Hippocampal Spine Research Articles

MGlu5 receptors regulate synaptic sumoylation via a transient PKC-dependent diffusional trapping of Ubc9 into spines.

Sumoylation plays important roles in the modulation of protein function, neurotransmission and plasticity, but the mechanisms regulating this post-translational system in neurons remain largely unknown. Here we demonstrate that the synaptic diffusion of Ubc9, the sole conjugating enzyme of the sumoylation pathway, is regulated by synaptic activity. We use restricted photobleaching/photoconversion of individual hippocampal spines to measure the diffusion properties of Ubc9 and show that it is regulated through an mGlu5R-dependent signalling pathway. Increasing synaptic activity with a GABAA receptor antagonist or directly activating mGlu5R increases the synaptic residency time of Ubc9 via a Gαq/PLC/Ca(2+)/PKC cascade. This activation promotes a transient synaptic trapping of Ubc9 through a PKC phosphorylation-dependent increase of Ubc9 recognition to phosphorylated substrates and consequently leads to the modulation of synaptic sumoylation. Our data demonstrate that Ubc9 diffusion is subject to activity-dependent regulatory processes and provide a mechanism for the dynamic changes in sumoylation occurring during synaptic transmission.

Reduced hippocampal dendritic spine density and BDNF expression following acute postnatal exposure to di(2-ethylhexyl) phthalate in male Long Evans rats.

Early developmental exposure to di(2-ethylhexyl) phthalate (DEHP) has been linked to a variety of neurodevelopmental changes, particularly in rodents. The primary goal of this work was to establish whether acute postnatal exposure to a low dose of DEHP would alter hippocampal dendritic morphology and BDNF and caspase-3 mRNA expression in male and female Long Evans rats. Treatment with DEHP in male rats led to a reduction in spine density on basal and apical dendrites of neurons in the CA3 dorsal hippocampal region compared to vehicle-treated male controls. Dorsal hippocampal BDNF mRNA expression was also down-regulated in male rats exposed to DEHP. No differences in hippocampal spine density or BDNF mRNA expression were observed in female rats treated with DEHP compared to controls. DEHP treatment did not affect hippocampal caspase-3 mRNA expression in male or female rats. These results suggest a gender-specific vulnerability to early developmental DEHP exposure in male rats whereby postnatal DEHP exposure may interfere with normal synaptogenesis and connectivity in the hippocampus. Decreased expression of BDNF mRNA may represent a molecular mechanism underlying the reduction in dendritic spine density observed in hippocampal CA3 neurons. These findings provide initial evidence for a link between developmental exposure to DEHP, reduced levels of BDNF and hippocampal atrophy in male rats.

Chronic D-serine reverses arc expression and partially rescues dendritic abnormalities in a mouse model of NMDA receptor hypofunction

Activity-regulated cytoskeleton-associated protein (Arc) is an immediate early gene that is expressed almost exclusively in glutamatergic neurons. Arc protein is enriched in the postsynaptic density (PSD) and colocalizes with the N-methyl-D-aspartate receptor (NMDAR) complex. Arc transcription is positively modulated by NMDAR activity and is important for dendritic spine plasticity. Genetic ablation of serine racemase (SR−/−), the enzyme that converts L-serine to D-serine, a coagonist at the NMDAR, reduces dendritic spine density in the hippocampus. Here we demonstrate that SR deficient (SR−/−) mice also have reduced Arc protein expression in the hippocampus that can be reversed with chronic D-serine administration in adulthood. Furthermore, D-serine treatment partially rescues the hippocampal spine deficit in SR−/− mice. These results demonstrate the importance of D-serine in regulating the hippocampal expression of Arc in vivo. In addition, our findings underscore the potential utility of using the glycine modulatory site agonist D-serine to treat disorders that exhibit Arc and dendritic spine dysregulation as a consequence of NMDAR hypofunction, such as schizophrenia.

