PGC-1α signalling in the DG, whereas increases in cell proliferation and LTP were not observed when PGC-1α signalling was pharmacologically inhibited. In sum, chronic AdipoRon treatment partially mimics the benefits of physical exercise for learning and memory and hippocampal neuroplasticity in the diabetic brain. The results suggested that AdipoRon could be a potential physical exercise mimetic to improve hippocampal plasticity and hence rescue learning and memory impairment typically associated with diabetes. Supplementary Information The online version contains supplementary material available at 10.1007/s12035-021-02441-7.

Background and Objectives: We examined how acute ethanol (EtOH) exposure affects long term depression (LTD) in the dentate gyrus (DG) of the hippocampus in juvenile rats. EtOH is thought to directly modulate n-methyl-D-aspartate receptor (NMDAr) currents, which are believed important for LTD induction. LTD in turn is believed to play an important developmental role in the hippocampus by facilitating synaptic pruning. Methods: Hippocampal slices (350μm) were obtained at post-natal day (PND) 14, 21, or 28. Field EPSPs (excitatory post-synaptic potential) or whole-cell EPSCs (excitatory post-synaptic conductance) were recorded from the DG (dentate gyrus) in response to medial perforant path activation. Low-frequency stimulation (LFS; 900 pulses; 120 s pulse) was used to induce LTD. Results: Whole-cell recordings indicated that EtOH exposure at 50mM did not significantly impact ensemble NMDAr EPSCs in slices obtained from animals in the PND14 or 21 groups, but it reliably produced a modest inhibition in the PND28 group. Increasing the concentration to 100 mM resulted in a modest inhibition of NMDAr EPSCs in all three groups. LTD induction and maintenance was equivalent in magnitude in all three age groups in control conditions, however, and surprisingly, NMDA antagonist AP5 only reliably blocked LTD in the PND21 and 28 age groups. The application of 50 mM EtOH attenuated LTD in all three age groups, however increasing the concentration to 100 mM did not reliably inhibit LTD. Conclusions: These results indicate that the effect of EtOH on NMDAr-EPSCs recorded from DGCs is both age and concentration dependent in juveniles. Low concentrations of EtOH can attenuate, but did not block LTD in the DG. The effects of EtOH on LTD do not align well with it’s effects on NNMDA receptors.

Cannabinoid receptors are widely expressed throughout the hippocampal formation, but are particularly dense in the dentate gyrus (DG) subregion. We, and others, have shown in mice that cannabinoid type 1 receptors (CB1Rs) are involved in a long-term depression (LTD) that can be induced by prolonged 10 Hz stimulation of the medial perforant path (MPP)-granule cell synaptic input to the DG. Here, we extend this work to examine the involvement of CB1Rs in other common forms of LTD in the hippocampus of juvenile male and female Sprague–Dawley rats (Rattus norvegicus). We found, as in mice, that prolonged 10 Hz stimulation (6000 pulses) could reliably induce a form of LTD that was dependent upon CB1R activation. In addition, we also discovered a role for both CB1R and mGluR proteins in LTD induced with 1 Hz low-frequency stimulation (1 Hz-LTD; 900 pulses) and in LTD induced by bath application of the group I mGluR agonist (RS)-3,5-Dihydroxyphenylglycine (DHPG; DHPG-LTD). This study elucidates an essential role for endocannabinoid receptors in a number of forms of LTD in the rat DG, and identifies a novel role for CB1Rs as potential therapeutic targets for conditions that involve impaired LTD in the DG.

AdipoRon, an adiponectin receptor agonist, elicits similar antidiabetic, anti-atherogenic, and anti-inflammatory effects on mouse models as adiponectin does. Since AdipoRon can cross the blood-brain barrier, its chronic effects on regulating hippocampal function are yet to be examined. This study investigated whether AdipoRon treatment promotes hippocampal neurogenesis and spatial recognition memory in a dose-dependent manner. Adolescent male C57BL/6J mice received continuous treatment of either 20 mg/kg (low dose) or 50 mg/kg (high dose) AdipoRon or vehicle intraperitoneally for 14 days, followed by the open field test to examine anxiety and locomotor activity, and the Y maze test to examine hippocampal-dependent spatial recognition memory. Immunopositive cell markers of neural progenitor cells, immature neurons, and newborn cells in the hippocampal dentate gyrus were quantified. Immunosorbent assays were used to measure the serum levels of factors that can regulate hippocampal neurogenesis, including adiponectin, brain-derived neurotrophic factor (BDNF), and corticosterone. Our results showed that 20 mg/kg AdipoRon treatment significantly promoted hippocampal cell proliferation and increased serum levels of adiponectin and BDNF, though there were no effects on spatial recognition memory and locomotor activity. On the contrary, 50 mg/kg AdipoRon treatment impaired spatial recognition memory, suppressed cell proliferation, neuronal differentiation, and cell survival associated with reduced serum levels of BDNF and adiponectin. The results suggest that a low-dose AdipoRon treatment promotes hippocampal cell proliferation, while a high-dose AdipoRon treatment is detrimental to the hippocampus function.

Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in ageing or Alzheimer's disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. Genetic deletion of Fndc5/irisin (global Fndc5 knock-out (KO) mice; F5KO) impairs cognitive function in exercise, ageing and AD. Diminished pattern separation in F5KO mice can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety. In F5KO mice, adult-born neurons in the dentate gyrus are morphologically, transcriptionally and functionally abnormal. Importantly, elevation of circulating irisin levels by peripheral delivery of irisin via adeno-associated viral overexpression in the liver results in enrichment of central irisin and is sufficient to improve both the cognitive deficit and neuropathology in AD mouse models. Irisin is a crucial regulator of the cognitive benefits of exercise and is a potential therapeutic agent for treating cognitive disorders including AD.

