scholarly journals Congenital hypothyroidism impairs spine growth of dentate granule cells by downregulation of CaMKIV

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Qingying Tang ◽  
Shuxia Chen ◽  
Hui Wu ◽  
Honghua Song ◽  
Yongjun Wang ◽  
...  
Keyword(s):  
Congenital Hypothyroidism ◽  
Granule Cells ◽  
Spine Density ◽  
Drug Induced ◽  
Distinct Cell Type ◽  
Cognitive Behaviors ◽  
Dentate Granule Cells ◽  
Rat Pups ◽  
Cognitive Deficiency ◽  
Underlying Mechanisms

AbstractCongenital hypothyroidism (CH), a common neonatal endocrine disorder, can result in cognitive deficits if delay in diagnose and treatment. Dentate gyrus (DG) is the severely affected subregion of the hippocampus by the CH, where the dentate granule cells (DGCs) reside in. However, how CH impairs the cognitive function via affecting DGCs and the underlying mechanisms are not fully elucidated. In the present study, the CH model of rat pups was successfully established, and the aberrant dendrite growth of the DGCs and the impaired cognitive behaviors were observed in the offspring. Transcriptome analysis of hippocampal tissues following rat CH successfully identified that calcium/calmodulin-dependent protein kinase IV (CaMKIV) was the prominent regulator involved in mediating deficient growth of DGC dendrites. CaMKIV was shown to be dynamically regulated in the DG subregion of the rats following drug-induced CH. Interference of CaMKIV expression in the primary DGCs significantly reduced the spine density of dendrites, while addition of T3 to the primary DGCs isolated from CH pups could facilitate the spine growth of dendrites. Insights into relevant mechanisms revealed that CH-mediated CaMKIV deficiency resulted in the significant decrease of phosphorylated CREB in DGCs, in association with the abnormality of dendrites. Our results have provided a distinct cell type in hippocampus that is affected by CH, which would be beneficial for the treatment of CH-induced cognitive deficiency.

Glutamate Currents in Morphologically Identified Human Dentate Granule Cells in Temporal Lobe Epilepsy

1997 ◽  
Vol 77 (6) ◽  
pp. 3355-3369 ◽  
Author(s):  
Masako Isokawa ◽  
Michel Levesque ◽  
Itzhak Fried ◽  
Jerome Engel
Keyword(s):  
Nmda Receptor ◽  
Temporal Lobe Epilepsy ◽  
Temporal Lobe ◽  
Granule Cells ◽  
Spine Density ◽  
Postsynaptic Potentials ◽  
Dentate Granule Cells ◽  
Current Voltage ◽  
Current Voltage Relationship ◽  
Voltage Relationship

Isokawa, Masako, Michel Levesque, Itzhak Fried, and Jerome Engel, Jr. Glutamate currents in morphologically identified human dentate granule cells in temporal lobe epilepsy. J. Neurophysiol. 77: 3355–3369, 1997. Glutamate-receptor-mediated synaptic transmission was studied in morphologically identified hippocampal dentate granule cells (DGCs; n = 31) with the use of whole cell patch-clamp recording and intracellular injection of biocytin or Lucifer yellow in slices prepared from surgically removed medial temporal lobe specimens of epileptic patients (14 specimens from 14 patients). In the current-clamp recording, low-frequency stimulation of the perforant path generated depolarizing postsynaptic potentials that consisted of excitatory postsynaptic potentials and phase-inverted inhibitory postsynaptic potentials mediated by the γ-aminobutyric acid-A (GABAA) receptor at a resting membrane potential of −62.7 ± 2.0 (SE) mV. In the voltage-clamp recording, two glutamate conductances, a fast α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-receptor-mediated excitatory postsynaptic current (EPSC; AMPA EPSC) and a slowly developing N-methyl-d-aspartate (NMDA)-receptor-mediated EPSC (NMDA EPSC), were isolated in the presence of a GABAA receptor antagonist. NMDA EPSCs showed a voltage-dependent increase in conductance with depolarization by exhibiting an N-shaped current-voltage relationship. The slope conductance of the NMDA EPSC ranged from 1.1 to 9.4 nS in 31 DGCs, reaching up to twice the size of the AMPA conductance. This widely varying size of the NMDA conductance resulted in the generation of double-peaked EPSCs and a nonlinear increase of the slope conductance of up to 37.5 nS with positive membrane potentials, which resembled “paroxysmal currents,” in a subpopulation of the neurons. In contrast, AMPA EPSCs, which were isolated in the presence of an NMDA receptor antagonist (2-amino-5-phosphonovaleric acid), showed voltage-independent linear changes in the current-voltage relationship and were blocked by 6-cyano-7-nitroquinoxaline-2,3-dione. The AMPA conductance showed little variance, regardless of the size of the NMDA conductance of a given neuron. The average AMPA slope conductance was 5.28 ± 0.65 (SE) nS in 31 human DGCs. This value was similar to AMPA EPSC conductances in normal rat DGCs (5.35 ± 0.52 nS, mean ± SE; n = 55). Dendritic morphology and spine density were quantified in the individual DGCs to assess epileptic pathology. Dendritic spine density showed an inverse correlation ( r 2 = 0.705) with a slower rise time and a longer half-width of the excitatory postsynaptic potentials mediated by the NMDA receptor. It is concluded that both AMPA and NMDA EPSCs contribute to human DGC synaptic transmission in epileptic hippocampus. However, a wide range of changes in the slope conductance of the NMDA EPSCs suggests that the NMDA-receptor-mediated conductance could be altered in human epileptic DGCs. These changes may influence the generation of chronic subthreshold epileptogenic synaptic activity and give rise to pathological excitation leading to epileptic seizures and dendritic pathology.