Intriguing Roles of Hippocampus-Synthesized 17β-Estradiol in the Modulation of Hippocampal Synaptic Plasticity

Accumulated studies have shown that 17β-estradiol (E2) can be de novo synthesized in the hippocampus, and its role in the regulation of hippocampal synaptic plasticity, which is the basis of learning and memory, has long been exploring. Steroidogenic enzymes (e.g., aromatase) that are essential to the hippocampus-synthesized synthesis of E2 have been detected in the hippocampus. Inhibition of E2 synthesis by aromatase inhibitors significantly reduces the density of hippocampal spine synapses, levels of some synaptic proteins such as spinopholin and synaptophysin. Moreover, the electrophysiological properties of hippocampal neurons are also changed in response to this inhibition. The influences of gonadal and hippocampal E2 on synaptic plasticity may exist some differences, since some reports showed that gonadal (or circulating) estrogens have no obvious effects in the modulation of hippocampal synaptic proteins as evidenced in some ovariectomized animals and postmenopausal women who suffered from Alzheimer's disease (AD). These evidences leads to a hypothesis that hippocampal E2 may play a more important role in modulation of synaptic plasticity than gonadal E2. The signaling pathways, whereby hippocampal E2 modulates synaptic plasticity, insist of classical chronic genomic pathway and rapid nongenomic pathway, which mediated by nonnuclear estrogen receptor (GPER) and/or nuclear or nonnuclear estrogen receptors, which require coactivators for their transcription activity. Among which steroid receptor coactivator-1 (SRC-1) is the predominant coactivator p160 family members in the brain. Several clues have shown that SRC-1 is expressed in hippocampus and is highly correlated with some key synaptic proteins developmentally or after orchidectomy but not ovariectomy, indicating SRC-1 may be regulated by hippocampus-synthesized E2 and profoundly involved in the mediation of hippocampal E2 regulation of hippocampal synaptic plasticity. Further studies about the exact roles of hippocampus-synthesized E2 and therefore SRC-1 are urgently needed in order to facilitate our understanding of hippocampal E2, which will be very important to the development of novel strategies of estrogen replacement therapy against neurodegenerative deficits such as Alzheimer's disease (AD).

Differential expression of hippocampal EphA4 and ephrinA3 in anhedonic-like behavior, stress resilience, and antidepressant drug treatment after chronic unpredicted mild stress

Stress exposure is one of the major risk factors of depression, but the mechanism is not understood. While some individuals show resilience to stress exposure, antidepressants only partially reduce stress-induced depression in both humans and rodents. Stress could dysregulate the remodeling of neuronal dendrites and spines in hippocampus while antidepressants could recover the deficiency induced by stress. EphA4 and its ligand ephrinA3 are critical in the remodeling of neuronal dendrites and spines, but the relationship between ephrinA3/EphA4, stress-induced depression and antidepressants treatment is largely unknown. Based on a rat chronic unpredicted mild stress (CUMS) model, we investigated ephrinA3/EphA4 expression in stress susceptibility, stress resilience, treatment response and treatment resistance in rats. CUMS led to downregulation of EphA4 expression and upregulation of ephrinA3 expression in the hippocampus of stress-susceptible rats, but not in stress-resilient rats. Dysregulated EphA4 and ephrinA3 can be rescued by fluoxetine administration in drug responders, but not in fluoxetine resistant rats. These data provide insights into the potential role of EphA4 and ephrinA3 after stressor exposure, stress adaptation, fluoxetine response and drug treatment refraction.

Long term delivery of pulsed magnetic fields does not alter visual discrimination learning or dendritic spine density in the mouse CA1 pyramidal or dentate gyrus neurons

Repetitive transcranial magnetic stimulation (rTMS) is thought to facilitate brain plasticity. However, few studies address anatomical changes following rTMS in relation to behaviour. We delivered 5 weeks of daily pulsed rTMS stimulation to adult ephrin-A2-/- and wildtype (C57BI/6j) mice (n=10 per genotype) undergoing a visual learning task and analysed learning performance, as well as spine density, in the dentate gyrus molecular and CA1 pyramidal cell layers in Golgi-stained brain sections. We found that neither learning behaviour, nor hippocampal spine density was affected by long term rTMS. Our negative results highlight the lack of deleterious side effects in normal subjects and are consistent with previous studies suggesting that rTMS has a bigger effect on abnormal or injured brain substrates than on normal/control structures.

