Modulation of neurogenesis by targeted hippocampal irradiation fails to affect kindling progression

Changes in the rate of dentate granule cell neurogenesis and in the fate of newborn granule cells have been implicated in the development and progression of epilepsies. Strategies to normalize neurogenesis in chronic epilepsy models are thought to increase our understanding of the functional consequences of aberrant neurogenesis in the epileptic brain. Therefore, we modulated neurogenesis in an amygdala kindling paradigm in rats by targeted irradiation of the hippocampus using a medical linear accelerator device. Selective irradiation normalized the hippocampal cell proliferation rate in kindled animals. Both, in kindled and nonkindled rats the number of BrdU/NeuN‐labeled newborn neurons was reduced in response to irradiation. Whereas kindling resulted in a pronounced increase in the number of neuroblasts identified based on doublecortin‐labeling, irradiation prevented the expansion of the neuroblast population. Moreover, irradiation counteracted the kindling‐associated increase in hilar basal dendrites, and kept the fraction of cells with basal dendrites at control levels. Despite the efficacious modulation of neurogenesis, irradiation did not affect the rate of kindling progression. Both, the number of stimulations as well as the cumulative afterdischarge duration to reach respective seizure stages were comparable in animals with and without irradiation. In addition, pre‐ and postkindling thresholds as well as seizure parameters recorded at threshold stimulation remained unaffected by irradiation. In conclusion, the fact that the efficacious modulation of neurogenesis by irradiation did not exert any effects on kindling acquisition and kindled seizures suggests that newborn neurons do not critically contribute to the hyperexcitable state in the chronic epilepsy model used. © 2010 Wiley‐Liss, Inc.     

Temporal and spacial changes of highly polysialylated neural cell adhesion molecule immunoreactivity in amygdala kindling development

To investigate the migration of neural stem cells as well as neural plastic changes in epileptic brain, spaciotemporal expression of immunoreactive highly polysialylated neural cell adhesion molecule (PSA-NCAM) was examined in amygdala kindling development of rat. The neural migration and synaptic remodeling detected with PSA-NCAM staining occurred in dentate gyrus of hippocampus, subventricular zone and pyriform cortex with amygdaloid kindling in generalized seizure but not in partial seizure. Although PSA-NCAM positive dendrite in dentate gyrus was minimally found in the control brain, it extended slightly in animals with partial seizure, and greatly toward the molecular layer with generalized seizure. Thus, the migration of neural stem cells as well as neural plastic changes were specially and temporally different between brain regions depending on different kindling stages. These changes may mainly contribute to the reorganization of neural network in epileptic brain.     

Roles of astrocytes and microglia in seizure‐induced aberrant neurogenesis in the hippocampus of adult rats

Recent evidence showed that epileptic seizures increase hippocampal neurogenesis in the adult rat, but prolonged seizures result in the aberrant hippocampal neurogenesis that often leads to a recurrent excitatory circuitry and thus contributes to epileptogenesis. However, the mechanism underlying the aberrant neurogenesis after prolonged seizures remains largely unclear. In this study, we examined the role of activated astrocytes and microglia in the aberrant hippocampal neurogenesis induced by status epilepticus. Using a lithium‐pilocarpine model to mimic human temporal lobe epilepsy, we found that status epilepticus induced a prominent activation of astrocytes and microglia in the dentate gyrus 3, 7, 14, and 20 days after the initial seizures. Then, we injected fluorocitrate stereotaxicly into the dentate hilus to inhibit astrocytic metabolism and found that fluorocitrate failed to prevent the seizure‐induced formation of ectopic hilar basal dendrites but instead promoted the degeneration of dentate granule cells after seizures. In contrast, a selective inhibitor of microglia activation, minocycline, inhibited the aberrant migration of newborn neurons at 14 days after status epilepticus. Furthermore, with stereotaxic injection of lipopolysaccharide into the intact dentate hilus to activate local microglia, we found that lipopolysaccharide promoted the development of ectopic hilar basal dendrites in the hippocampus. These results indicate that the activated microglia in the epileptic hilus may guide the aberrant migration of newborn neurons and that minocycline could be a potential drug to impede seizure‐induced aberrant migration of newborn neurons. © 2009 Wiley‐Liss, Inc.     