Background Marijuana and alcohol are both substances that, when used during pregnancy, may have profound effects on the developing fetus. There is evidence to suggest that both drugs have the capacity to affect working memory, one function of the hippocampal formation; however, there is a paucity of data on how perinatal exposure to alcohol or cannabis impacts the process of adult neurogenesis. Methods This systematic review examines immunohistochemical data from adult rat and mouse models that assess perinatal alcohol or perinatal marijuana exposure. A comprehensive list of search terms was designed and used to search 3 separate databases. All results were imported to Mendeley and screened by 2 authors. Consensus was reached on a set of final papers that met the inclusion criteria, and their results were summarized. Results Twelve papers were identified as relevant, 10 of which pertained to the effects of perinatal alcohol on the adult hippocampus, and 2 pertained to the effects of perinatal marijuana on the adult hippocampus. Cellular proliferation in the dentate gyrus was not affected in adult rats and mice exposed to alcohol perinatally. In general, perinatal alcohol exposure did not have a significant and reliable effect on the maturation and survival of adult born granule neurons in the dentate gyrus. In contrast, interneuron numbers appear to be reduced in the dentate gyrus of adult rats and mice exposed perinatally to alcohol. Perinatal marijuana exposure was also found to reduce inhibitory interneuron numbers in the dentate gyrus. Conclusions Perinatal alcohol exposure and perinatal marijuana exposure both act on inhibitory interneurons in the hippocampal formation of adult rats. These findings suggest simultaneous perinatal alcohol and marijuana exposure (SAM) may have a dramatic impact on inhibitory processes in the dentate gyrus.

Binge drinking is a significant problem in adolescent populations, and because of the reciprocal interactions between ethanol (EtOH) consumption and the endocannabinoid (eCB) system, we sought to determine if adolescent EtOH intake altered the localization and function of the cannabinoid 1 (CB(1)) receptors in the adult brain. Adolescent mice were exposed to a 4-day-per week drinking in the dark (DID) procedure for a total of 4 weeks and then tested after a 2-week withdrawal period. Field excitatory postsynaptic potentials (fEPSPs), evoked by medial perforant path (MPP) stimulation in the dentate gyrus molecular layer (DGML), were significantly smaller. Furthermore, unlike control animals, CB(1) receptor activation did not depress fEPSPs in the EtOH-exposed animals. We also examined a form of excitatory long-term depression that is dependent on CB(1) receptors (eCB-eLTD) and found that it was completely lacking in the animals that consumed EtOH during adolescence. Histological analyses indicated that adolescent EtOH intake significantly reduced the CB(1) receptor distribution and proportion of immunopositive excitatory synaptic terminals in the medial DGML. Furthermore, there was decreased binding of [(35)S]guanosine-5*-O-(3-thiotriphosphate) ([(35)S] GTPγS) and the guanine nucleotide-binding (G) protein Gαi2 subunit in the EtOH-exposed animals. Associated with this, there was a significant increase in monoacylglycerol lipase (MAGL) mRNA and protein in the hippocampus of EtOH-exposed animals. Conversely, deficits in eCB-eLTD and recognition memory could be rescued by inhibiting MAGL with JZL184. These findings indicate that repeated exposure to EtOH during adolescence leads to long-term deficits in CB(1) receptor expression, eCB-eLTD, and reduced recognition memory, but that these functional deficits can be restored by treatments that increase endogenous 2-arachidonoylglycerol.

Hippocampal slices are widely used for in vitro electrophysiological experiments to study underlying mechanisms for synaptic transmission and plasticity, and there is a growing appreciation for sex differences in synaptic plasticity. To date, several studies have shown that the process of making slices from male animals can induce synaptogenesis in cornu ammonis area 1 (CA1) pyramidal cells, but there is a paucity of data for females and other brain regions. In the current study we use microcrystals of the lipophilic carbocyanine dye DiI (1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate) to stain individual neurons in the CA1 and dentate gyrus (DG) hippocampal subfields of postnatal day 21 male and female rats. We show that the preparation of sections for electrophysiology produces significant increases in spines in sections obtained from females, similar to that observed in males. We also show that the procedures used for in vitro electrophysiology also result in significant spine increases in the DG and CA1 subfields. These results demonstrate the utility of this refined DiI procedure for staining neuronal dendrites and spines. They also show, for the first time, that in vitro electrophysiology slice preparations enhance spine numbers on hippocampal cells equivalently in both juvenile females and males.NEW & NOTEWORTHY This study introduces a new DiI technique that elucidates differences in spine numbers in juvenile female and male hippocampus, and shows that slice preparations for hippocampal electrophysiology in vitro may mask these differences.

BACKGROUND: The hippocampus is particularly vulnerable to the teratogenic effects of prenatal ethanol exposure (PNEE), and hippocampal structural and functional deficits are thought to contribute to the learning and memory deficits that are a hallmark feature of fetal alcohol spectrum disorders (FASDs). METHOD: Sprague-Dawley dams were exposed to a liquid diet that contained EtOH (35.5% EtOH-derived calories) throughout gestation, and then PNEE juvenile (P21-28) male and female offspring were used for in vitro electrophysiological recordings. We examined long-term potentiation (LTP), long-term depression (LTD) and depotentiation in the medial perforant path (MPP) input to the dentate gyrus (DG) to determine the impact of PNEE on the dynamic range of bidirectional synaptic plasticity in both sexes. RESULTS: PNEE reduced the responsiveness of the DGs of male but not in female offspring, and this effect was no longer apparent when GABAergic signalling was inhibited. There was also a sex-specific LTD impairment in males, but increasing the duration of the conditioning stimulus could overcome this deficit. The magnitude of LTP was also reduced, but in both sexes following PNEE. This appears to be an increase in the threshold for induction, not in capacity, as the level of LTP induced in PNEE animals was increased to control-levels when additional conditioning stimuli were administered. CONCLUSIONS: These data are the first to describe, in a single study, the impact of PNEE on the dynamic range of bidirectional synaptic plasticity in the juvenile DG in both males and in females. The data suggest that PNEE increases the threshold for LTP in the DG in both sexes, but produces a sex-specific increase in the threshold for LTD in males These alterations reduce the dynamic range for synaptic plasticity in both sexes.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. It is caused by the overexpansion of cytosine-guanine-guanine (CGG) trinucleotide in Fmr1 gene, resulting in complete loss of the fragile X mental retardation protein (FMRP). Previous studies using Fmr1 knockout (Fmr1 KO) mice have suggested that a N-methyl-D-aspartate receptors (NMDAR) hypofunction in the hippocampal dentate gyrus may partly contribute to cognitive impairments in FXS. Since activation of NMDAR plays an important role in dendritic arborization during neuronal development, we examined whether deficits in NMDAR function are associated with alterations in dendritic complexity in the hippocampal dentate region. The dentate granule cell layer (GCL) presents active postnatal neurogenesis, and consists of a heterogenous neuronal population with gradient ages from the superficial to its deep layer. Here, we show that neurons with multiple primary dendrites that reside in the outer GCL of Fmr1 KO mice display significantly smaller NMDAR excitatory post-synaptic currents (EPSCs) and a higher α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to NMDA ratio in comparison to their wild-type counterparts. These deficits were associated with a significant decrease in dendritic complexity, with both dendritic length and number of intersections being significantly reduced. In contrast, although neurons with a single primary dendrite resided in the inner GCL of Fmr1 KO mice had a trend toward a reduction in NMDAR EPSCs and a higher AMPA/NMDA ratio, no alterations were found in dendritic complexity at this developmental stage. Our data indicate that the loss of FMRP causes NMDAR deficits and reduced dendritic complexity in granule neurons with multiple primary dendrites which are thought to be more mature in the GCL.