Orchidectomy does not significantly affect spine synapse density in the CA3 hippocampal subfield in St. Kitts vervet monkeys (Chlorocebus aethiops sabaeus)

Gonadal hormones induce significant changes in cognitive function, associated with alterations in the structure of the hippocampus. We have previously shown that androgens increase the number of spine synapses in the CA1 stratum radiatum of the monkey hippocampus. Recent evidence, however, suggests that loss of testicular hormone production may have variable effects on neuroplasticity in different regions of the hippocampus. To test this hypothesis, we examined the effects of orchidectomy in the dentate gyrus and CA3 subfield of the hippocampus in male St. Kitts vervet monkeys (Chlorocebus aethiops sabaeus). Spine synapse density was significantly reduced (39%) after orchidectomy in the dentate gyrus, consistent with previously published reports in CA1 (40%). However, in CA3 orchidectomy induced a much smaller (22%) reduction in synapse density, which did not reach the limits of statistical significance. These results suggest that orchidectomy exerts heterogeneous effects on hippocampal spine synapse density, the CA3 subfield being relatively spared compared to CA1 and the dentate gyrus. This heterogeneity may contribute to the mixed functional responses observed in males following loss of testicular hormone secretions.

MDMA enhances hippocampal-dependent learning and memory under restrictive conditions, and modifies hippocampal spine density

Addictive drugs produce forms of structural plasticity in the nucleus accumbens and prefrontal cortex. The aim of this study was to investigate the impact of chronic MDMA exposure on pyramidal neurons in the CA1 region of hippocampus and drug-related spatial learning and memory changes. Adolescent rats were exposed to saline or MDMA in a regime that mimicked chronic administration. One week later, when acquisition or reference memory was evaluated in a standard Morris water maze (MWM), no differences were obtained between groups. However, MDMA-exposed animals performed better when the MWM was implemented under more difficult conditions. Animals of MDMA group were less anxious and were more prepared to take risks, as in the open field test they ventured more frequently into the central area. We have demonstrated that MDMA caused an increase in brain-derived neurotrophic factor (BDNF) expression. When spine density was evaluated, MDMA-treated rats presented a reduced density when compared with saline, but overall, training increased the total number of spines, concluding that in MDMA-group, training prevented a reduction in spine density or induced its recovery. This study provides support for the conclusion that binge administration of MDMA, known to be associated to neurotoxic damage of hippocampal serotonergic terminals, increases BDNF expression and stimulates synaptic plasticity when associated with training. In these conditions, adolescent rats perform better in a more difficult water maze task under restricted conditions of learning and memory. The effect on this task could be modulated by other behavioural changes provoked by MDMA.

Long term delivery of pulsed magnetic fields does not alter visual discrimination learning or dendritic spine density in the mouse CA1 pyramidal or dentate gyrus neurons

Repetitive transcranial magnetic stimulation (rTMS) is thought to facilitate brain plasticity. However, few studies address anatomical changes following rTMS in relation to behaviour. We delivered 5 weeks of daily pulsed rTMS stimulation to adult ephrin-A2 -/- and wildtype (C57BI/6j) mice (n=10 per genotype) undergoing a visual learning task and analysed learning performance, as well as spine density, in the dentate gyrus molecular and CA1 pyramidal cell layers in Golgi-stained brain sections. We found that neither learning behaviour, nor hippocampal spine density was affected by long term rTMS. Our negative results highlight the lack of deleterious side effects in normal subjects and are consistent with previous studies suggesting that rTMS has a bigger effect on abnormal or injured brain substrates than on normal/control structures.