Targeting the endocannabinoid system in the amygdala kindling model of temporal lobe epilepsy in mice

The endocannabinoid system can be considered as a putative target to affect ictogenesis as well as the generation of a hyperexcitable epileptic network. Therefore, we evaluated the effect of a CB1 receptor agonist (WIN55.212-2) and of an inhibitor of the enzymatic degradation of the endocannabinoid anandamide (fatty acid hydrolase inhibitor URB597) in the amygdala kindling model of temporal lobe epilepsy. Only minor effects on seizure thresholds and seizure parameters without a clear dose-dependency were observed in fully kindled mice. When evaluating the impact on kindling acquisition, WIN55.212-2 significantly delayed the progression of seizure severity. In contrast, URB597 did not affect the development of seizures in the kindling paradigm. Analysis of cell proliferation and neurogenesis during the kindling process revealed that URB597 significantly reduced the number of newborn neurons. These data give first evidence that CB1-receptor activation might render a disease-modifying approach. Future studies are necessary that further analyze the role of CB1 receptors and to confirm the efficacy of CB1-receptor agonists in other models of chronic epilepsy.     

Polysialylation of NCAM is upregulated by hyperthermia and participates in heat shock preconditioning-induced neuroprotection

"Brain tolerance"--a phenomenon in which a subtoxic challenge confers resistance to subsequent brain injuries--provides an ideal opportunity for investigating endogenous neuroprotective mechanisms. We investigated the potential role of the polysialylated (PSA) form of neural cell adhesion molecule (NCAM), which is thought to play a key role in plasticity. In a model where prior exposure to heat shock protects against kainate-induced cell damage in the hippocampus, we show that hyperthermia upregulates PSA-NCAM expression for at least 1 week, without affecting neurogenesis. Pharmacological manipulation of heat shock protein (HSP) expression demonstrates a tight positive link between HSP70 and PSA-NCAM. Finally, the presence of PSA was functionally linked to brain tolerance, as protection against kainate-induced cell death by heat shock pre-exposure was abolished in the absence of NCAM polysialylation. The upregulation of PSA-NCAM by hyperthermia may have a significant impact on hippocampal plasticity, permitting induction of the complex molecular cascade responsible for neuroprotection.     

Newborn neurons with hilar basal dendrites hallmark epileptogenic networks

Basal dendrites are transiently present on developing newly generated granule cells in adult rats. In epileptic rats, basal dendrites often fail to retract, resulting in the generation of persisting hilar basal dendrites that have been proposed to contribute to hyperexcitability. Here, we demonstrate that the formation of hilar basal dendrites also occurs in the absence of seizures following induction of an epileptogenic neuronal network by amygdala kindling. The number of newly generated neurons with hilar basal dendrites was significantly increased 6-8 weeks after the last kindled seizure. Thus, even in periods without seizure activity, persistence of hilar basal dendrites presents a hallmark of hyperexcitable epileptogenic networks in the rodent brain and may contribute to disease progression.     

Different effects of mild and severe seizures on hippocampal neurogenesis in adult rats

Recent evidence shows that functional neurogenesis exists in the adult hippocampus and that epileptic seizures can increase neurogenesis in the dentate gyrus (DG). However, it is unknown whether different seizure severity has different effects on neurogenesis in the DG of adult rats. In this study, we examined hippocampal neurogenesis in the rat mild and severe seizure preparations characterized with frequent wet dog shakes and severe status epilepticus, respectively. Both mild and severe seizures promoted the mitotic activity in the DG, but severe seizures caused a stronger cell proliferative response than mild seizures. Less than 20% of newborn cells in the DG differentiated into neurons in rats suffering severe seizures, whereas more than 60% of newborn dentate cells differentiated into neurons in control and mild seizure groups. Most newborn neurons migrated into the granular cell layer in control and mild seizure groups, but severe seizures were associated with an aberrant migration of newborn neurons into the dentate hilus. Severe seizures induced astrocyte activation and the expression of nestin and the migration directional molecules netrin 1 and Sema-3A in the hilus, which were not present in the hilus of control and mild seizure-attacked rats, suggesting that these molecules are involved in the aberrant migration of newborn neurons.     