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability that can be traced to a single gene mutation. This disorder is caused by the hypermethylation of the Fmr1 gene, which impairs translation of Fragile X Mental Retardation Protein (FMRP). In Fmr1 knockout (KO) mice, the loss of FMRP has been shown to negatively impact adult hippocampal neurogenesis, and to contribute to learning, memory, and emotional deficits. Conversely, physical exercise has been shown to enhance cognitive performance, emotional state, and increase adult hippocampal neurogenesis. In the current experiments, we used two different voluntary running paradigms to examine how exercise impacts adult neurogenesis in the dorsal and ventral hippocampal dentate gyrus (DG) of Fmr1 KO mice. Immunohistochemical analyses showed that short-term (7 day) voluntary running enhanced cell proliferation in both wild-type (WT) and Fmr1 KO mice. In contrast, long-term (28 day) running only enhanced cell proliferation in the whole DG of WT mice, but not in Fmr1 KO mice. Interestingly, cell survival was enhanced in both WT and Fmr1 KO mice following exercise. Interestingly we found that running promoted cell proliferation and survival in the ventral DG of WTs, but promoted cell survival in the dorsal DG of Fmr1 KOs. Our data indicate that long-term exercise has differential effects on adult neurogenesis in ventral and dorsal hippocampi in Fmr1 KO mice. These results suggest that physical training can enhance hippocampal neurogenesis in the absence of FMRP, may be a potential intervention to enhance learning and memory and emotional regulation in FXS.

Synaptic plasticity is an experience-dependent process that results in long-lasting changes in synaptic communication. This phenomenon stimulates structural, molecular, and genetic changes in the brain and is the leading biological model for learning and memory processes. Synapses are able to show persistent increases in synaptic strength, or long-term potentiation (LTP), as well as persistent decreases in synaptic strength, known as long-term depression (LTD). Understanding the complex interactions that regulate these activity-dependent processes can provide insight for the development of strategies to improve cognitive function. Twenty years ago, we provided the first evidence indicating that aerobic exercise can reliably enhance LTP, and went on to show that it can also regulate some of the mechanisms involved in LTD induction. Since then, several laboratories have confirmed and expanded these findings, helping to identify different molecular mechanisms involved in exercise-mediated changes in synaptic efficacy. This chapter reviews this material and shows how these experimental findings may prove valuable for alleviating the burden of neurodegenerative diseases in an aging population.

The endocannabinoid system modulates synaptic plasticity in the hippocampus, but a link between long-term synaptic plasticity and the type 1 cannabinoid (CB1) receptor at medial perforant path (MPP) synapses remains elusive. Here, immuno-electron microscopy in adult mice showed that similar to 26% of the excitatory synaptic terminals in the middle 1/3 of the dentate molecular layer (DML) contained CB1 receptors, and field excitatory postsynaptic potentials evoked by MPP stimulation were inhibited by CB1 receptor activation. In addition, MPP stimulation at 10 Hz for 10 min triggered CB, receptor-dependent excitatory long-term depression (eCB-eLTD) at MPP synapses of wild-type mice but not on CB1-knockout mice. This eCB-eLTD was group I mGluR-dependent, required intracellular calcium influx and 2-arachydonoyl-glycerol (2-AG) synthesis but did not depend on N-methyl-d-aspartate (NMDA) receptors. Overall, these results point to a functional role for CB1 receptors with eCB-eLTD at DML MPP synapses and further involve these receptors in memory processing within the adult brain. We thank all members of P. Grandes laboratory for their helpful comments, suggestions, and discussions during the performance of this study. The authors thank Giovanni Marsicano (INSERM, U1215 Neurocentre Magendie, Endocannabinoids and Neuroadaptation, Bordeaux, France. University de Bordeaux, France), Beat Lutz (Institute of Physiological Chemistry and German Resilience Center, University Medical Center of the Johannes Gutenberg University Mainz, Germany) and Susana Mato (Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, Leioa, Vizcaya, Spain) for providing the CB1 receptor knock-out mice. This work was supported by MINECO/FEDER, UE (grant number SAF2015-65034-R to PG); The Basque Government (grant number BCG IT764-13 to PG); Red de Trastornos Adictivos, Instituto de Salud Carlos III (ISC-III) and European Regional Development Funds-European Union (ERDF-EU; grant RD16/0017/0012 to PG); PhD contract from MINECO (BES-2013-065057 to SP); Vanier Canada Graduate Scholarship (NSERC to CJF).

Fragile-X Syndrome (FXS) is the most common form of inherited intellectual disability and the leading genetic cause of autism spectrum disorder. FXS is caused by transcriptional silencing of the Fragile X Mental Retardation 1 (Fmr1) gene due to a CGG repeat expansion, resulting in the loss of Fragile X Mental Retardation Protein (FMRP). FMRP is involved in transcriptional regulation and trafficking of mRNA from the nucleus to the cytoplasm and distal sites both in pre- and post-synaptic terminals. Consequently, FXS is a multifaceted disorder associated with impaired synaptic plasticity. One region of the brain that is significantly impacted by the loss of FMRP is the hippocampus, a structure that plays a critical role in the regulation of mood and cognition. This review provides an overview of the neuropathology of Fragile-X Syndrome, highlighting how structural and synaptic deficits in hippocampal subregions, including the CA1 exhibiting exaggerated metabotropic glutamate receptor dependent long-term depression and the dentate gyrus displaying hypofunction of N-methyl-d-aspartate receptors, contribute to cognitive impairments associated with this neurodevelopmental disorder.