Environmental Enrichment Reveals Effects of Genotype on Hippocampal Spine Morphologies in the Mouse Model of Fragile X Syndrome

Fragile X Syndrome (FXS) and the Fmr1 knockout (KO) mouse model of this disorder exhibit abnormal dendritic spines in neocortex, but the degree of spine disturbances in hippocampus is not clear. The present studies tested if the mutation influences dendritic branching and spine measures for CA1 pyramidal cells in Fmr1 KO and wild-type (WT) mice provided standard or enriched environment (EE) housing. Automated measures from 3D reconstructions of green fluorescent protein (GFP)-labeled cells showed that spine head volumes were ∼ 40% lower in KOs when compared with WTs in both housing conditions. With standard housing, average spine length was greater in KOs versus WTs but there was no genotype difference in dendritic branching, numbers of spines, or spine length distribution. However, with EE rearing, significant effects of genotype emerged including greater dendritic branching in WTs, greater spine density in KOs, and greater numbers of short thin spines in KOs when compared with WTs. Thus, EE rearing revealed greater effects of the Fmr1 mutation on hippocampal pyramidal cell morphology than was evident with standard housing, suggesting that environmental enrichment allows for fuller appreciation of the impact of the mutation and better representation of abnormalities likely to be present in human FXS.

Long term delivery of pulsed magnetic fields does not improve learning or alter dendritic spine density in the mouse hippocampus

Repetitive transcranial magnetic stimulation (rTMS) is thought to facilitate brain plasticity. However, few studies address anatomical changes following rTMS in relation to behaviour. We delivered 5 weeks of daily pulsed rTMS stimulation to ephrin-A2-/- and wildtype mice (n=10 per genotype) undergoing a visual learning task and analysed learning performance, as well as spine density, in the dentate gyrus molecular and CA1 pyramidal cell layers in Golgi-stained brain sections. We found that neither learning behaviour, nor hippocampal spine density was affected by long term rTMS. Our negative results highlight the lack of deleterious side effects in normal subjects and are consistent with previous studies suggesting that rTMS has a bigger effect on abnormal or injured brain substrates than on normal/control structures.

Dizocilpine reduces head diameter of dendritic spines in the hippocampus of adolescent rats

Cognitive deficits are the core symptoms of schizophrenia. Spine deficits have been found in hippocampus of schizophrenia patients, and were associated with cognitive impairments. N-methyl-d-asparate receptors (NMDARs) had been known to play a critical role in synaptic pruning and stabilization during adolescence. In the present study, male adolescent rats were exposed to dizocilpine (MK-801) (0.2mg/kg i.p qd) or 0.9% saline for 14 days. Then spatial memory, spine morphological changes and RhoA, Rac1, Cdc42 mRNA levels in hippocampus were measured. As a result, MK-801 impaired spatial memory in the adolescent rats, as well as reduced the proportion of mushroom spines and increased the proportion of stubby spines in hippocampus. MK-801 also reduced the expression levels of Rac1 and Cdc42 mRNA and upregulated RhoA mRNA in hippocampus. These results imply that subchronic MK-801 administration during adolescence might disturb the expression of RhoA, Rac1 and Cdc42 mRNA, and then lead to the decay of the spines in hippocampus, which could be involved in cognitive impairments in schizophrenia.

Neuropeptide Signaling: From the Gut

In the defecation motor program of Caenorhabditis elegans, a pacemaker rhythm generated by the intestine leads to the activation of motor neurons controlling enteric muscle contraction. A new study demonstrates that this signal is conveyed by a neuropeptide that is released from intestinal cells and acutely depolarizes the motorneurons, acting much like a classical neurotransmitter.

Seasonal Changes in Neuronal Spacing of Hippocampus of Psittacula krameri (Scopoli, 1769)

Neural plasticity in avian hippocampus is accompanied by seasonal changes. The previous studies have reported that the fluctuation in season results in changes in thickness of dendrite, spine turnover and morphology of spine in hippocampus of birds whereas the present investigation indicates that neuronal spacing in hippocampus of birds is also associated with seasonal variations. Neuronal spacing was higher to be in breeding Psittacula krameri than in non-breeding bird.