Aberrant hippocampal neurogenesis after limbic kindling: Relationship to BDNF and hippocampal-dependent memory

Seizures dramatically increase the number of adult generated neurons in the hippocampus. However, it is not known whether this effect depends on seizures that originate in specific brain regions or whether it is nonspecific to seizure activity regardless of origin. We used kindling of different brain sites to address this question. Rats received 99 kindling stimulations of the basolateral amygdala, dorsal hippocampus, or caudate nucleus over a 6-week period. After kindling, we counted the number of adult generated hippocampal neurons that were birth-dated with the proliferative marker bromodeoxyuridine (BrdU) to evaluate cell proliferation and survival under conditions of repeated seizures. Next, we counted the number of doublecortin immunoreactive (DCX-ir) cells and evaluated their dendritic complexity to determine if limbic and nonlimbic seizures have differential effects on neuronal maturation. We also quantified hippocampal brain-derived neurotrophin factor (BDNF) protein levels using an ELISA kit and assessed memory performance using a hippocampal-dependent fear conditioning paradigm. We found that limbic, but not nonlimbic, seizures dramatically increased hippocampal cell proliferation and the number of hilar-CA3 ectopic granule cells. Further, limbic kindling promoted dendritic outgrowth of DCX-ir cells and the number of DCX-ir cells containing basal dendrites. Limbic kindling also enhanced BDNF protein levels throughout the entire hippocampus and impaired the retrieval of fear memories. Collectively, our results suggest a relationship between limbic seizures, neurogenesis, BDNF protein, and cognition.     

Long-term genetic fate mapping of adult generated neurons in a mouse temporal lobe epilepsy model

In the epileptic brain, seizures can increase hippocampal neurogenesis, while opposingly seizure-associated brain pathology has been shown to detrimentally affect neurogenesis. The long-term impact of recurrent seizures on the number of new neurons as well as their relative contribution to the granule cell layer remains an open question. Therefore we analyzed neuron addition based on genetic fate mapping in a chronic model of epilepsy comparing non-kindled animals and kindled animals having at least one generalized seizure with and without further seizures. The number of all new granule cells added to the dentate gyrus following the onset of kindling was significantly increased (7.0-8.9 fold) in kindled groups. The hyperexcitable kindled state and a prior seizure history proved to be sufficient to cause a pronounced long-term net effect on neuron addition. An ongoing continuous occurrence of seizures did not further increase the number of new granule cells in the long-term. In contrast, a correlation was found between the cumulative duration of seizures and neuron addition following a kindled state. In addition, the overall number of seizures influenced the relative portion of new cells among all granule cells. Non-kindled animals showed 1.6% of new granule cells among all granular cells by the end of the experiment. This portion reached 5.7% in the animals which experienced either 10 or 22 seizures. A percentage of 8.4% new cells were determined in the group receiving 46 seizures which is a significant increase in comparison to the control group. In conclusion, permanent genetic fate mapping analysis demonstrated that recurrent seizures result in a lasting change in the makeup of the granule cell layer with alterations in the relative contribution of newborn neurons to the granule cell network. Interestingly, the formation of a hyperexcitable kindled network even without recent seizure activity can result in pronounced long-term alterations in the absolute number of new granule cells. However, seizure density also seems to play a critical role with more frequent seizures resulting in increased fractions of new neurons.     

PSA-NCAM: an important regulator of hippocampal plasticity

The Neural Cell Adhesion Molecule (NCAM) serves as a temporally and spatially regulated modulator of a variety of cell-cell interactions. This review summarizes recent results of studies aimed at understanding its regulation of expression and biological function, thereby focussing on its polysialylated isoforms (PSA-NCAM). The detailed analysis of the expression of PSA and NCAM in the hippocampal mossy fiber system and the morphological consequences of PSA-NCAM deficiency in mice support the notion that the levels of expression of NCAM are important not only for the regulation and maintenance of structural changes, such as migration, axonal growth and fasciculation, but also for activity-induced plasticity. There is evidence that PSA-NCAM can specifically contribute to a presynaptic form of plasticity, namely long-term potentiation at hippocampal mossy fiber synapses. This is consistent with previous observations that NCAM-deficient mice show deficits in spatial learning and exploratory behavior. Furthermore, our data points to an important role of the hypothalamic-pituitary-adrenal axis, which is the principle adaptive response of the organism to environmental challenges, in the control of PSA-NCAM expression in the hippocampal formation. In particular, we evidence an inhibitory influence of corticosterone on PSA-NCAM expression.     