Background Our previous work has shown that exposure to the stress hormone corticosterone (40 mg/kg CORT) for two weeks induces dendritic atrophy of pyramidal neurons in the hippocampal CA3 region and behavioral deficits. However, it is unclear whether this treatment also affects the dentate gyrus (DG), a subregion of the hippocampus comprising a heterogeneous population of young and mature neurons. Objective We examined the effect of CORT treatment on the dendritic complexity of mature and young granule cells in the DG. Methods We utilized a Golgi staining method to investigate the dendritic morphology and spine density of young neurons in the inner granular cell layer (GCL) and mature neurons in the outer GCL in response to CORT application. The expressions of glucocorticoid receptors during neuronal maturation were examined using Western blot analysis in a primary hippocampal neuronal culture. Results Sholl analysis revealed that CORT treatment decreased the number of intersections and shortened the dendritic length in mature, but not young, granule cells. However, the spine density of mature and young neurons was not affected. Western blot analysis showed a progressive increase in the protein levels of glucocorticoid receptors (GRs) in the cultured primary hippocampal neurons during neuronal maturation. Conclusion These data suggest that mature neurons are likely more vulnerable to chronic exposure to CORT; this may be due to their higher expression of GRs when compared to younger DG neurons.

Guanosine is a purine nucleoside that occurs naturally in the central nervous system, exerting trophic effects. Given its neuroprotective properties, the potential of guanosine as an antidepressant has been recently examined. Within this context, the present study sought to investigate the effects of chronic treatment with guanosine on the tail suspension test (TST), open field test and adult hippocampal neurogenesis. Swiss mice were administered guanosine for 21 days (5 mg/kg/day, p.o.) and subsequently submitted to the TST and open-field test. Following behavioural testing, animals were killed and the brains were processed for immunohistochemical analyses of hippocampal cell proliferation and neuronal differentiation. Animals treated with guanosine showed a reduction in immobility time in the TST without alterations in locomotor activity, confirming the antidepressant-like effect of this compound. Quantitative microscopic analysis did not reveal significant alterations in the numbers of Ki-67- and proliferating cell nuclear antigen (PCNA)-positive cells in the hippocampal dentate gyrus (DG) of guanosine-treated mice. However, guanosine treatment resulted in a significant increase in the number of immature neurons, as assessed by immunohistochemistry for the neurogenic differentiation protein. Interestingly, this effect was localized to the ventral hippocampal DG, a functionally distinct region of this structure known to regulate emotional and motivational behaviours. Taken together, our results suggest that the antidepressant-like effect of chronic guanosine treatment is associated with an increase in neuronal differentiation, reinforcing the notion that this nucleoside may be an endogenous mood modulator.

In this review, the benefits of physical exercise on structural and functional plasticity in the hippocampus are discussed. The evidence is clear that voluntary exercise in rats and mice can lead to increases in hippocampal neurogenesis and enhanced synaptic plasticity which ultimately result in improved performance in hippocampal-dependent tasks. Furthermore, in models of neurological disorders, including fetal alcohol spectrum disorders, traumatic brain injury, stroke, and neurodegenerative disorders including Alzheimer’s, Parkinson’s and Huntington’s disease exercise can also elicit beneficial effects on hippocampal function. Ultimately this review highlights the multiple benefits of exercise on hippocampal function in both the healthy and the diseased brain.

The rodent hippocampus is a large and complex bilateral structure lying directly beneath the cortex. It has often been described as resembling a set of “ram’s horns” denoting the fact that it projects from a midline or septal point and extends outward (temporal) and downward (ventral) as you move rostral toward the temporal pole. Perhaps not surprisingly, the dorsal (septal), middle (intermediate), and ventral (temporal) portions of this structure appear to subserve different cognitive and limbic functions, thus researchers are likely to vary in which portion of the structure they wish to record from. The purpose of this chapter is to provide those with a desire to conduct in vivo electrophysiology with the practical knowledge they will need to conduct such investigations. We focus on stimulating the medial perforant pathway and recording from the hilus of the dentate gyrus along the dorsoventral extent of the hippocampal formation.

The fragile X mental retardation protein (FMRP) is an important regulator of protein translation, and a lack of FMRP expression leads to a cognitive disorder known as fragile X syndrome (FXS). Clinical symptoms characterizing FXS include learning impairments and heightened anxiety in response to stressful situations. Here, we report that, in response to acute stress, mice lacking FMRP show a faster elevation of corticosterone and a more immediate impairment in N-methyl- d -aspartate receptor (NMDAR) dependent long-term potentiation (LTP) in the dentate gyrus (DG). These stress-induced LTP impairments were rescued by administering the glucocorticoid receptor (GR) antagonist RU38486. Administration of RU38486 also enhanced LTP in Fmr1−/y mice in the absence of acute stress to wild-type levels, and this enhancement was blocked by application of the NMDAR antagonist 2-amino-5-phosphonopentanoic acid. These results suggest that a loss of FMPR results in enhanced GR signaling that may adversely affect NMDAR dependent synaptic plasticity in the DG.

Fragile X syndrome (FXS) is the most common form of inherited intellectual impairment. The Fmr1-/y mouse model has been previously shown to have deficits in context discrimination tasks but not in the elevated plus-maze. To further characterize this FXS mouse model and determine whether hippocampal-mediated behaviours are affected in these mice, dentate gyrus (DG)-dependent spatial processing and Cornu ammonis 1 (CA1)-dependent temporal order discrimination tasks were evaluated. In agreement with previous findings of long-term potentiation deficits in the DG of this transgenic model of FXS, the results reported here demonstrate that Fmr1-/y mice perform poorly in the DG-dependent metric change spatial processing task. However, Fmr1-/y mice did not present deficits in the CA1-dependent temporal order discrimination task, and were able to remember the order in which objects were presented to them to the same extent as their wild-type littermate controls. These data suggest that the previously reported subregional-specific differences in hippocampal synaptic plasticity observed in the Fmr1-/y mouse model may manifest as selective behavioural deficits in hippocampal-dependent tasks.

