Spine Density In Hippocampal Neurons Research Articles

High-fat diet induces learning and memory impairments and hippocampal dendritic spine density in rats

Objective To explore the influence of high fat diet on learning and memory, as well as the alteration of the number of neurons and morphology of dendritic spines in rat hippocampi. Methods 24 male adult SD rats were randomly assigned to high fat diet group or control group. The rats were fed with high-fat diet or standard laboratory rodent chow diet for 12 weeks. Learning and memory were tested by Morris water maze and object recognition tests, and mood and motor ability were tested by open field tests.Golgi staining detected dendritic spine density of hippocampal neurons, and Nissl staining was used to observe the number of hippocampal neurons and pathological changes. Results High-fat diet induced rat spatial learning deficits, which was demonstrated by the prolonged escape latency ((38.50±9.70)s, (20.08±7.35)s, (19.96±10.56)s, (22.75±12.51)s, (14.56±4.82)s) compared with the control ((33.61±12.41)s, (14.25±7.89)s, (15.06±7.59)s, (5.53±2.81)s, (4.7±1.58)s). The spatial memory deficits demonstrated that the latency reaching platform ((30.46±21.43)s) was prolonged compared with control ((5.18±1.33)s). The working memory was impaired, which was demonstrated by the prolonged escape latency compared with control group(P<0.05). Discrimination index lowered than control group ((0.67±0.12) vs (0.81±0.08)), and the difference was significant (P=0.038), but no anxiety behaviors were observed(P=0.461). The neuron number of hippocampal neurons and dendritic spine density were significantly lowered than those in the control group((209.73±24.29)vs(262.2±18.94), (17.9±2.84)vs(21.93±2.56), respectively)(P<0.05). Conclusion Intake of high-fat diet can impair learning and memory in rats, as well as decrease the number of neurons and the density of dendritic spines in the hippocampus. Key words: High fat diet; Cognitive impairment; Hippocampus; Dendritic spine

ICLIP identifies novel roles for SAFB1 in regulating RNA processing and neuronal function.

BackgroundSAFB1 is a RNA binding protein implicated in the regulation of multiple cellular processes such as the regulation of transcription, stress response, DNA repair and RNA processing. To gain further insight into SAFB1 function we used iCLIP and mapped its interaction with RNA on a genome wide level.ResultsiCLIP analysis found SAFB1 binding was enriched, specifically in exons, ncRNAs, 3’ and 5’ untranslated regions. SAFB1 was found to recognise a purine-rich GAAGA motif with the highest frequency and it is therefore likely to bind core AGA, GAA, or AAG motifs. Confirmatory RT-PCR experiments showed that the expression of coding and non-coding genes with SAFB1 cross-link sites was altered by SAFB1 knockdown. For example, we found that the isoform-specific expression of neural cell adhesion molecule (NCAM1) and ASTN2 was influenced by SAFB1 and that the processing of miR-19a from the miR-17-92 cluster was regulated by SAFB1. These data suggest SAFB1 may influence alternative splicing and, using an NCAM1 minigene, we showed that SAFB1 knockdown altered the expression of two of the three NCAM1 alternative spliced isoforms. However, when the AGA, GAA, and AAG motifs were mutated, SAFB1 knockdown no longer mediated a decrease in the NCAM1 9–10 alternative spliced form. To further investigate the association of SAFB1 with splicing we used exon array analysis and found SAFB1 knockdown mediated the statistically significant up- and downregulation of alternative exons. Further analysis using RNAmotifs to investigate the frequency of association between the motif pairs (AGA followed by AGA, GAA or AAG) and alternative spliced exons found there was a highly significant correlation with downregulated exons. Together, our data suggest SAFB1 will play an important physiological role in the central nervous system regulating synaptic function. We found that SAFB1 regulates dendritic spine density in hippocampal neurons and hence provide empirical evidence supporting this conclusion.ConclusionsiCLIP showed that SAFB1 has previously uncharacterised specific RNA binding properties that help coordinate the isoform-specific expression of coding and non-coding genes. These genes regulate splicing, axonal and synaptic function, and are associated with neuropsychiatric disease, suggesting that SAFB1 is an important regulator of key neuronal processes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-015-0220-7) contains supplementary material, which is available to authorized users.

Neuritin can normalize neural deficits of Alzheimer's disease.

Reductions in hippocampal neurite complexity and synaptic plasticity are believed to contribute to the progressive impairment in episodic memory and the mild cognitive decline that occur particularly in the early stages of Alzheimer's disease (AD). Despite the functional and therapeutic importance for patients with AD, intervention to rescue or normalize dendritic elaboration and synaptic plasticity is scarcely provided. Here we show that overexpression of neuritin, an activity-dependent protein, promoted neurite outgrowth and maturation of synapses in parallel with enhanced basal synaptic transmission in cultured hippocampal neurons. Importantly, exogenous application of recombinant neuritin fully restored dendritic complexity as well as spine density in hippocampal neurons prepared from Tg2576 mice, whereas it did not affect neurite branching of neurons from their wild-type littermates. We also showed that soluble recombinant neuritin, when chronically infused into the brains of Tg2576 mice, normalized synaptic plasticity in acute hippocampal slices, leading to intact long-term potentiation. By revealing the protective actions of soluble neuritin against AD-related neural defects, we provide a potential therapeutic approach for patients with AD.

