scholarly journals Oxytocin Regulates Synaptic Transmission in the Sensory Cortices in a Developmentally Dynamic Manner

2021 ◽  
Vol 15 ◽  
Author(s):  
Jing Zhang ◽  
Shu-Jing Li ◽  
Wanying Miao ◽  
Xiaodi Zhang ◽  
Jing-Jing Zheng ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Knockout Mice ◽  
Pyramidal Neurons ◽  
Neural Circuit ◽  
Brain Slices ◽  
Building Blocks ◽  
Sensory Experience ◽  
Conditional Knockout ◽  
Excitatory Synaptic Transmission ◽  
Loss Of Function

The development and stabilization of neuronal circuits are critical to proper brain function. Synapses are the building blocks of neural circuits. Here we examine the effects of the neuropeptide oxytocin on synaptic transmission in L2/3 pyramidal neurons of the barrel field of the primary somatosensory cortex (S1BF). We find that perfusion of oxytocin onto acute brain slices significantly increases the frequency of miniature excitatory postsynaptic currents (mEPSC) of S1BF L2/3 pyramidal neurons at P10 and P14, but reduces it at the later ages of P22 and P28; the transition occurs at around P18. Since oxytocin expression is itself regulated by sensory experience, we also examine whether the effects of oxytocin on excitatory synaptic transmission correlate with that of sensory experience. We find that, indeed, the effects of sensory experience and oxytocin on excitatory synaptic transmission of L2/3 pyramidal neurons both peak at around P14 and plateau around P18, suggesting that they regulate a specific form of synaptic plasticity in L2/3 pyramidal neurons, with a sensitive/critical period ending around P18. Consistently, oxytocin receptor (Oxtr) expression in glutamatergic neurons of the upper layers of the cerebral cortex peaks around P14. By P28, however, Oxtr expression becomes more prominent in GABAergic neurons, especially somatostatin (SST) neurons. At P28, oxytocin perfusion increases inhibitory synaptic transmission and reduces excitatory synaptic transmission, effects that result in a net reduction of neuronal excitation, in contrast to increased excitation at P14. Using oxytocin knockout mice and Oxtr conditional knockout mice, we show that loss-of-function of oxytocin affects baseline excitatory synaptic transmission, while Oxtr is required for oxytocin-induced changes in excitatory synaptic transmission, at both P14 and P28. Together, these results demonstrate that oxytocin has complex and dynamic functions in regulating synaptic transmission in cortical L2/3 pyramidal neurons. These findings add to existing knowledge of the function of oxytocin in regulating neural circuit development and plasticity.

scholarly journals Multiple Morphological Factors Underlie Experience-Dependent Cross-Modal Plasticity in the Developing Sensory Cortices

2019 ◽  
Vol 30 (4) ◽  
pp. 2418-2433
Author(s):  
Miao Wang ◽  
Zixian Yu ◽  
Guangying Li ◽  
Xiang Yu
Keyword(s):  
Synaptic Transmission ◽  
Pyramidal Neurons ◽  
Neural Circuit ◽  
Barrel Cortex ◽  
Dendritic Tree ◽  
Primary Auditory Cortex ◽  
Sensory Experience ◽  
Spine Density ◽  
In Utero Electroporation ◽  
Sensory Cortices

Abstract Sensory experience regulates the structural and functional wiring of sensory cortices. In previous work, we showed that whisker deprivation (WD) from birth not only reduced excitatory synaptic transmission of layer (L) 2/3 pyramidal neurons of the correspondent barrel cortex in mice, but also cross-modally reduced synaptic transmission of L2/3 pyramidal neurons in other sensory cortices. Here, we used in utero electroporation, in combination with optical clearing, to examine the main morphological components regulating neural circuit wiring, namely presynaptic bouton density, spine density, as well as dendrite and axon arbor lengths. We found that WD from P0 to P14 reduced presynaptic bouton density in both L4 and L2/3 inputs to L2/3 pyramidal neurons, as well as spine density across the dendritic tree of L2/3 pyramidal neurons, in the barrel field of the primary somatosensory cortex. The cross-modal effects in the primary auditory cortex were manifested mostly as reduced dendrite and axon arbor size, as well as reduced bouton density of L2/3 inputs. Increasing sensory experience by rearing mice in an enriched environment rescued the effects of WD. Together, these results demonstrate that multiple morphological factors contribute to experience-dependent structural plasticity during early wiring of the sensory cortices.

scholarly journals BACE1 Is Necessary for Experience-Dependent Homeostatic Synaptic Plasticity in Visual Cortex

