Neonatal hyperglycemia alters the neurochemical profile,dendritic arborization and gene expression in the developing rat hippocampus

Hyperglycemia (blood glucose concentration >150 mg/dL) is common in extremely low gestational age newborns (ELGANs; birth at <28 week gestation). Hyperglycemia increases the risk of brain injury in the neonatal period. The long‐term effects are not well understood. In adult rats, hyperglycemia alters hippocampal energy metabolism. The effects of hyperglycemia on the developing hippocampus were studied in rat pups. In Experiment 1, recurrent hyperglycemia of graded severity (moderate hyperglycemia (moderate‐HG), mean blood glucose 214.6 ± 11.6 mg/dL; severe hyperglycemia (severe‐HG), 338.9 ± 21.7 mg/dL; control, 137.7 ± 2.6 mg/dL) was induced from postnatal day (P) 3 to P12. On P30, the hippocampal neurochemical profile was determined using in vivo ¹H MR spectroscopy. Dendritic arborization in the hippocampal CA1 region was determined using microtubule‐associated protein (MAP)‐2 immunohistochemistry. In Experiment 2, continuous hyperglycemia (mean blood glucose 275.3 ± 25.8 mg/dL; control, 142.3 ± 2.6 mg/dL) was induced from P2 to P6 by injecting streptozotocin (STZ) on P2. The mRNA expression of glycogen synthase 1 (Gys1), lactate dehydrogenase (Ldh), glucose transporters 1 (Glut1) and 3 (Glut3) and monocarboxylate transporters 1 (Mct1), 2 (Mct2) and 4 (Mct4) in the hippocampus was determined on P6. In Experiment 1, MRS demonstrated lower lactate concentration and glutamate/glutamine (Glu/Gln) ratio in the severe‐HG group, compared with the control group (p < 0.05). Phosphocreatine/creatine ratio was higher in both hyperglycemia groups (p < 0.05). MAP‐2 histochemistry demonstrated longer apical segment length, indicating abnormal synaptic efficacy in both hyperglycemia groups (p < 0.05). Experiment 2 showed lower Glut1, Gys1 and Mct4 expression and higher Mct1 expression in the hyperglycemia group, relative to the control group (p < 0.05). These results suggest that hyperglycemia alters substrate transport, lactate homeostasis, dendritogenesis and Glu‐Gln cycling in the developing hippocampus. Abnormal neurochemical profile and dendritic structure due to hyperglycemia may partially explain the long‐term hippocampus‐mediated cognitive deficits in human ELGANs.     

Posttraumatic Early Epilepsy and Minor Head Injury

The mechanism of “early epilepsy” sometimes observed after trivial head injury is controversial. Also, the risk of developing late epilepsy after these convulsions, so far, have not been clear.

In order to clarify the mechanism of this posttraumatic early epilepsy after trivial head injury, an attempt was made to observe the role of extracellular potassium ion concentration ([K⁺]_o) in initiation of seizure discharges, in both adult cats and kittens, with K-sensitive microelectrodes.

It was concluded that an increase of [K⁺]_o was not a simple factor for epileptogenesis but minor head injury actually increased seizure slisceptability of immature cat cortex.     

TrkB signaling in parvalbumin-positive interneurons is critical for gamma-band network synchronization in hippocampus

Although brain-derived neurotrophic factor (BDNF) is known to regulate circuit development and synaptic plasticity, its exact role in neuronal network activity remains elusive. Using mutant mice (TrkB-PV(-/-)) in which the gene for the BDNF receptor, tyrosine kinase B receptor (trkB), has been specifically deleted in parvalbumin-expressing, fast-spiking GABAergic (PV+) interneurons, we show that TrkB is structurally and functionally important for the integrity of the hippocampal network. The amplitude of glutamatergic inputs to PV+ interneurons and the frequency of GABAergic inputs to excitatory pyramidal cells were reduced in the TrkB-PV(-/-) mice. Functionally, rhythmic network activity in the gamma-frequency band (30-80 Hz) was significantly decreased in hippocampal area CA1. This decrease was caused by a desynchronization and overall reduction in frequency of action potentials generated in PV+ interneurons of TrkB-PV(-/-) mice. Our results show that the integration of PV+ interneurons into the hippocampal microcircuit is impaired in TrkB-PV(-/-) mice, resulting in decreased rhythmic network activity in the gamma-frequency band.     