Δ9-THC-Caused Synaptic and Memory Impairments Are Mediated through COX-2 Signaling

Marijuana has been used for thousands of years as a treatment for medical conditions. However, untoward side effects limit its medical value. Here, we show that synaptic and cognitive impairments following repeated exposure to Δ(9)-tetrahydrocannabinol (Δ(9)-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids in thebrain. COX-2 induction by Δ(9)-THC is mediated via CB1 receptor-coupled G protein βγ subunits. Pharmacological or genetic inhibition of COX-2 blocks downregulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ(9)-THC exposures. Ablation of COX-2 also eliminates Δ(9)-THC-impaired hippocampal long-term synaptic plasticity, working, and fear memories. Importantly, the beneficial effects of decreasing β-amyloid plaques and neurodegeneration by Δ(9)-THC in Alzheimer's disease animals are retained in the presence of COX-2 inhibition. These results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2.

Effects of triptolide on degeneration of dendritic spines induced by Aβ1–40 injection in rat hippocampus

Although the exact cause of Alzheimer's disease (AD) remains elusive, mounting evidence continues to support the involvement of neuroinflammation in the development of AD. Triptolide isolated from the herb Tripterygium wilfordii Hook F has anti-inflammatory and immunosuppressive activities. In this study, we observed the effects of triptolide on dendritic spines of hippocampal neurons in model rats with AD. Thirty male SD rats were randomly divided into control group, AD model group and triptolide-treated group. The AD model group was made with bilateral microinjection of aggregated beta-amyloid protein (Aβ)1-40 into hippocampus in rats and the control group rats were injected with normal saline in the same way. The triptolide-treated group rats were administered triptolide intraperitoneally for 30 days after microinjection of aggregated Aβ1-40 into hippocampus. Dendritic morphology of hippocampal neurons in each group was analyzed using Golgi staining and ImageJ software. Our data showed that the total number of intersection points of dendrites and spine density in hippocampal neurons in the AD model group were decreased as compared with the control group. However, the total number of intersection points of dendrites and spine density in hippocampal neurons in the triptolide-treated group were increased as compared with the AD model group. Our results indicate that triptolide can alleviate the degeneration of dendritic spines in hippocampal neurons in model rats with AD.

FoxO6 regulates memory consolidation and synaptic function

The FoxO family of transcription factors is known to slow aging downstream from the insulin/IGF (insulin-like growth factor) signaling pathway. The most recently discovered FoxO isoform in mammals, FoxO6, is highly enriched in the adult hippocampus. However, the importance of FoxO factors in cognition is largely unknown. Here we generated mice lacking FoxO6 and found that these mice display normal learning but impaired memory consolidation in contextual fear conditioning and novel object recognition. Using stereotactic injection of viruses into the hippocampus of adult wild-type mice, we found that FoxO6 activity in the adult hippocampus is required for memory consolidation. Genome-wide approaches revealed that FoxO6 regulates a program of genes involved in synaptic function upon learning in the hippocampus. Consistently, FoxO6 deficiency results in decreased dendritic spine density in hippocampal neurons in vitro and in vivo. Thus, FoxO6 may promote memory consolidation by regulating a program coordinating neuronal connectivity in the hippocampus, which could have important implications for physiological and pathological age-dependent decline in memory.

Hippocampal CA1 pyramidal neurons of Mecp2 mutant mice show a dendritic spine phenotype only in the presymptomatic stage.

Alterations in dendritic spines have been documented in numerous neurodevelopmental disorders, including Rett Syndrome (RTT). RTT, an X chromosome-linked disorder associated with mutations in MECP2, is the leading cause of intellectual disabilities in women. Neurons in Mecp2-deficient mice show lower dendritic spine density in several brain regions. To better understand the role of MeCP2 on excitatory spine synapses, we analyzed dendritic spines of CA1 pyramidal neurons in the hippocampus of Mecp2tm1.1Jae male mutant mice by either confocal microscopy or electron microscopy (EM). At postnatal-day 7 (P7), well before the onset of RTT-like symptoms, CA1 pyramidal neurons from mutant mice showed lower dendritic spine density than those from wildtype littermates. On the other hand, at P15 or later showing characteristic RTT-like symptoms, dendritic spine density did not differ between mutant and wildtype neurons. Consistently, stereological analyses at the EM level revealed similar densities of asymmetric spine synapses in CA1 stratum radiatum of symptomatic mutant and wildtype littermates. These results raise caution regarding the use of dendritic spine density in hippocampal neurons as a phenotypic endpoint for the evaluation of therapeutic interventions in symptomatic Mecp2-deficient mice. However, they underscore the potential role of MeCP2 in the maintenance of excitatory spine synapses.

Shank Expression Is Sufficient to Induce Functional Dendritic Spine Synapses in Aspiny Neurons

Shank proteins assemble glutamate receptors with their intracellular signaling apparatus and cytoskeleton at the postsynaptic density. Whether Shank plays a role in spinogenesis and synaptogenesis remained unclear. Here, we report that knock-down of Shank3/prolinerich synapse-associated protein-2 by RNA interference reduces spine density in hippocampal neurons. Moreover, transgene expression of Shank 3 is sufficient to induce functional dendritic spines in aspiny cerebellar neurons. Transfected Shank protein recruits functional glutamate receptors, increases the number and size of synaptic contacts, and increases amplitude, frequency, and the AMPA component of miniature EPSCs, similar to what is observed during synapse developmental maturation. Mutation/deletion approaches indicate that these effects require interactions of Shank3 with the glutamate receptor complex. Consistent with this observation, chronic treatment with glutamate receptor antagonists alters maturation of the Shank3-induced spines. These results strongly suggest that Shank proteins and the associated glutamate receptors participate in a concerted manner to form spines and functional synapses.