PSA‐NCAM‐dependent GDNF signaling limits neurodegeneration and epileptogenesis in temporal lobe epilepsy

Polysialylated neuronal cell adhesion molecule (PSA‐NCAM), a polysialylated protein constitutively expressed in the hippocampus, is involved in neuronal growth, synaptic plasticity and neurotrophin signaling. In particular, PSA‐NCAM mediates Ret‐independent glial‐derived neurotrophic factor (GDNF) signaling, leading to downstream FAK activation. GDNF has potent seizure‐suppressant action, whereas PSA‐NCAM is upregulated by seizure activity. However, the involvement of Ret‐independent GDNF signaling in temporal lobe epilepsy (TLE) is not established. We tested the effects of PSA‐NCAM inactivation on neurodegeneration and epileptogenesis in a mouse model of TLE. In this model, unilateral intrahippocampal kainic acid (KA) injection induced degeneration of CA1, CA3c and hilar neurons, followed by spontaneous recurrent focal seizures. In the contralateral, morphologically preserved hippocampus, a long‐lasting increase of PSA‐NCAM immunoreactivity was observed. Inactivation of PSA‐NCAM by endoneuraminidase (EndoN) administration into the contralateral ventricle of KA‐treated mice caused severe degeneration of CA3a,b neurons and dentate gyrus granule cells in the epileptic focus, and led to early onset of focal seizures. This striking trans‐hemispheric alteration suggested that PSA‐NCAM mediates GDNF signaling, leading to transport of neuroprotective signals into the lesioned hippocampus. This hypothesis was confirmed by injecting GDNF antibodies into the contralateral hippocampus of KA‐treated mice, thereby reproducing the enhanced neurodegeneration seen after PSA‐NCAM inactivation. Furthermore, contralateral EndoN and anti‐GDNF treatment decreased GDNF family receptor α1 immunoreactivity and FAK phosphorylation in the epileptic focus. Thus, Ret‐independent GDNF signaling across the commissural projection might protect CA3a,b neurons and delay seizure onset. These findings implicate GDNF in the control of epileptogenesis and offer a possible mechanism explaining lesion asymmetry in mesial TLE.     

Cell surface expression of polysialic acid on NCAM is a prerequisite for activity-dependent morphological neuronal and glial plasticity.

Polysialic acid (PSA) on the extracellular domain of the neural cell adhesion molecule (NCAM) reduces cell adhesion and is considered an important regulator of cell surface interactions. The hypothalamo-neurohypophysial system (HNS), whose glia, neurons, and synapses undergo striking, reversible morphological changes in response to physiological stimulation, expresses high levels of PSA-NCAM throughout life. Light and electron microscopic immunocytochemistry in normal rats and rats in which cell transport was blocked with colchicine showed that PSA-NCAM is expressed in both HNS neurons and glia, particularly at the level of astrocytic processes that envelop neuronal profiles and can undergo remodeling. Moreover, we confirmed that the overall levels of PSA-NCAM were not greatly altered by stimulation (lactation and chronic salt ingestion). Nevertheless, PSA is essential to morphological plasticity. Using comparative ultrastructural analysis, we found that, after specific enzymatic removal of PSA from NCAM by microinjection of endoneuraminidase close to the hypothalamic magnocellular nuclei in vivo, there was no apparent withdrawal of astrocytic processes nor any increase in synaptic contacts normally induced by lactation and dehydration. Our observations demonstrate, therefore, that expression of PSA on cell surfaces in the adult HNS is indispensable to its capacity for activity-dependent morphological neuronal-glial and synaptic plasticity. The carbohydrate PSA on NCAM can thus be considered a necessary permissive factor to allow neuronal and glial remodeling to occur whenever the proper inductive stimulus intervenes.     