MAP2 Splicing is Altered in Huntington's Disease

Dendritic alteration of striatal medium spiny neurons is one of the earliest morphological abnormalities in Huntington's disease (HD). The main microtubule‐associated protein in dendrites is MAP2. The low‐molecular weight isoforms of MAP2 (LMW‐MAP2) are the juvenile forms resulting from exclusion of the sequence encoded by exons E7‐E9 and are downregulated after the early stages of neuronal development when E7‐E9 exon‐including high‐molecular weight isoforms (HMW‐MAP2) are favored. Splicing alteration has recently been proposed to contribute to HD in view of two pathogenic missplicing events resulting in a highly toxic N‐terminal version of mutant huntingtin and in a detrimental imbalance in MAP Tau isoforms with three or four tubulin‐binding repeats. Both splicing events are postulated targets of the SR splicing factor SRSF6 which has recently been reported to be dramatically altered in HD. SR proteins often regulate functionally related sets of genes and SRSF6 targets are enriched in genes involved in brain organogenesis including several actin‐and tubulin‐binding proteins. Here we hypothesized that MAP2 might be target of SRSF6 and altered in HD. By SRSF6 knockdown in neuroblastoma cells, we demonstrate that splicing of MAP2 E7‐E9 exons is affected by SRSF6. We then show a disbalance in LMW and HMW MAP2 mRNA isoforms in HD striatum in favor of the juvenile LMW forms together with a decrease in total MAP2 mRNA. This is accompanied by a global decrease in total MAP2 protein due to almost total disappearance of HMW‐MAP2 isoforms with preservation of LMW‐MAP2 isoforms. Accordingly, the predominant dendritic MAP2 staining in striatal neuropil of control subjects is absent in HD cases. In these, MAP2‐immunoreactivity is faint and restricted to neuronal cell bodies often showing a sharp boundary at the base of dendrites. Together, our results highlight the importance of splicing alteration in HD and suggest that MAP2 alteration contributes to dendritic atrophy.     

Cajal-Retzius细胞调节锥体细胞顶树突发育及海马片层化的形成

目的 探讨Cajal-Retzius(CR)细胞与海马锥体细胞顶树突发育以及海马片层化形成的关系.方法 利用DiI示踪法标记槽通路和穿通通路,并采用微管蛋白(tubulin)、神经元核抗原(NeuN)和Reelin免疫荧光染色法,对120例小鼠苔藓纤维的发生、锥体细胞顶树突的生长以及海马分子层Reelin阳性的CR细胞...     

Intensification of maternal care by double‐mothering boosts cognitive function and hippocampal morphology in the adult offspring

Mice born from high care‐giving females show, as adults, low anxiety levels, decreased responsiveness to stress, and substantial improvements in cognitive function and hippocampal plasticity. Given the relevance of this issue for preventing emotional and cognitive abnormalities in high‐risk subjects, this study examines the possibility to further enhance the beneficial effects observed in the progeny by augmenting maternal care beyond the highest levels females can display in standard laboratory conditions. This was produced by placing a second female with the dam and its litter in the rearing cage from the partum until pups weaning. Maternal behavior of all females was scored during the first week postpartum, and behavioral indices of emotionality, prestress and poststress corticosterone levels, cognitive performance, and hippocampal morphology were assessed in the adult offspring. We found that pups reared by female dyads received more maternal care than pups reared by dams alone, but as adults, they did not exhibit alterations in emotionality or corticosterone response estimated in basal condition or following restraint stress. Conversely, they showed enhanced performance in hippocampal‐dependent tasks including long‐term object discrimination, reactivity to spatial change, and fear conditioning together with an increase in dendritic length and spine density in the CA1 region of the hippocampus. In general, the beneficial effects of dyadic maternal care were stronger when both the females were lactating. This study demonstrates that double‐mothering exerts a long‐term positive control on cognitive function and hippocampal neuronal connectivity. This experimental manipulation, especially if associated with increased feeding, might offer a concrete possibility to limit or reverse the consequences of negative predisposing conditions for normal cognitive development. © 2010 Wiley‐Liss, Inc.     