scholarly journals Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Yuntao Duan ◽  
Shih-Hsiu Wang ◽  
Juan Song ◽  
Yevgeniya Mironova ◽  
Guo-li Ming ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Dendritic Spine ◽  
Granule Cells ◽  
Susceptibility Gene ◽  
Autism Spectrum ◽  
Spine Density ◽  
Dentate Granule Cells ◽  
Dendritic Spine Density ◽  
Spectrum Disorders ◽  
Semaphorin 5A

Human SEMAPHORIN 5A (SEMA5A) is an autism susceptibility gene; however, its function in brain development is unknown. In this study, we show that mouse Sema5A negatively regulates synaptogenesis in early, developmentally born, hippocampal dentate granule cells (GCs). Sema5A is strongly expressed by GCs and regulates dendritic spine density in a cell-autonomous manner. In the adult mouse brain, newly born Sema5A−/− GCs show an increase in dendritic spine density and increased AMPA-type synaptic responses. Sema5A signals through PlexinA2 co-expressed by GCs, and the PlexinA2-RasGAP activity is necessary to suppress spinogenesis. Like Sema5A−/− mutants, PlexinA2−/− mice show an increase in GC glutamatergic synapses, and we show that Sema5A and PlexinA2 genetically interact with respect to GC spine phenotypes. Sema5A−/− mice display deficits in social interaction, a hallmark of autism-spectrum-disorders. These experiments identify novel intra-dendritic Sema5A/PlexinA2 interactions that inhibit excitatory synapse formation in developmentally born and adult-born GCs, and they provide support for SEMA5A contributions to autism-spectrum-disorders.

scholarly journals Preferential targeting of lateral entorhinal inputs onto newly integrated granule cells

2017 ◽  
Author(s):  
Nicholas I. Woods ◽  
Christopher E. Vaaga ◽  
Christina Chatzi ◽  
Jaimie D. Adelson ◽  
Matthew F. Collie ◽  
...  
Keyword(s):  
Entorhinal Cortex ◽  
Spatial Information ◽  
Granule Cells ◽  
Molecular Layer ◽  
Critical Role ◽  
Perforant Path ◽  
Spine Density ◽  
Unique Role ◽  
Dentate Granule Cells ◽  
Episodic Memories

AbstractMature dentate granule cells in the hippocampus receive input from the entorhinal cortex via the perforant path in precisely arranged lamina, with medial entorhinal axons innervating the middle molecular layer and lateral entorhinal cortex axons innervating the outer molecular layer. Although vastly outnumbered by mature granule cells, adult-generated newborn granule cells play a unique role in hippocampal function, which has largely been attributed to their enhanced excitability and plasticity (Schmidt-Hieber et al., 2004; Ge et al., 2007). Inputs from the medial and lateral entorhinal cortex carry different informational content, thus the distribution of inputs onto newly integrated granules will affect their function in the circuit. Therefore we examined the functional innervation and synaptic maturation of newly-generated dentate granule cells using retroviral labeling in combination with selective optogenetic activation of medial or lateral entorhinal inputs. Our results indicate that lateral entorhinal inputs provide nearly all the functional innervation of newly integrated granule cells. Despite preferential functional targeting, the dendritic spine density of immature granule cells was not increased in the outer molecular layer compared to the middle molecular layer. However, chronic blockade of neurotransmitter release in medial entorhinal axons with tetanus toxin disrupted normal synapse development from both medial and lateral entorhinal inputs. Our results support a role for preferential lateral perforant path input onto newly generated neurons in mediating pattern separation, but also indicates that medial perforant path input is necessary for normal synaptic development.Significance StatementThe formation of episodic memories involves the integration of contextual and spatial information. Newly integrated neurons in the dentate gyrus of the hippocampus play a critical role in this process, despite constituting only a minor fraction of total granule cells. Here we demonstrate that these neurons preferentially receive information thought to convey the context of an experience - a unique role that each newly integrated granule cell serves for about a month before reaching maturity.