Complex regulation of the expression of the polysialylated form of the neuronal cell adhesion molecule by glucocorticoids in the rat hippocampus

The gyrus dentatus is one of the few areas of the brain that continues to produce neurons after birth. The newborn cells differentiate into granule cells which project axons to their postsynaptic targets. This step is accompanied by the transient expression of the polysialylated isoforms of neuronal cell adhesion molecules (PSA-NCAM) by the developing neurons. Glucocorticoid hormones have been shown to inhibit neurogenesis. We noted a functional correlation between PSA-NCAM expression and glucocorticoid action after manipulation of corticosterone levels in the adrenalectomized rat. Adrenalectomy increased neurogenesis, evaluated from the incorporation of 5-bromo-2′-deoxyuridine in neuronal precursors, as well as PSA-NCAM expression. The increase in PSA-NCAM-immunoreactive (IR) cells in the gyrus dentatus, evidenced 72 h following adrenalectomy, persisted for at least a month. It was accompanied by enhanced dendritic arborization of PSA-NCAM-IR cells in the gyrus dentatus and by an increase in number of PSA-NCAM-IR fibres in the CA3 subfield. Neurogenesis was normalized by restitution of diurnal or nocturnal levels of corticosterone, whereas normalization of PSA-NCAM expression was only observed after simulation of the complete circadian fluctuation of the hormone. Our findings reveal the complex action of corticosterone in modulating the expression of PSA-NCAM in the gyrus dentatus of the hippocampal formation. They also highlight the importance of corticosterone fluctuations in the control of neurogenesis and plasticity in this structure.     

NDRG2通过Hes1参与癫痫发作后海马齿状回的神经发生

目的 探讨N-Myc下游调节基因2(N-Myc downstream regulated gene 2,NDRG2)与癫痫发作后海马齿状回神经发生的关系。方法 C57BL/6小鼠20只,随机分为癫痫组和对照组,每组又分为癫痫造模后1和7 d两个时间点,每个时间点5只,通过蛋白免疫印迹检测癫痫后海马齿状回NDRG2蛋白相对表达水平和mRNA相对表达水平变化; 使用双皮质素(DCX)染色标记未成熟神经元,神经巢蛋白(Nestin)标记神经干细胞,神经核蛋白(NeuN)标记成熟神经元,观察NDRG2对海马齿状回神经干细胞增殖影响; 采用RT-PCR检测发状分裂相关增强子1(hairy and enhancer of split 1,Hes 1)、NDRG2 mRNA相对表达表达水平,并分析两者之间的相关性; 观察NDRG2参与癫痫发作后神经发生的可能机制。结果 癫痫组与对照组比较,DCX、Nestin、NeuN、Hes1、NDRG2蛋白相对表达水平在1和7 d这2个时间点有显著性增高,并随时间逐渐递增。结论 癫痫发作后海马NDRG2蛋白相对表达水平增高,与癫痫发作后海马齿状回的神经细胞增值时间具有一致性和相关性,NDRG2可能参与癫痫发作后海马齿状回的神经发生过程; 同时发现海马NDRG2表达增加和Hes1分子表达增加具有相关性,故推测NDRG2可能通过Hes1参与癫痫发作后海马齿状回的神经发生。     

Serotonergic reinnervation reverses lesion-induced decreases in PSA-NCAM labeling and proliferation of hippocampal cells in adult rats

Serotonin (5-HT) is believed to play a role in structural plasticity in the adult brain, and cell adhesion molecules may be involved in such adaptive processes. The present study sought to determine the effects of 5-HT denervation and reinnervation of the hippocampal formation on the expression of glial and neuronal markers and neurogenesis in adult rats. Injections of 5,7-dihydroxytryptamine (5,7-DHT) in the dorsal and medial raphe nuclei, producing a partial loss of 5-HT neurons, induced rapid and transient increases in glial fibrillary acidic protein immunoreactivity indicative of a reactive gliosis, but no changes in the S100beta or tenascin-C normally secreted by astroglial cells. In contrast, as long as the hippocampal formation was deprived of 5-HT innervation, significant decreases were observed in the number of granule cells expressing the highly polysialylated form of the neural cell adhesion molecule (PSA-NCAM) as well as the PSA-NCAM staining of the hilus in the dentate gyrus. Similar decreases in the number of newly generated granule cells labeled with bromodeoxyuridine were also detected during this time. All these effects were reversed later, when the hippocampal formation was reinnervated by 5-HT fibers. These results indicate that 5-HT is one factor which may regulate the number of granule cells proliferating in the adult dentate gyrus and thereafter expressing PSA-NCAM immunoreactive at the level of cell bodies, dendrites, and axonal paths (mossy fibers). They emphasize the critical role played by 5-HT in the neuronal organization of the hippocampus.     

