Faculty Opinions recommendation of A Novel Human CAMK2A Mutation Disrupts Dendritic Morphology and Synaptic Transmission, and Causes ASD-Related Behaviors.

Glutamatergic synaptic transmission is essential for binaural auditory processing in birds and mammals. Using whole cell voltage clamp recordings, we characterized the development of synaptic ionotropic glutamate receptor (iGluR) function from auditory neurons in the chick nucleus laminaris (NL), the first nucleus responsible for binaural processing. We show that synaptic transmission is mediated by AMPA- and N-methyl-d-aspartate (NMDA)-type glutamate receptors (AMPA-R and NMDA-R, respectively) when hearing is first emerging and dendritic morphology is being established across different sound frequency regions. Puff application of glutamate agonists at embryonic day 9 (E9) revealed that both iGluRs are functionally present prior to synapse formation (E10). Between E11 and E19, the amplitude of isolated AMPA-R currents from high-frequency (HF) neurons increased 14-fold. A significant increase in the frequency of spontaneous events is also observed. Additionally, AMPA-R currents become faster and more rectifying, suggesting developmental changes in subunit composition. These developmental changes were similar in all tonotopic regions examined. However, mid- and low-frequency neurons exhibit fewer spontaneous events and evoked AMPA-R currents are smaller, slower, and less rectifying than currents from age-matched HF neurons. The amplitude of isolated NMDA-R currents from HF neurons also increased, reaching a peak at E17 and declining sharply by E19, a trend consistent across tonotopic regions. With age, NMDA-R kinetics become significantly faster, indicating a developmental switch in receptor subunit composition. Dramatic increases in the amplitude and speed of glutamatergic synaptic transmission occurs in NL during embryonic development. These changes are first seen in HF neurons suggesting regulation by peripheral inputs and may be necessary to enhance coincidence detection of binaural auditory information.

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STXBP5/tomosyn regulates the small RhoA GTPase to control the dendritic stability of neurons and the surface expression of AMPA receptors

10.1101/617845 ◽

2019 ◽

Author(s):

Wenjuan Shen ◽

Michaela B.C. Kilander ◽

Morgan S. Bridi ◽

Jeannine A. Frei ◽

Robert F. Niescier ◽

...

Keyword(s):

Synaptic Transmission ◽

Ampa Receptors ◽

Surface Expression ◽

Autism Spectrum ◽

Dendritic Morphology ◽

Dendritic Arborization ◽

Neuronal Morphology ◽

Rhoa Gtpase ◽

Wd40 Domain

AbstractTomosyn, a protein encoded by syntaxin-1-binding protein 5 (STXBP5) gene, has a well-established presynaptic role in the inhibition of neurotransmitter release and the reduction of synaptic transmission by its conical interaction with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) machinery. The postsynaptic role of tomosyn in dendritic arborization, spine stability, and trafficking of ionotropic glutamate receptors remains to be elucidated. We used short hairpin RNA (shRNA) to knock down tomosyn in mouse primary neurons to evaluate the postsynaptic cellular function and molecular signaling regulated by tomosyn. Knockdown of tomosyn led to an increase of RhoA GTPase activity accompanied by compromised dendritic arborization, loss of dendritic spines, decreased surface expression of AMPA receptors, and reduced miniature excitatory postsynaptic current (mEPSC) frequency. Inhibiting RhoA signaling was sufficient to rescue the abnormal dendritic morphology and the surface expression of AMPA receptors. The function of tomosyn regulating RhoA is mediated through the N-terminal WD40 motif, where two variants each carrying a single nucleotide mutation in this region, were found in individuals with autism spectrum disorder (ASD). We demonstrated that these variants displayed loss-of-function phenotypes. Unlike the wild-type tomosyn, these two variants failed to restore the reduced dendritic complexity, spine density, as well as decreased surface expression of AMPA receptors in tomosyn knockdown neurons. This study uncovers a critical role of tomosyn, independent of its interaction with the SNARE machinery, in maintaining neuronal function by inhibiting RhoA activity. Further analysis of tomosyn variants also provides a potential mechanism for explaining cellular pathology in ASD.Significance StatementThis study unveils a vital role of tomosyn in the maintenance of neuronal morphology, basal synaptic transmission, and AMPA receptor surface expression that is distinct from its presynaptic role. Tomosyn affects dendritic stability and glutamate receptor trafficking via the regulation of the Rho signaling pathway and this interaction is likely independent of the interaction with the dendritic SNARE complex, such as syntaxin-4. The WD40 domain of tomosyn is necessary to conduct the Rho regulation and two autism-associated variants localized at the WD40 domain perturb this function. The current study reveals a novel molecular link between dendritic stability and synaptic function, which could advance a greater understanding of the cellular pathologies involved in neurodevelopmental disorders, such as ASD.

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Cordycepin Ameliorates Synaptic Dysfunction and Dendrite Morphology Damage of Hippocampal CA1 via A1R in Cerebral Ischemia

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2021.783478 ◽

2021 ◽

Vol 15 ◽

Author(s):

Zhao-Hui Chen ◽

Yuan-Yuan Han ◽

Ying-Jie Shang ◽

Si-Yi Zhuang ◽

Jun-Ni Huang ◽

...