Female hippocampal estrogens have a significant correlation with cyclic fluctuation of hippocampal spines

Synaptic plasticity of the female hippocampus may cyclically fluctuate across the estrous cycle. The spine density fluctuation had been explained by fluctuation of plasma estradiol (E2) and progesterone (PROG), with the assumption that these steroids penetrate into the hippocampus. Recently, however, we demonstrated that male hippocampal levels of sex steroids are much higher than those in plasma, suggesting a weak contribution of plasma steroids to the spine density. By combination of mass-spectrometric analysis with HPLC-purification and picolinoyl-derivatization of hippocampal sex steroids, we determined the accurate concentration of E2 and PROG at four stages of plasma estrous cycle including Proestrus (Pro), Estrus (Est), Diestrus 1 (D1), and Diestrus 2 (D2). Hippocampal levels of E2 and PROG showed cyclic fluctuation with a peak at Pro for E2 and at D1 for PROG, having a positive correlation with the plasma estrous cycle. All these sex steroid levels are much higher in the hippocampus than in plasma. Even after ovariectomy a significant levels of E2 and PROG were observed in the hippocampus. The total spine density showed higher values at Pro and D1, and lower values at Est and D2, having a good correlation with the peak levels of hippocampal E2 or PROG. We also examined fluctuation of the head diameter of spines. Interestingly, mRNA expression level of steroidogenic enzymes (P450arom and 17β-HSD, etc.) and sex-steroid receptors did not significantly change across the estrous cycle. Therefore, the fluctuation of total hippocampal PROG (equal to sum of hippocampus-synthesized PROG and plasma PROG) may be originated from the contribution of cyclic change in plasma PROG, which can induce the fluctuation of total hippocampal E2, since steroid conversion activity of hippocampus might be nearly the same across the estrus cycle.

B12 The influence of kalirin-7 deficiency on the phenotype of YAC128 mice

<h3>Background</h3> The guanine-nucleotide exchange factor kalirin is a key regulator of spine morphogenesis and important for synaptic function and glutamatergic transmission. <i>Kalirin-7</i>-knockout mice (Kal7KO) deficient for the most abundant isoform of <i>kalirin</i> in the adult brain show a decrease in hippocampal spine density and specific behavioural changes. In Huntington9s disease (HD) there is evidence for abnormalities in synaptic plasticity and transmission in several brain regions in patients and mouse models. These alterations are supposed to account for cognitive and motoric deficits in HD. <h3>Aims</h3> To analyse the interaction between Huntingtin and proteins involved in synaptic plasticity in vivo on a behavioural and molecular level we generated a mouse model lacking <i>kalirin-7 (Kal7)</i> while overexpressing the human <i>huntingtin (htt)</i> with 128 CAGs (YAC128). The YAC128 mice show motor deficits, cognitive impairment and a striatal degeneration reproducing symptoms of the human disease. <h3>Methods</h3> The Kal7KO-YAC128 mouse model was first analysed in a set of behavioural tests. Kal7KO-YAC128 mice were compared with littermates heterozygous for <i>htt</i> (YAC128), homozygous deficient for <i>Kal7</i> (Kal7KO) and wildtype controls. 13–15 males of each group were repeatedly tested from 4 to 15 months in Rotarod, Simple swimming test, Elevated plus maze (EPM) and the automated home cage system LabMaster (LM; TSE Systems). The influence of <i>kalirin-7</i> deficiency on the expression of mutant huntingtin, the glutamatergic NMDA receptor subunits NR1, NR2A and NR2B as well as on the level of synaptic proteins like PSD-95 were analysed by immunoblotting and immunohistochemistry in cortex, striatum and hippocampus. Moreover we examined in the same brain regions the morphology of neurons and the synaptic morphology by electron microscopy. <h3>Results</h3> The motoric deficit of the YAC128 was not changed by the Kalirin 7-deficiency. No significant difference in anxiety could be found between YAC128 and Kal7KO-YAC128. Results of the Simple swimming test and LM are still under analysis. First results of the biochemical analysis are going to be presented. <h3>Conclusions</h3> Preliminary results indicate that <i>kalirin-7</i> deletion does not influence the behavioural phenotype of YAC128 mice.