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Emily Petrus ◽  
Hey-Kyoung Lee
Keyword(s):  
Synaptic Plasticity ◽  
Visual Cortex ◽  
Synaptic Transmission ◽  
Sensory Experience ◽  
Synaptic Function ◽  
Excitatory Synaptic Transmission ◽  
Early Gene ◽  
Dependent Manner ◽  
Homeostatic Synaptic Plasticity ◽  
Activity Dependent

Alzheimer’s disease (AD) is the most common form of age-related dementia, which is thought to result from overproduction and/or reduced clearance of amyloid-beta (Aβ) peptides. Studies over the past few decades suggest that Aβis produced in an activity-dependent manner and has physiological relevance to normal brain functions. Similarly, physiological functions forβ- andγ-secretases, the two key enzymes that produce Aβby sequentially processing the amyloid precursor protein (APP), have been discovered over recent years. In particular, activity-dependent production of Aβhas been suggested to play a role in homeostatic regulation of excitatory synaptic function. There is accumulating evidence that activity-dependent immediate early gene Arc is an activity “sensor,” which acts upstream of Aβproduction and triggers AMPA receptor endocytosis to homeostatically downregulate the strength of excitatory synaptic transmission. We previously reported that Arc is critical for sensory experience-dependent homeostatic reduction of excitatory synaptic transmission in the superficial layers of visual cortex. Here we demonstrate that mice lacking the major neuronalβ-secretase, BACE1, exhibit a similar phenotype: stronger basal excitatory synaptic transmission and failure to adapt to changes in visual experience. Our results indicate that BACE1 plays an essential role in sensory experience-dependent homeostatic synaptic plasticity in the neocortex.

scholarly journals Risperidone Mitigates Enhanced Excitatory Neuronal Function and Repetitive Behavior Caused by an ASD-Associated Mutation of SIK1

2021 ◽  
Vol 14 ◽  
Author(s):  
Moataz Badawi ◽  
Takuma Mori ◽  
Taiga Kurihara ◽  
Takahiro Yoshizawa ◽  
Katsuhiro Nohara ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Repetitive Behavior ◽  
Epileptic Encephalopathy ◽  
Excitatory Synaptic Transmission ◽  
Excitatory Synapses ◽  
Behavioral Deficits ◽  
Neural Excitability ◽  
Autistic Symptoms

Six mutations in the salt-inducible kinase 1 (SIK1)-coding gene have been identified in patients with early infantile epileptic encephalopathy (EIEE-30) accompanied by autistic symptoms. Two of the mutations are non-sense mutations that truncate the C-terminal region of SIK1. It has been shown that the C-terminal-truncated form of SIK1 protein affects the subcellular distribution of SIK1 protein, tempting to speculate the relevance to the pathophysiology of the disorders. We generated SIK1-mutant (SIK1-MT) mice recapitulating the C-terminal-truncated mutations using CRISPR/Cas9-mediated genome editing. SIK1-MT protein was distributed in the nucleus and cytoplasm, whereas the distribution of wild-type SIK1 was restricted to the nucleus. We found the disruption of excitatory and inhibitory (E/I) synaptic balance due to an increase in excitatory synaptic transmission and enhancement of neural excitability in the pyramidal neurons in layer 5 of the medial prefrontal cortex in SIK1-MT mice. We also found the increased repetitive behavior and social behavioral deficits in SIK1-MT mice. The risperidone administration attenuated the neural excitability and excitatory synaptic transmission, but the disrupted E/I synaptic balance was unchanged, because it also reduced the inhibitory synaptic transmission. Risperidone also eliminated the repetitive behavior but not social behavioral deficits. These results indicate that risperidone has a role in decreasing neuronal excitability and excitatory synapses, ameliorating repetitive behavior in the SIK1-truncated mice.

scholarly journals How could N-Methyl-D-Aspartate Receptor Antagonists Lead to Excitation Instead of Inhibition?

2018 ◽  
Vol 4 (2) ◽  
pp. 73-98 ◽  
Author(s):  
Tonghui Su ◽  
Yi Lu ◽  
Yang Geng ◽  
Wei Lu ◽  
Yelin Chen
Keyword(s):  
Synaptic Transmission ◽  
Low Dose ◽  
Excitatory Synaptic Transmission ◽  
Inhibitory Neurons ◽  
Allosteric Modulators ◽  
Loss Of Function ◽  
The Past ◽  
Aspartate Receptor ◽  
Nmdar Activation ◽  
Abnormal Brain