Liver and Statins: A Critical Appraisal of the Evidence

2019 ◽  
Vol 25 (42) ◽  
pp. 5835-5846 ◽  
Author(s):  
Anna Licata ◽  
Antonina Giammanco ◽  
Maria Giovanna Minissale ◽  
Salvatore Pagano ◽  
Salvatore Petta ◽  
...  
Keyword(s):  
Adverse Events ◽  
Association Studies ◽  
Organic Anion ◽  
Genome Wide Association Studies ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Organic Anion Transporting Polypeptide ◽  
Treatment And Prevention ◽  
Genome Wide ◽  
Underlying Mechanisms

Adverse drug reactions (ADRs) represent an important cause of morbidity and mortality worldwide. Statins are a class of drugs whose main adverse effects are drug-induced liver injury (DILI) and myopathy. Some of these may be predictable, due to their pharmacokinetic and pharmacodynamic properties, while others, unfortunately, are idiosyncratic. Genetic factors may also influence patient susceptibility to DILI and myopathy in the case of statins. This review will first discuss the role of statins in cardiovascular disease treatment and prevention and the underlying mechanisms of action. Furthermore, to explore the susceptibility of statin-induced adverse events such as myopathy and hepatotoxicity, it will then focus on the recent Genome-Wide Association Studies (GWAS) concerning the transporter genes, Cytochrome P450 (CYP), organic anion-transporting polypeptide (OATP) and ABCB1 and ABCC1, which seem to play a role in the development of clinically relevant adverse events. Finally, we appraise the evidence for and against the use of statins in metabolic syndrome and in HCV-infected patients, in terms of their safety and efficacy in cardiovascular events.

scholarly journals Neurogranin Regulates Adult-Born Olfactory Granule Cell Spine Density and Odor-Reward Associative Memory in Mice

2021 ◽  
Vol 22 (8) ◽  
pp. 4269
Author(s):  
Simona Gribaudo ◽  
Daniele Saraulli ◽  
Giulia Nato ◽  
Sara Bonzano ◽  
Giovanna Gambarotta ◽  
...  
Keyword(s):  
Associative Memory ◽  
Molecular Mechanisms ◽  
Granule Cells ◽  
Large Population ◽  
Adult Life ◽  
Long Term Potentiation ◽  
Spine Density ◽  
Knock Out ◽  
Memory Impairments ◽  
Dependent Learning

Neurogranin (Ng) is a brain-specific postsynaptic protein, whose role in modulating Ca2+/calmodulin signaling in glutamatergic neurons has been linked to enhancement in synaptic plasticity and cognitive functions. Accordingly, Ng knock-out (Ng-ko) mice display hippocampal-dependent learning and memory impairments associated with a deficit in long-term potentiation induction. In the adult olfactory bulb (OB), Ng is expressed by a large population of GABAergic granule cells (GCs) that are continuously generated during adult life, undergo high synaptic remodeling in response to the sensory context, and play a key role in odor processing. However, the possible implication of Ng in OB plasticity and function is yet to be investigated. Here, we show that Ng expression in the OB is associated with the mature state of adult-born GCs, where its active-phosphorylated form is concentrated at post-synaptic sites. Constitutive loss of Ng in Ng-ko mice resulted in defective spine density in adult-born GCs, while their survival remained unaltered. Moreover, Ng-ko mice show an impaired odor-reward associative memory coupled with reduced expression of the activity-dependent transcription factor Zif268 in olfactory GCs. Overall, our data support a role for Ng in the molecular mechanisms underlying GC plasticity and the formation of olfactory associative memory.

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