Fragile X Syndrome (FXS) is the most common inherited cause of intellectual disability, and is the leading known single-gene cause of autism spectrum disorder. FXS patients display varied behavioural deficits that include mild to severe cognitive impairments in addition to mood disorders. Currently there is no cure for this condition, however minocycline is becoming commonly prescribed as a treatment for FXS patients. Minocycline has been reported to alleviate social behavioural deficits, and improve verbal functioning in patients with FXS; however, its mode of action is not well understood. Previously we have shown that FXS results in learning impairments that involve deficits in N-methyl-d-aspartate (NMDA) receptor-dependent synaptic plasticity in the hippocampal dentate gyrus (DG). Here we tested whether chronic treatment with minocycline can improve these deficits by enhancing NMDA receptor-dependent functional and structural plasticity in the DG. Minocycline treatment resulted in a significant enhancement in NMDA receptor function in the dentate granule cells. This was accompanied by an increase in PSD-95 and GluN2A and GluN2B subunits in hippocampal synaptoneurosome fractions. Minocycline treatment also enhanced dentate granule cell dendritic length and branching. In addition, our results show that chronic minocycline treatment can rescue performance in novel object recognition in FXS mice. These findings indicate that minocycline treatment has both structural and functional benefits for hippocampal cells, which may partly contribute to the pro-cognitive effects minocycline appears to have for treating FXS.

Exposure to ethanol in utero is associated with a myriad of sequelae for the offspring. Some of these effects are morphological in nature and noticeable from birth, while others involve more subtle changes to the brain that only become apparent later in life when the individuals are challenged cognitively. One brain structure that shows both functional and structural deficits following prenatal ethanol exposure is the hippocampus. The hippocampus is composed of two interlocking gyri, the cornu ammonis (CA) and the dentate gyrus (DG), and they are differentially affected by prenatal ethanol exposure. The CA shows a more consistent loss in neuronal numbers, with different ethanol exposure paradigms, than the DG, which in contrast shows more pronounced and consistent deficits in synaptic plasticity. In this study we show that significant deficits in adult hippocampal neurogenesis are apparent in aged animals following prenatal ethanol exposure. Deficits in hippocampal neurogenesis were not apparent in younger animals. Surprisingly, even when ethanol exposure occurred in conjunction with maternal stress, deficits in neurogenesis did not occur at this young age, suggesting that the capacity for neurogenesis is highly conserved early in life. These findings are unique in that they demonstrate for the first time that deficits in neurogenesis associated with prenatal ethanol consumption appear later in life.

Alcohol consumption during pregnancy is deleterious to the developing brain of the fetus and leads to persistent deficits in adulthood. Long-term potentiation (LTP) is a biological model for learn- ing and memory processes and previous evidence has shown that prena- tal ethanol exposure (PNEE) affects LTP in a sex specific manner during adolescence. The objective of this study was to determine if there are sex specific differences in adult animals and to elucidate the underlying molecular mechanisms that contribute to these differences. Pregnant Sprague-Dawley dams were assigned to either; liquid ethanol, pair-fed or standard chow diet. In vivo electrophysiology was performed in the hippocampal dentate gyrus (DG) of adult offspring. LTP was induced by administering 400 Hz stimuli. Western blot analysis for glutamine syn- thetase (GS) and glutamate decarboxylase from tissue of the DG indi- cated that GS expression was increased following PNEE. Surprisingly, adult females did not show any deficit in N-methyl-D-aspartate (NMDA)-dependent LTP after PNEE. In contrast, males showed a 40% reduction in LTP. It was indicated that glutamine synthetase expression was increased in PNEE females, suggesting that altered excitatory neuro- transmitter replenishment may serve as a compensatory mechanism. Ovariectomizing females did not influence LTP in control or PNEE ani- mals, suggesting that circulating estradiol levels do not play a major role in maintaining LTP levels in PNEE females. These results demon- strate the sexually dimorphic effects of PNEE on the ability for the adult brain to elicit LTP in the DG. The mechanisms for these effects are not fully understood, but an increase in glutamine synthetase in females may underlie this phenomenon. V C 2013 Wiley Period- icals, Inc.

Previous studies from our laboratory have shown that prenatal ethanol exposure (PNEE) causes a significant deficit in synaptic plasticity, namely long-term potentiation (LTP), in the dentate gyrus (DG) region of the hippocampus of male rats. PNEE has also been shown to induce an increase in oxidative stress and a reduction in antioxidant capacity in the brains of both male and female animals. In this study the interaction between LTP and the major antioxidant in the brain, glutathione (GSH), is examined. We show that depletion of the intracellular reserves of GSH with diethyl maleate (DEM) reduces LTP in control male, but not female animals, mirroring the effects of PNEE. Furthermore, treatment of PNEE animals with N-acetyl cysteine (NAC), a cysteine donor for the synthesis of GSH, increases GSH levels in the hippocampus and completely restores the deficits in LTP in PNEE males. These results indicate that in males GSH plays a major role in regulating LTP, and that PNEE may cause reductions in LTP by reducing the intracellular pool of this endogenous antioxidant.

Fetal alcohol spectrum disorders result in long-lasting neurological deficits including decreases in synaptic plasticity and deficits in learning and memory. In this study we examined the effects of prenatal ethanol exposure on hippocampal synaptic plasticity in male and female Sprague-Dawley rats. Furthermore, we looked at the capacity for postnatal dietary intervention to rescue deficits in synaptic plasticity. Animals were fed an omega-3 enriched diet from birth until adulthood (PND55-70) and in vivo electrophysiology was performed by stimulating the medial perforant path input to the dentate gyrus and recording field excitatory post-synaptic potentials. LTP was induced by administering bursts of five 400 Hz pulses as a theta-patterned train of stimuli (200 ms inter-burst interval). Ethanol-exposed adult males, but not females, exhibited a significant reduction in LTP. This deficit in male animals was completely reversed with an omega-3 enriched diet. These results demonstrate that omega-3 fatty acids can have benefits following prenatal neuropathological insults and may be a viable option for alleviating some of the neurological deficits associated with FASD.

Fetal alcohol spectrum disorders occur when a mother drinks during pregnancy and can greatly influence synaptic plasticity and cognition in the offspring. In this study we determined whether there are periods during brain development that are more susceptible to the effects of ethanol exposure on hippocampal synaptic plasticity. In particular, we evaluated how the ability to elicit long-term potentiation (LTP) in the hippocampal dentate gyrus (DG) was affected in young adult rats that were exposed to ethanol during either the 1st, 2nd, or 3rd trimester equivalent. As expected, the effects of ethanol on young adult DG LTP were less severe when exposure was limited to a particular trimester equivalent when compared to exposure throughout gestation. In males, ethanol exposure during the 1st, 2nd or 3rd trimester equivalent did not significantly reduce LTP in the DG. In females, ethanol exposure during either the 1st or 2nd trimester equivalents did not impact LTP in early adulthood, but following exposure during the 3rd trimester equivalent alone, LTP was significantly increased in the female DG. These results further exemplify the disparate effects between the ability to elicit LTP in the male and female brain following perinatal ethanol exposure (PNEE).