Retina ganglion cell degeneration in glaucoma: an opportunity missed? A review

Retinal ganglion cell degeneration has been reported in a range of experimental models of glaucoma. Manifest as pruning of retinal ganglion cell dendrites, it is likely to influence both the function and viability of affected cells. Electrophysiological studies in primate glaucoma have shown that affected cells retain some function and could therefore form a neural substrate for the recovery of visual function in glaucoma. Clinical studies in which the intraocular pressure is reduced have suggested that some improvement in retinal function may be possible in hypotensive eyes. These experimental studies highlight the importance of establishing the extent to which retinal ganglion cell degeneration occurs in human glaucoma. If substantial numbers of degenerating retinal ganglion cells are present in glaucoma, they could present an ideal target for the recovery of vision.     

TrkB-mediated activation of geranylgeranyltransferase I promotes dendritic morphogenesis

Dendrite morphogenesis is regulated by neuronal activity or neurotrophins, which may function by activating intrinsic signaling proteins, including Rho family GTPases. Here we report that activity- and brain-derived neurotrophic factor (BDNF)–dependent dendritic morphogenesis requires activation of geranylgeranyltransferase I (GGT), a prenyltransferase that mediates lipid modification of Rho GTPases. Dendritic arborization in cultured hippocampal neurons was promoted by over-expression of GGT, and reduced by inhibition or down-regulation of GGT. Furthermore, GGT was activated by neuronal depolarization or BDNF, both of which promote dendritic arborization, in cultured hippocampal neurons. Moreover, exploration of a novel environment caused activation of GGT in the mice hippocampus, suggesting that neural activity activates GGT in vivo. Interestingly, GGT was physically associated with tropomyosin-related kinase B (TrkB), the receptor for BDNF, and this association was enhanced by depolarization. Disrupting the GGT-TrkB interaction or down-regulating GGT activity attenuated depolarization- or BDNF-induced dendrite development. Finally, the GGT effect on dendrite arborization was prevented by over-expressing Rac1 with the prenylation site deleted or mutated. Thus depolarization- or BDNF-dependent dendrite development may be mediated by GGT-induced prenylation of Rho GTPases.     

Increased proximal bifurcation of CA1 pyramidal apical dendrites in sema3A mutant mice

Semaphorin‐3A (Sema3A) is an attractive guidance molecule for cortical apical dendrites. To elucidate the role of Sema3A in hippocampal dendritic formation, we examined the Sema3A expression pattern in the perinatal hippocampal formation and analyzed hippocampal dendrites of the brains from young adult sema3A mutant mice. Sema3A protein was predominantly expressed in the hippocampal plate and the inner marginal zone at the initial period of apical dendritic growth. Neuropilin‐1 and plexin‐A, the receptor components for Sema3A, were also localized in the same regions. The Golgi impregnation method revealed that in wildtype mice more than 90% of hippocampal CA1 pyramidal neurons extended a single trunk or apical trunks bifurcated in stratum radiatum. Seven percent of the pyramidal neurons showed proximal bifurcation of apical trunks in stratum pyramidale or at the border of the stratum pyramidale and stratum radiatum. In sema3A mutant mice, proximally bifurcated apical dendrites were increased to 32%, while the single apical dendritic pyramidal neurons were decreased. We designate this phenotype in sema3A mutant mice as “proximal bifurcation.” In the dissociated culture system, approximately half of the hippocampal neurons from wildtype mice resembled pyramidal neurons, which possess a long, thick, and tapered dendrite. In contrast, only 30% of the neurons from sema3A mutants exhibited pyramidal‐like morphology. Proximal bifurcation of CA1 pyramidal neurons was also increased in the mutant mice of p35, an activator of cyclin‐dependent kinase 5 (Cdk5). Thus, Sema3A may facilitate the initial growth of CA1 apical dendrites via the activation of p35/Cdk5, which may in turn signal hippocampal development. J. Comp. Neurol. 516:360–375, 2009. © 2009 Wiley‐Liss, Inc.