Effects of short- and long-term (--)-deprenyl administration on mRNA for copper,zinc- and manganese-superoxide dismutase and glutathione peroxidase in rat brain

The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) continues to be expressed in the adult hippocampus, mainly in a subset of neurons located in the innermost portion of the granule cell layer. PSA-NCAM immunoreactive neurons have also been described outside this layer in humans, where they are severely reduced in schizophrenic brains. Given this important clinical implication, we were interested in finding whether similar neurons existed in the adult rat hippocampus and to characterize their distribution, morphology and phenotype. PSA-NCAM immunocytochemistry reveals labeled neurons in the subiculum, fimbria, alveus, hilus, and stratum oriens, lucidum and radiatum of CA3 and CA1. They are mainly distributed in the ventral hippocampus, and have polygonal or fusiform somata with multipolar or bipolar morphology. These neurons show long straight dendrites, which reach several strata and even enter the fimbria and the alveus. These dendrites are often varicose, appear devoid of excrescences and apparently do not show spines. Most of these neurons display GABA immunoreactivity and further analysis has shown that a subpopulation expresses calretinin, but not somatostatin, neuropeptide Y, parvalbumin, calbindin or NADPH diaphorase. Our study demonstrates that there is an important subpopulation of PSA-NCAM immunoreactive neurons, many of which can be considered interneurons, outside the rat granule cell layer, probably homologous to those described in the human hippocampus. The presence of the polysialylated form of NCAM in these neurons could indicate that they are undergoing continuous remodeling during adulthood and may have an important role in hippocampal structural plasticity.     

Region‐dependent and stage‐specific effects of stress,environmental enrichment,and antidepressant treatment on hippocampal neurogenesis

Chronic stress and depression are associated with decreased levels of hippocampal neurogenesis. On the other hand, antidepressants as well as environmental enrichment may rely in part on their pro‐neurogenic effects to improve cognition and mood. Because a functional heterogeneity has been consistently reported along the septo‐temporal axis of the hippocampus, regional changes in neurogenesis could differentially contribute to these effects and affect distinct hippocampal functions. Mapping these regional changes could therefore provide a better understanding of the function of newborn neurons. While some studies report region‐specific effects of stress and antidepressants on neurogenesis, it is unclear whether these changes affect distinct populations of newborn neurons according to their developmental stage in a region‐specific manner. By using endogenous markers and BrdU labeling we quantified the regional changes in cell proliferation and survival as well as in the number of neuronal progenitors and immature neurons following unpredictable chronic mild stress (UCMS), environmental enrichment (EE) and chronic fluoxetine (20 mg/kg/day) treatment along the septo‐temporal axis of the hippocampus. EE promoted cell proliferation and survival of 4‐week‐old newborn cells as well as increased the number and proportion of post‐mitotic immature neurons specifically within the septal hippocampus. By contrast, UCMS uniformly decreased cell proliferation, survival and immature newborn neurons but differentially affected progenitor cells with a decrease restricted to the temporal regions of the hippocampus. Whereas fluoxetine treatment in control mice affected proliferation and survival specifically in the temporal hippocampus, it reversed most of the UCMS‐induced alterations all along the septo‐temporal axis. These results highlight that different factors known for exerting a mood improving effect differentially regulate neurogenesis along the septo‐temporal axis of the hippocampus. Such region and stage specific effects may correlate to distinct functional properties of newborn neurons along the septo‐temporal axis of the hippocampus which may contribute differently to the pathophysiology of affective disorders. © 2013 Wiley Periodicals, Inc.     