Mild traumatic brain injury (mTBI) is becoming recognized as a significant concern in modern society. In particular, youth is being increasingly seen as a vulnerable time period for mTBI, as this is the final developmental period for the brain and typically involves robust synaptic reorganization and axonal myelination. Another issue that is being hotly debated is whether mTBI differentially impacts the male and female brain. To examine the impact of mTBI in the juvenile brain, we measured hippocampal synaptic plasticity using a closed-head mTBI model in male and female Long-Evans rats (25-28 days of age) at either 1 h, 1 day, 7 days, or 28 days post-injury. In female rats, the dentate gyrus (DG) region ipsilateral to the impact showed a significant reduction in long-term potentiation (LTP) at 1 day, which persisted to 28 days following injury. In male rats, the deficit in LTP was maximal in the CA1 and DG subfields ipsilateral to the impact site 7 days post-injury; however, these deficits did not persist to 28 days post-injury. These data indicate that mTBI can produce more immediate and persistent impairments in synaptic plasticity in the female brain.

Fragile-X syndrome (FXS) is caused by the transcriptional repression of the Fmr1 gene resulting in loss of the Fragile-X mental retardation protein (FMRP). This leads to cognitive impairment in both male and female patients, however few studies have focused on the impact of FXS in females. Significant cognitive impairment has been reported in approximately 35% of women who exhibit a heterozygous Fmr1 gene mutation, however to date there is a paucity of information regarding the mechanistic underpinnings of these deficits. We, and others, have recently reported that there is significant impairment in N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD) in the hippocampal dentate gyrus (DG) of male Fmr1 knock out mice. Here we examined if female mice displaying a heterozygous loss of the Fmr1 gene (Fmr1+/‐) would exhibit similar impairments in DG-dependent spatial memory processing and NMDAR hypofunction. We found that Female Fmr1+/‐ mice did not show impaired metabotropic glutamate receptor (mGluR)-LTD in the CA1 region, and could perform well on a temporal ordering task that is thought to involve this brain region. In contrast, female Fmr1+/‐ mice showed impairments in a pattern separation task thought to involve the DG, and also displayed a significant impairment in both NMDAR-dependent LTD and LTP in this region. The LTP impairment could be rescued by administering the NMDAR co-agonist, glycine. Our data suggests that NMDAR hypofunction in the DG may partly contribute to learning and memory impairment in female Fmr1+/‐ mice. Targeting NMDAR-dependent mechanisms may offer hope as a new therapeutic approach for treating female FXS patients with learning and memory impairments.

Background The consumption of alcohol during pregnancy can result in abnormal fetal development and impaired brain function in humans and experimental animal models. Depending on the pattern of consumption, the dose, and the period of exposure to ethanol (EtOH), a variety of structural and functional brain deficits can be observed. Methods This study compared the effects of EtOH exposure during distinct periods of brain development on oxidative damage and endogenous antioxidant status in various brain regions of adult female and male Sprague Dawley rats. Pregnant dams and neonatal rats were exposed to EtOH during one of the following time windows: between gestational days (GDs) 1 and 10 (first trimester equivalent); between GDs 11 and 21 (second trimester equivalent); or between postnatal days (PNDs) 4 and 10 (third trimester equivalent). Results EtOH exposure during any of the 3 trimester equivalents significantly increased lipid peroxidation in both the cornus ammonis (CA) and dentate gyrus (DG) subregions of the hippocampus, while also decreasing the levels of the endogenous antioxidant glutathione in the hippocampal CA and DG subregions as well as the prefrontal cortex of young adult animals (PND 60). Conclusions These results indicate that EtOH exposure during restricted periods of brain development can have long-term consequences in the adult brain by dysregulating its redox status. This dysfunction may underlie, at least in part, the long-term alterations in brain function associated with fetal alcohol spectrum disorders.

Adult hippocampal neurogenesis can be modulated by various physiological and pathological conditions, including stress, affective disorders, and several neurological conditions. Given the proposed role of this form of structural plasticity in the functioning of the hippocampus (namely learning and memory and affective behaviors), it is believed that alterations in hippocampal neurogenesis might underlie some of the behavioral deficits associated with these psychiatric and neurological conditions. Thus, the search for compounds that can reverse these deficits with minimal side effects has become a recognized priority. In the present study we tested the pro-neurogenic effects of isoxazole 9 (Isx-9), a small synthetic molecule that has been recently identified through the screening of chemical libraries in stem cell-based assays. We found that administration of Isx-9 for 14days was able to potentiate cell proliferation and increase the number of immature neurons in the hippocampal DG of adult rats. In addition, Isx-9 treatment was able to completely reverse the marked reduction in these initial stages of the neurogenic process observed in vehicle-treated animals (which were submitted to repeated handling and exposure to daily intraperitoneal injections). Based on these results, we recommend that future neurogenesis studies that require repeated handling and manipulation of animals should include a naive (non-manipulated) control to determine the baseline levels of hippocampal cell proliferation and neuronal differentiation. Overall, these findings demonstrate that Isx-9 is a promising synthetic compound for the mitigation of stress-induced deficits in adult hippocampal neurogenesis. Future studies are thus warranted to evaluate the pro-neurogenic properties of Isx-9 in animal models of affective and neurological disorders associated with impaired hippocampal structural plasticity.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an unstable expansion of CAG repeats in the HD gene. The symptoms include cognitive dysfunction and severe motor impairments. The neuropathology is characterized by neuronal loss mainly in the striatum and cortex, although other regions including the hippocampus are also affected. In this review we discuss the different mouse models of HD, and how the process of neurogenesis in the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ) is affected in each. Deficits in adult hippocampal neurogenesis have been repeatedly shown in different genetic models of HD, raising the possibility that an impairment of the neurogenic process might underlie some of the cognitive deficits associated with this neurodegenerative disorder. On the other hand, an increase in SVZ neurogenesis has been observed in human HD brains while no differences in SVZ cell proliferation have been detected in the mouse models. In this review we will discuss the discrepancies between these findings as well as the several mechanisms that might contribute to a dysregulation of adult neurogenesis in HD. Finally, we will provide an overview of the various therapeutic strategies aimed at stimulating the endogenous neurogenic capacity that have been tested in HD genetic models. Ultimately, the insights obtained from these and future studies will greatly improve our understanding of the cognitive impairment characteristic of HD.