N-methyl-D-aspartate receptors (NMDARs) are a family of ionotropic glutamate receptors mainly known to mediate excitatory synaptic transmission and plasticity. Interestingly, low-dose NMDAR antagonists lead to increased, instead of decreased, functional connectivity; and they could cause schizophrenia- and/or antidepressant-like behavior in both humans and rodents. In addition, human genetic evidences indicate that NMDAR loss of function mutations underlie certain forms of epilepsy, a disease featured with abnormal brain hyperactivity. Together, they all suggest that under certain conditions, NMDAR activation actually lead to inhibition, but not excitation, of the global neuronal network. Apparently, these phenomena are rather counterintuitive to the receptor's basic role in mediating excitatory synaptic transmission. How could it happen? Recently, this has become a crucial question in order to fully understand the complexity of NMDAR function, particularly in disease. Over the past decades, different theories have been proposed to address this question. These include theories of “NMDARs on inhibitory neurons are more sensitive to antagonism”, or “basal NMDAR activity actually inhibits excitatory synapse”, etc. Our review summarizes these efforts, and also provides an introduction of NMDARs, inhibitory neurons, and their relationships with the related diseases. Advances in the development of novel NMDAR pharmacological tools, particularly positive allosteric modulators, are also included to provide insights into potential intervention strategies.

scholarly journals Forebrain HCN1 Channels Contribute to Hypnotic Actions of Ketamine

2013 ◽  
Vol 118 (4) ◽  
pp. 785-795 ◽  
Author(s):  
Cheng Zhou ◽  
Jennifer E. Douglas ◽  
Natasha N. Kumar ◽  
Shaofang Shu ◽  
Douglas A. Bayliss ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Pyramidal Neurons ◽  
Conditional Knockout ◽  
Membrane Properties ◽  
Membrane Hyperpolarization ◽  
Loss Of Righting Reflex ◽  
Neural Substrate ◽  
Righting Reflex ◽  
Mechanistic Basis ◽  
Hcn1 Channels

Abstract Background: Ketamine is a commonly used anesthetic, but the mechanistic basis for its clinically relevant actions remains to be determined. The authors previously showed that HCN1 channels are inhibited by ketamine and demonstrated that global HCN1 knockout mice are twofold less sensitive to hypnotic actions of ketamine. Although that work identified HCN1 channels as a viable molecular target for ketamine, it did not determine the relevant neural substrate. Methods: To localize the brain region responsible for HCN1-mediated hypnotic actions of ketamine, the authors used a conditional knockout strategy to delete HCN1 channels selectively in excitatory cells of the mouse forebrain. A combination of molecular, immunohistochemical, and cellular electrophysiologic approaches was used to verify conditional HCN1 deletion; a loss-of-righting reflex assay served to ascertain effects of forebrain HCN1 channel ablation on hypnotic actions of ketamine. Results: In conditional knockout mice, HCN1 channels were selectively deleted in cortex and hippocampus, with expression retained in cerebellum. In cortical pyramidal neurons from forebrain-selective HCN1 knockout mice, effects of ketamine on HCN1-dependent membrane properties were absent; notably, ketamine was unable to evoke membrane hyperpolarization or enhance synaptic inputs. Finally, the EC50 for ketamine-induced loss-of-righting reflex was shifted to significantly higher concentrations (by approximately 31%). Conclusions: These data indicate that forebrain principal cells represent a relevant neural substrate for HCN1-mediated hypnotic actions of ketamine. The authors suggest that ketamine inhibition of HCN1 shifts cortical neuron electroresponsive properties to contribute to ketamine-induced hypnosis.

scholarly journals Autism spectrum disorder-like behavior caused by reduced excitatory synaptic transmission in pyramidal neurons of mouse prefrontal cortex

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiroaki Sacai ◽  
Kazuto Sakoori ◽  
Kohtarou Konno ◽  
Kenichiro Nagahama ◽  
Honoka Suzuki ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Prefrontal Cortex ◽  
Social Interaction ◽  
Synaptic Transmission ◽  
Pyramidal Neurons ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Spectrum Disorder ◽  
Excitatory Synaptic Transmission ◽  
Layer 2

Abstract Autism spectrum disorder (ASD) is thought to result from deviation from normal development of neural circuits and synaptic function. Many genes with mutation in ASD patients have been identified. Here we report that two molecules associated with ASD susceptibility, contactin associated protein-like 2 (CNTNAP2) and Abelson helper integration site-1 (AHI1), are required for synaptic function and ASD-related behavior in mice. Knockdown of CNTNAP2 or AHI1 in layer 2/3 pyramidal neurons of the developing mouse prefrontal cortex (PFC) reduced excitatory synaptic transmission, impaired social interaction and induced mild vocalization abnormality. Although the causes of reduced excitatory transmission were different, pharmacological enhancement of AMPA receptor function effectively restored impaired social behavior in both CNTNAP2- and AHI1-knockdown mice. We conclude that reduced excitatory synaptic transmission in layer 2/3 pyramidal neurons of the PFC leads to impaired social interaction and mild vocalization abnormality in mice.

Sign in / Sign up

Export Citation Format

Share Document