Glucocorticoid receptors are localized to dendritic spines and influence local actin signaling.

Glucocorticoids affect learning and memory but the cellular mechanisms involved are poorly understood. The present studies tested if the stress-responsive glucocorticoid receptor (GR) is present and regulated within dendritic spines, and influences local signaling to the actin cytoskeleton. In hippocampal field CA1, 13 % of synapses contained GR-immunoreactivity. Three-dimensional reconstructions of CA1 dendrites showed that GR aggregates are present in both spine heads and necks. Consonant with evidence that GRα mRNA associates with the translation regulator Fragile X Mental Retardation Protein (FMRP), spine GR levels were rapidly increased by group 1 mGluR activation and reduced in mice lacking FMRP. Treatment of cultured hippocampal slices with the GR agonist dexamethasone rapidly (15-30 min) increased total levels of phosphorylated (p) Cofilin and extracellular signal-regulated kinase (ERK) 1/2, proteins that regulate actin polymerization and stability. Dexamethasone treatment of adult hippocampal slices also increased numbers of PSD95+ spines containing pERK1/2, but reduced numbers of pCofilin-immunoreactive spines. Dexamethasone-induced increases in synaptic pERK1/2 were blocked by the GR antagonist RU-486. These results demonstrate that GRs are present in hippocampal spines where they mediate acute glucocorticoid effects on local spine signaling. Through effects on these actin regulatory pathways, GRs are positioned to exert acute effects on synaptic plasticity.

Aromatase Inhibition Abolishes LTP Generation in Female But Not in Male Mice

Inhibitors of aromatase, the final enzyme of estradiol synthesis, are suspected of inducing memory deficits in women. In previous experiments, we found hippocampal spine synapse loss in female mice that had been treated with letrozole, a potent aromatase inhibitor. In this study, we therefore focused on the effects of letrozole on long-term potentiation (LTP), which is an electrophysiological parameter of memory and is known to induce spines, and on phosphorylation of cofilin, which stabilizes the spine cytoskeleton and is required for LTP in mice. In acute slices of letrozole-treated female mice with reduced estradiol serum concentrations, impairment of LTP started as early as after 6 h of treatment and progressed further, together with dephosphorylation of cofilin in the same slices. Theta-burst stimulation failed to induce LTP after 1 week of treatment. Impairment of LTP was followed by spine and spine synapse loss. The effects were confirmed in vitro by using hippocampal slice cultures of female mice. The sequence of effects in response to letrozole were similar in ovariectomized female and male mice, with, however, differences as to the degree of downregulation. Our data strongly suggest that impairment of LTP, followed by loss of mushroom spines and spine synapses in females, may have implications for memory deficits in women treated with letrozole.

Low Doses of 17β-Estradiol Rapidly Improve Learning and Increase Hippocampal Dendritic Spines

While a great deal of research has been performed on the long-term genomic actions of estrogens, their rapid effects and implications for learning and memory are less well characterized. The often conflicting results of estrogenic effects on learning and memory may be due to complex and little understood interactions between genomic and rapid effects. Here, we investigated the effects of low, physiologically relevant, doses of 17β-estradiol on three different learning paradigms that assess social and non-social aspects of recognition memory and spatial memory, during a transcription independent period of memory maintenance. Ovariectomized female CD1 mice were subcutaneously administered vehicle, 1.5 μg/kg, 2 μg/kg, or 3 μg/kg of 17β-estradiol 15 minutes before social recognition, object recognition, or object placement learning. These paradigms were designed to allow the testing of learning effects within 40 min of hormone administration. In addition, using a different set of ovariectomized mice, we examined the rapid effects of 1.5 μg/kg, 2 μg/kg, or 3 μg/kg of 17β-estradiol on CA1 hippocampal dendritic spines. All 17β-estradiol doses tested impacted learning, memory, and CA1 hippocampal spines. 17β-Estradiol improved both social and object recognition, and may facilitate object placement learning and memory. In addition, 17β-estradiol increased dendritic spine density in the stratum radiatum subregion of the CA1 hippocampus, but did not affect dendritic spines in the lacunosum-moleculare, within 40 min of administration. These results demonstrate that the rapid actions of 17β-estradiol have important implications for general learning and memory processes that are not specific for a particular type of learning paradigm. These effects may be mediated by the rapid formation of new dendritic spines in the hippocampus.

