scholarly journals Somatostatin enhances visual processing and perception by suppressing excitatory inputs to parvalbumin-positive interneurons in V1

2020 ◽  
Vol 6 (17) ◽  
pp. eaaz0517 ◽  
Author(s):  
You-Hyang Song ◽  
Yang-Sun Hwang ◽  
Kwansoo Kim ◽  
Hyoung-Ro Lee ◽  
Jae-Hyun Kim ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Visual Processing ◽  
Excitatory Synaptic Transmission ◽  
Inhibitory Neurons ◽  
Excitatory Synapses ◽  
Gabaergic Interneurons ◽  
V1 Neurons ◽  
Block Face ◽  
Fast Spiking ◽  
Freely Moving

Somatostatin (SST) is a neuropeptide expressed in a major subtype of GABAergic interneurons in the cortex. Despite abundant expression of SST and its receptors, their modulatory function in cortical processing remains unclear. Here, we found that SST application in the primary visual cortex (V1) improves visual discrimination in freely moving mice and enhances orientation selectivity of V1 neurons. We also found that SST reduced excitatory synaptic transmission to parvalbumin-positive (PV+) fast-spiking interneurons but not to regular-spiking neurons. Last, using serial block-face scanning electron microscopy (SBEM), we found that axons of SST+ neurons in V1 often contact other axons that exhibit excitatory synapses onto the soma and proximal dendrites of the PV+ neuron. Collectively, our results demonstrate that the neuropeptide SST improves visual perception by enhancing visual gain of V1 neurons via a reduction in excitatory synaptic transmission to PV+ inhibitory neurons.

scholarly journals Restoration of FMRP expression in adult V1 neurons rescues visual deficits in a mouse model of fragile X syndrome

2021 ◽  
Author(s):  
Chaojuan Yang ◽  
Yonglu Tian ◽  
Feng Su ◽  
Yangzhen Wang ◽  
Mengna Liu ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Visual Processing ◽  
Fragile X ◽  
Autism Spectrum ◽  
Inhibitory Neurons ◽  
Local Network ◽  
V1 Neurons ◽  
Processing Deficits

AbstractMany people affected by fragile X syndrome (FXS) and autism spectrum disorders have sensory processing deficits, such as hypersensitivity to auditory, tactile, and visual stimuli. Like FXS in humans, loss of Fmr1 in rodents also cause sensory, behavioral, and cognitive deficits. However, the neural mechanisms underlying sensory impairment, especially vision impairment, remain unclear. It remains elusive whether the visual processing deficits originate from corrupted inputs, impaired perception in the primary sensory cortex, or altered integration in the higher cortex, and there is no effective treatment. In this study, we used a genetic knockout mouse model (Fmr1KO), in vivo imaging, and behavioral measurements to show that the loss of Fmr1 impaired signal processing in the primary visual cortex (V1). Specifically, Fmr1KO mice showed enhanced responses to low-intensity stimuli but normal responses to high-intensity stimuli. This abnormality was accompanied by enhancements in local network connectivity in V1 microcircuits and increased dendritic complexity of V1 neurons. These effects were ameliorated by the acute application of GABAA receptor activators, which enhanced the activity of inhibitory neurons, or by reintroducing Fmr1 gene expression in knockout V1 neurons in both juvenile and young-adult mice. Overall, V1 plays an important role in the visual abnormalities of Fmr1KO mice and it could be possible to rescue the sensory disturbances in developed FXS and autism patients.

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 Implications of Extended Inhibitory Neuron Development

2021 ◽  
Vol 22 (10) ◽  
pp. 5113
Author(s):  
Jae-Yeon Kim ◽  
Mercedes F. Paredes
Keyword(s):  
Neural Circuit ◽  
Inhibitory Neuron ◽  
Postnatal Period ◽  
Specific Pattern ◽  
Inhibitory Neurons ◽  
Gabaergic Interneuron ◽  
Gabaergic Interneurons ◽  
Neuron Development ◽  
Cortical Regions ◽  
Circuit Formation

A prolonged developmental timeline for GABA (γ-aminobutyric acid)-expressing inhibitory neurons (GABAergic interneurons) is an amplified trait in larger, gyrencephalic animals. In several species, the generation, migration, and maturation of interneurons take place over several months, in some cases persisting after birth. The late integration of GABAergic interneurons occurs in a region-specific pattern, especially during the early postnatal period. These changes can contribute to the formation of functional connectivity and plasticity, especially in the cortical regions responsible for higher cognitive tasks. In this review, we discuss GABAergic interneuron development in the late gestational and postnatal forebrain. We propose the protracted development of interneurons at each stage (neurogenesis, neuronal migration, and network integration), as a mechanism for increased complexity and cognitive flexibility in larger, gyrencephalic brains. This developmental feature of interneurons also provides an avenue for environmental influences to shape neural circuit formation.

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