Alcohol consumption during pregnancy can result in a myriad of health problems in the affected offspring ranging from growth deficiencies to central nervous system impairments that result in cognitive deficits. Adult hippocampal neurogenesis is thought to play a role in cognition (i.e. learning and memory) and can be modulated by extrinsic factors such as alcohol consumption and physical exercise. We examined the impact of voluntary physical exercise on adult hippocampal neurogenesis in a rat model of fetal alcohol spectrum disorders (FASD). Intragastric intubation was used to deliver ethanol to rats in a highly controlled fashion through all three trimester equivalents (i.e. throughout gestation and during the first 10 days of postnatal life). Ethanol-exposed animals and their pair-fed and ad libitum controls were left undisturbed until they reached a young adult stage at which point they had free access to a running wheel for 12 days. Prenatal and early postnatal ethanol exposure altered cell proliferation in young adult female rats and increased early neuronal maturation without affecting cell survival in the dentate gyrus (DG) of the hippocampus. Voluntary wheel running increased cell proliferation, neuronal maturation and cell survival as well as levels of brain-derived neurotrophic factor in the DG of both ethanol-exposed female rats and their pair-fed and ad libitum controls. These results indicate that the capacity of the brain to respond to exercise is not impaired in this model of FASD, highlighting the potential therapeutic value of physical exercise for this developmental disorder.

Exposure to ethanol during pregnancy can be devastating to the developing nervous system, leading to significant central nervous system dysfunction. The hippocampus, one of the two brain regions where neurogenesis persists into adulthood, is particularly sensitive to the teratogenic effects of ethanol. In the present study, we tested a rat model of fetal alcohol syndrome (FAS) with ethanol administered via gavage throughout all three trimester equivalents. Subsequently, we assessed cell proliferation, as well as neuronal survival, and differentiation in the dentate gyrus of the hippocampus of adolescent (35 days old), young adult (60 days old) and adult (90 days old) Sprague-Dawley rats. Using both extrinsic (bromodeoxyuridine) and intrinsic (Ki-67) markers, we observed no significant alterations in cell proliferation and survival in ethanol-exposed animals when compared with their pair-fed and ad libitum controls. However, we detected a significant increase in the number of new immature neurons in animals that were exposed to ethanol throughout all three trimester equivalents. This result might reflect a compensatory mechanism to counteract the deleterious effects of prenatal ethanol exposure or an ethanol-induced arrest of the neurogenic process at the early neuronal maturation stages. Taken together these results indicate that exposure to ethanol during the period of brain development causes a long-lasting dysregulation of the neurogenic process, a mechanism that might contribute, at least in part, to the hippocampal deficits that have been reported in rodent models of FAS.

Perturbations in neurogenesis in the adult brain have been implicated in impaired learning and memory. In the present study, we investigated which stages of the neurogenic process are affected in the transgenic YAC128 mouse model of Huntington disease (HD). Hippocampal neuronal proliferation was altered in the dentate gyrus (DG) of YAC128 mice as compared with wild-type (WT) littermate controls in early symptomatic to end-stage mice. In addition, we detected a significantly lower number of immature neurons in the DG of young, pre-symptomatic YAC128 mice. This decrease in neuronal differentiation persisted through the progression of the disease, and resulted in an overall reduction in the number of new mature neurons in the DG of YAC128 mice. There were no changes in cell proliferation and differentiation in the subventricular zone (SVZ). In this study, we demonstrate decreases in neurogenesis in the DG of YAC128 mice, and these deficits may contribute to the cognitive abnormalities observed in these animals.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability in humans. This X-linked disorder is caused by the transcriptional repression of a single gene, Fmr1. The loss of Fmr1 transcription prevents the production of Fragile X mental retardation protein (FMRP) which in turn disrupts the expression of a variety of key synaptic proteins that appear to be important for intellectual ability. A clear link between synaptic dysfunction and behavioral impairment has been elusive, despite the fact that several animal models of FXS have been generated. Here we report that Fmr1 knockout mice exhibit impaired bidirectional synaptic plasticity in the dentate gyrus (DG) of the hippocampus. These deficits are associated with a novel decrease in functional NMDARs (N-methyl-D-aspartate receptors). In addition, mice lacking the Fmr1 gene show impaired performance in a context discrimination task that normally requires functional NMDARs in the DG. These data indicate that Fmr1 deletion results in significant NMDAR-dependent electrophysiological and behavioral impairments specific to the DG.

Prenatal ethanol exposure is invariably detrimental to the developing central nervous system and the hippocampus is particularly sensitive to the teratogenic effects of ethanol. Prenatal ethanol exposure has been shown to result in hippocampal cell loss, altered neuronal morphology and impaired performance on hippocampal-dependent learning and memory tasks in rodents. The dentate gyrus (DG) of the hippocampus is one of the few brain regions where neurogenesis continues into adulthood. This process appears to have functional significance and these newly generated neurons are believed to play important functions in learning and memory. Recently, several groups have shown that adult hippocampal neurogenesis is compromised in animal models of fetal alcohol spectrum disorders (FASD). The direction and magnitude of any changes in neurogenesis, however, appear to depend on a variety of factors that include: the rodent model used; the blood alcohol concentration achieved; the developmental time point when alcohol was administered; and the frequency of ethanol exposure. In this review we will provide an overview of the different rodent models of FASD that are commonly used in this research, emphasizing each of their strengths and limitations. We will also present an up-to-date summary on the effects of prenatal/neonatal ethanol exposure on adult hippocampal neurogenesis and cell loss, highlighting some of the possible molecular mechanisms that might be involved.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the selective loss of the expression of the Fmr1 gene. Key symptoms in FXS include intellectual impairment and abnormal anxiety-related behaviors. Fmr1 knockout (KO) mice exhibited reduced anxiety on two behavioral tests as well as a blunted corticosterone response to acute stress. Spatial learning and memory was not impaired when tested with both the classic Morris water and Plus-shaped mazes. Adult hippocampal neurogenesis has been associated with spatial learning and memory and emotions such as anxiety and depression. The process of neurogenesis appears abnormal in young adult Fmr1 KO mice, with significantly fewer bromodeoxyuridine-positive cells surviving for at least 4 weeks in the ventral subregion of the dentate gyrus (DG), a hippocampal subregion more closely associated with emotion than the dorsal DG. Within this smaller pool of surviving cells, we observed a concomitant increase in the proportion of surviving cells that acquire a neuronal phenotype. We did not observe a clear difference in cell proliferation using both endogenous and exogenous markers. This work indicates that loss of Fmr1 expression can alter anxiety-related behaviors in mice as well as produce region-specific alterations in hippocampal adult neurogenesis.