Consolidation of memory for odour-reward association requires transient polysialylation of the neural cell adhesion molecule in the rat hippocampal dentate gyrus

Cell adhesion molecule function is involved in hippocampal synaptic plasticity and is associated with memory consolidation. At the infragranular zone of the dentate gyrus, neurons expressing the polysialylated form of the neural cell adhesion molecule (NCAM PSA) transiently increase their frequency at the 12-hr posttraining time in behaviours elicited by stressful stimuli, such as those associated with conditioned avoidance, water maze, and fear conditioning paradigms. To determine whether learning-induced modulation of NCAM polysialylation is limited to stressful paradigms, we employed a reward-based odour discrimination task. Animals show a rapid acquisition and recall of this task in terms of latency to identify the food-associated odour and the number of choice errors. Immunohistochemical procedures were employed to determine the change in NCAM PSA expression following task acquisition. NCAM PSA immunoreactivity in the hippocampal formation was most intense on the granule-like neurons in the infragranular zone of the dentate gyrus, and their frequency transiently increased in the 12-hr posttraining period. The nature of the transient increase in NCAM PSA-immunoreactive neurons was indistinguishable from that observed following avoidance conditioning or spatial learning, in that it occurred at the same time. The transient increase in NCAM PSA expression is suggested to facilitate dendritic elaboration in response to the acquisition of novel behavioural repertoires.     

CX3 chemokine receptor 1 deficiency leads to reduced dendritic complexity and delayed maturation of newborn neurons in the adult mouse hippocampus

Previous studies have shown that microglia impact the proliferation and differentiation of neurons during hippocampal neurogenesis via the fractalkine/CX3 chemokine receptor 1 (CX3CR1) signaling pathway. However, whether microglia can influence the maturation and dendritic growth of newborn neurons during hippocampal neurogenesis remains unclear. In the present study, we found that the number of doublecortin-positive cells in the hippocampus was decreased, and the dendritic length and number of intersections in newborn neurons in the hippocampus were reduced in transgenic adult mice with CX3CR1 deficiency (CX3CR1^GFP/GFP). Furthermore, after experimental seizures were induced with kainic acid in these CX3CR1-deficient mice, the expression of c-fos, a marker of neuronal activity, was reduced compared with wild-type mice. Collectively, the experimental findings indicate that the functional maturation of newborn neurons during hippocampal neurogenesis in adult mice is delayed by CX3CR1 deficiency.     

Mice deficient in the polysialyltransferase ST8SiaIV/PST-1 allow discrimination of the roles of neural cell adhesion molecule protein and polysialic acid in neural development and synaptic plasticity.

Functional properties of the neural cell adhesion molecule (NCAM) are strongly influenced by polysialylation. We used gene-targeting to generate mice lacking ST8SiaIV/PST-1, one of the polysialyltransferases responsible for addition of polysialic acid (PSA) to NCAM. Mice homozygous for the null mutation reveal normal development of gross anatomical features. In contrast to NCAM-deficient mice, olfactory precursor cells in the rostral migratory stream express PSA and follow their normal pathway. Furthermore, delamination of mossy fibers in the hippocampal CA3 region, as found in NCAM-deficient mice, does not occur in ST8SiaIV mutants. However, during postnatal development these animals show a decrease of PSA in most brain regions compared to wild-type animals. Loss of PSA in the presence of NCAM protein but in the absence of obvious histological changes allowed us to directly address the role of PSA in synaptic plasticity. Schaffer collateral-CA1 synapses, which express PSA in wild types, showed impaired long-term potentiation (LTP) and long-term depression (LTD) in adult mutants. This impairment was age-dependent, following the time course of developmental disappearance of PSA. Contrary to NCAM mutant mice, LTP in ST8SiaIV mutants was undisturbed at mossy fiber-CA3 synapses, which do not express PSA in wild-type mice. The results demonstrate an essential role for ST8SiaIV in synaptic plasticity in hippocampal CA1 synapses, whereas PSA produced by different polysialyltransferase or polysialyltransferases at early stages of differentiation regulates migration of neural precursor cells and correct lamination of mossy fibers. We suggest that NCAM but not PSA is likely to be important for LTP in the hippocampal CA3 region.