Keyword(s):

Cerebral Ischemia ◽

Synaptic Transmission ◽

Learning And Memory ◽

Hippocampal Slices ◽

Long Term Potentiation ◽

Dendritic Morphology ◽

Synaptic Dysfunction ◽

Dendrite Morphology ◽

Memory Impairments ◽

Hippocampal Ca1

Cordycepin exerted significant neuroprotective effects and protected against cerebral ischemic damage. Learning and memory impairments after cerebral ischemia are common. Cordycepin has been proved to improve memory impairments induced by cerebral ischemia, but its underlying mechanism has not been revealed yet. The plasticity of synaptic structure and function is considered to be one of the neural mechanisms of learning and memory. Therefore, we investigated how cordycepin benefits dendritic morphology and synaptic transmission after cerebral ischemia and traced the related molecular mechanisms. The effects of cordycepin on the protection against ischemia were studied by using global cerebral ischemia (GCI) and oxygen-glucose deprivation (OGD) models. Behavioral long-term potentiation (LTP) and synaptic transmission were observed with electrophysiological recordings. The dendritic morphology and histological assessment were assessed by Golgi staining and hematoxylin-eosin (HE) staining, respectively. Adenosine A1 receptors (A1R) and adenosine A2A receptors (A2AR) were evaluated with western blotting. The results showed that cordycepin reduced the GCI-induced dendritic morphology scathing and behavioral LTP impairment in the hippocampal CA1 area, improved the learning and memory abilities, and up-regulated the level of A1R but not A2AR. In the in vitro experiments, cordycepin pre-perfusion could alleviate the hippocampal slices injury and synaptic transmission cripple induced by OGD, accompanied by increased adenosine content. In addition, the protective effect of cordycepin on OGD-induced synaptic transmission damage was eliminated by using an A1R antagonist instead of A2AR. These findings revealed that cordycepin alleviated synaptic dysfunction and dendritic injury in ischemic models by modulating A1R, which provides new insights into the pharmacological mechanisms of cordycepin for ameliorating cognitive impairment induced by cerebral ischemia.

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An intracellular study of synaptic transmission and dendritic morphology in sympathetic neurons of the chick embryo

Developmental Brain Research ◽

10.1016/0165-3806(85)90073-2 ◽

1985 ◽

Vol 22 (1) ◽

pp. 99-111 ◽

Cited By ~ 13

Author(s):

Stuart E. Dryer ◽

Vincent A. Chiappinelli

Keyword(s):

Chick Embryo ◽

Synaptic Transmission ◽

Sympathetic Neurons ◽

Dendritic Morphology ◽

Intracellular Study

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Dendritic morphology, synaptic transmission, and activity of mature granule cells born following pilocarpine-induced status epilepticus in the rat

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2015.00384 ◽

2015 ◽

Vol 9 ◽

Cited By ~ 8

Author(s):

Fei Gao ◽

Xueying Song ◽

Dexiao Zhu ◽

Xiaochen Wang ◽

Aijun Hao ◽

...

Keyword(s):

Status Epilepticus ◽

Synaptic Transmission ◽

Granule Cells ◽

Dendritic Morphology

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Deficiency of Intellectual Disability-Related Gene Brpf1 Attenuated Hippocampal Excitatory Synaptic Transmission and Impaired Spatial Learning and Memory Ability

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.711792 ◽

2021 ◽

Vol 9 ◽

Author(s):

Weiwei Xian ◽

Jingli Cao ◽

Xiangshan Yuan ◽

Guoxiang Wang ◽

Qiuyan Jin ◽

...

Keyword(s):

Intellectual Disability ◽

Synaptic Transmission ◽

Learning And Memory ◽

Spatial Learning ◽

Hippocampal Neurons ◽

Dendritic Morphology ◽

Excitatory Synaptic Transmission ◽

Spatial Learning And Memory ◽

Memory Ability ◽

Cultured Hippocampal Neurons

Patients with monoallelic bromodomain and PHD finger-containing protein 1 (BRPF1) mutations showed intellectual disability. The hippocampus has essential roles in learning and memory. Our previous work indicated that Brpf1 was specifically and strongly expressed in the hippocampus from the perinatal period to adulthood. We hypothesized that mouse Brpf1 plays critical roles in the morphology and function of hippocampal neurons, and its deficiency leads to learning and memory deficits. To test this, we performed immunofluorescence, whole-cell patch clamp, and mRNA-Seq on shBrpf1-infected primary cultured hippocampal neurons to study the effect of Brpf1 knockdown on neuronal morphology, electrophysiological characteristics, and gene regulation. In addition, we performed stereotactic injection into adult mouse hippocampus to knock down Brpf1 in vivo and examined the learning and memory ability by Morris water maze. We found that mild knockdown of Brpf1 reduced mEPSC frequency of cultured hippocampal neurons, before any significant changes of dendritic morphology showed. We also found that Brpf1 mild knockdown in the hippocampus showed a decreasing trend on the spatial learning and memory ability of mice. Finally, mRNA-Seq analyses showed that genes related to learning, memory, and synaptic transmission (such as C1ql1, Gpr17, Htr1d, Glra1, Cxcl10, and Grin2a) were dysregulated upon Brpf1 knockdown. Our results showed that Brpf1 mild knockdown attenuated hippocampal excitatory synaptic transmission and reduced spatial learning and memory ability, which helps explain the symptoms of patients with BRPF1 mutations.

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