Although the existence of adult neurogenesis in the dentate gyrus is now almost universally accepted, it is not widely established that the new neurons perform any necessary function. However, evidence indicates that the number of new neurons that are generated and form functional synapses is clearly large enough to impact the circuitry of the hippocampus. Additionally, several treatments show parallel effects on neurogenesis and hippocampus-dependent behaviors, suggesting a possible causal relationship between new neurons and hippocampal function. Most importantly, several recent studies have found that killing or inhibiting proliferation of granule cell precursors impairs performance on several hippocampus-dependent tasks. Control experiments showing no impairment on slightly different behavioral tests suggest that the deficits are highly specific and unlikely to result from side effects of the neurogenesis-inhibiting treatments. In summary, the evidence to date strongly suggests that adult neurogenesis in the dentate gyrus plays a vital role in hippocampal function.

We examined synaptic plasticity in the dentate gyrus (DG) of the hippocampus in vitro in juvenile C57Bl6 mice (28-40 days of age), housed in control conditions with minimal enrichment (Controls) or with access to an exercise wheel (Runners). LTP expression was significantly greater in slices from Runners than in those from Controls, but could be blocked by APV in both groups. LTP was significantly reduced by NR2B subunit antagonists in both groups. NVP-AAM077, an antagonist with a higher preference for NR2A subunits over NR2B subunits, blocked LTP in slices from Runners and produced a slight depression in Control animals. LTD in the DG was also blocked by APV, but not by either of the NR2B specific antagonists. Strikingly, NVP-AAM077 prevented LTD in Runners, but not in Control animals, suggesting an increased involvement of NR2A subunits in LTD in animals that exercise. NVP-AAM077 did not block LTD in NR2A Knock Out (KO) animals that exercised, as expected. In an attempt to discern whether NMDA receptors located at extrasynaptic sites could play a role in the induction of LTD, DL-TBOA was used to block excitatory amino acid transport and increase extracellular glutamate levels. Under these conditions, LTD was not blocked by the co-application of a specific NR2B subunit antagonist in either group, but NVP-AAM077 again blocked LTD selectively in Runners. These results indicate that NR2A and NR2B subunits play a significant role in LTP in the DG, and that exercise can significantly alter the contribution of NMDA NR2A subunits to LTD.

Prenatal ethanol exposure (PNEE) causes significant deficits in functional (i.e., synaptic) plasticity in the dentate gyrus (DG) and cornu ammonis (CA) hippocampal sub-regions of young adult male rats. Previous research has shown that in the DG, these deficits are not apparent in age-matched PNEE females. This study aimed to expand these findings and determine if PNEE induces deficits in hippocampal-dependent behaviours in both male and female young adult rats (PND 60). The metric change behavioural test examines DG-dependent deficits by determining whether an animal can detect a metric change between two identical objects. The temporal order behavioural test is thought to rely in part on the CA sub-region of the hippocampus and determines whether an animal will spend more time exploring an object that it has not seen for a larger temporal window as compared to an object that it has seen more recently. Using the liquid diet model of FASD (where 6.6% (v/v) ethanol is provided through a liquid diet consumed ad libitum throughout the entire gestation), we found that PNEE causes a significant impairment in the temporal order task, while no deficits in the DG-dependent metric change task were observed. There were no significant differences between males and females for either task. These results indicate that behaviours relying partially on the CA-region may be more affected by PNEE than those that rely on the DG.

The dentate gyrus (DG) contains one of the few neuronal populations in the mammalian brain that are generated throughout life. Research into the regulation and function of adult neurogenesis continues its rapid growth in popularity. With the researcher new to the field in mind, we review the processes that together constitute adult neurogenesis and some of the methods most commonly used for studying these processes. (c) 2006 Wiley-Liss, Inc.

The spontaneous or targeted deletion of the nuclear receptor transcription factor Nr2e1 produces a mouse that shows hypoplasia of the hippocampal formation and reduced neurogenesis in adult mice. In these studies we show that hippocampal synaptic transmission appears normal in the dentate gyrus and cornu ammonis 1 subfields of adult mice that lack Nr2e1 (Nr2e1-/-), and that fEPSP shape, paired-pulse responses, and short-term plasticity are not substantially altered in either subfield. In contrast, the expression of long-term potentiation is selectively impaired in the dentate gyrus, and not in the cornu ammonis 1 subfield. Golgi analysis revealed that there was a significant reduction in both dendritic branching and dendritic length that was specific to dentate gyrus granule cells in the Nr2e1-/- mice. These results indicate that Nr2e1 deletion can significantly alter both synaptic plasticity and dendritic structure in the dentate gyrus.

Voluntary exercise produces a dramatic increase in the number of bromodeoxyuridine (BrdU)-positive cells in the adult dentate gyrus (DG); however, it has never been determined whether this increase reflects neurogenic activity or some exercise-induced change in the metabolic processing of systemically injected BrdU. In these experiments, we show that 1) 200 mg/kg is a saturating dose for single injections of BrdU in both control and voluntary exercise animals; 2) there is significantly more cell labeling in animals that exercise when saturating doses of BrdU are employed; 3) high doses of BrdU do not affect the number, appearance, or distribution of labeled cells; 4) voluntary exercise leads to similar increases in the number of cells expressing Ki67, an intrinsic marker of cellular proliferation; 5) both dendritic length and complexity are significantly increased in the DG of animals that exercise; and 6) spine density is significantly greater on dendrites in the DG following voluntary exercise. This study demonstrates that exercise up-regulates neurogenic activity in the DG of adult rats, independently of any putative changes in altered BrdU metabolism, and that it also substantially alters the morphology of dentate granule cell dendrites. The dramatic changes in the cytoarchitecture of the DG induced by voluntary exercise might underlie the enhancement of hippocampal long-term potentiation and hippocampal-dependent memory that our group has previously described. These results suggest that exercise may be an effective component of therapeutic regimes aimed at improving the functioning of individuals with neuropathologies that involve the degradation of cells in the hippocampus. J. Comp. Neurol. 486:39–47, 2005. © 2005 Wiley-Liss, Inc.