P.2.017 Size does matter: environmental enrichment rescues cognitive and synaptic deficits following olfactory bulbectomy in mice

Environmental enrichment (EE) has been shown to improve cognitive performance and enhance synaptic plasticity in various neurodegenerative animal models. Antidepressant efficacy of environmental enrichment, however, remains unclear. To investigate the effect of EE on cognitive and depressive symptoms, and on structural plasticity, we used olfactory bulbectomy (OBX) in mice. OBX is primarily known as a model for predicting antidepressant activity, since its hyperactivity is normalized by chronic antidepressant administration; however, the ablation of olfactory bulbs in a rodent also results in progressive neurodegeneration, behavioral disturbances, and cognitive impairments − symptoms reminiscent of those of Alzheimer’s and depressed patients [1]. Four weeks after the bulbectomy, mice were exposed to EE, consisting of tunnel, toys and nesting material, for 4 weeks. The animals’ locomotor activity was observed, using the open-field paradigm and their cognitive ability was measured throughout the study using passive avoidance (assessing fear memory) and T-maze (assessing spatial memory). Compared to sham-operated controls, OBX mice showed significantly increased locomotor activity (F(3,20) = 4.38, p< 0.05), impaired shortand long-term fear memory in the passive avoidance test, and hindered spatial memory in the T-maze. EE-treated OBX mice demonstrated significantly increased fear (both short and long-term) ((H(4) = 14.11, p< 0.01 and (H(4) = 7.15, p< 0.05, respectively) and spatial memory when compared to the non-enriched bulbectomized mice (H(4) = 8.12, p< 0.05). There was no antidepressant effect of EE on the OBX mice. The brain weights of the EE-OBX mice were significantly larger in comparison to the standard housed bulbectomized mice (F(3,20) = 5.73, p< 0.05) and coincided with improved cognitive functioning. Furthermore, preliminary data demonstrated EE treatment reversed the bulbectomy-induced reduction in dendritic spine density in hippocampus (F(3,8) = 18.86, p< 0.01) without affecting the OBX-mediated decrease in the number of neurons. Thus, despite a substantial neuronal loss, EE induced a refinement of the synaptic network, which may underlie the improved cognitive functioning in the OBX mice following EE, suggesting that the beneficial effects of enrichment on memory stems mainly from enhanced synaptic plasticity rather than impediment of general brain atrophy. Interestingly, in rats, bulbectomy also results in a loss of dendritic spines in hippocampus [2], and although EE recovers the reduced hippocampal weights in the OBX rat, it is unable to alleviate OBX-induced cognitive deficits, yet it exerts antidepressant effects in rats [3]. The lack of EE efficacy on the OBX mediated cognitive impairments in the rat compared to the mouse, may be due to differences in the ability of these species to rewire their brain after severe neurodegeneration. Why EE induced antidepressant effect in the OBX rat but not in mice remains to be elucidated. In addition to possible implications for the development of novel therapeutic agents that enhance the beneficial effects of EE, our findings raise an important question of translational value in animal research: is the mouse or the rat a better animal model for human neurodegenerative disorders and for testing therapeutic interventions for their efficacy? It appears that, after all, size does matter both at the level of the animal strain, brain size and dendritic spines.