Neuroligin 1 Regulates Autistic-Like Repetitive Behavior through Modulating the Activity of Striatal D2 Receptor-Expressing Medium Spiny Neurons.

Restricted and repetitive behavior (RRB) is a primary symptom of autism spectrum disorder (ASD), which poses a significant risk to individuals' health and is becoming increasingly prevalent. However, the specific cellular and neural circuit mechanisms underlying the generation of RRB remain unclear. In this study, it is reported that the absence of the ASD-related protein Neuroligin 1 (NLGN1) in dopamine receptor D2-expressing medium spiny neurons (D2-MSNs) in the dorsal striatum is associated with the duration and frequency of self-grooming and digging behaviors.

Astrocytic neuroligin 3 regulates social memory and synaptic plasticity through adenosine signaling in male mice.

Social memory impairment is a key symptom of many brain disorders, but its underlying mechanisms remain unclear. Neuroligins (NLGs) are a family of cell adhesion molecules essential for synapse development and function and their dysfunctions are linked to neurodevelopmental and neuropsychiatric disorders, including autism and schizophrenia. Although NLGs are extensively studied in neurons, their role in glial cells is poorly understood.

Novel Social Stimulation Ameliorates Memory Deficit in Alzheimer's Disease Model through Activating α-Secretase.

As the most common form of dementia in the world, Alzheimer's disease (AD) is a progressive neurological disorder marked by cognitive and behavioral impairment. According to previous researches, abundant social connections shield against dementia. However, it is still unclear how exactly social interactions benefit cognitive abilities in people with AD and how this process is used to increase their general cognitive performance.

Small-molecule targeting AMPA-mediated excitotoxicity has therapeutic effects in mouse models for multiple sclerosis.

While most research and treatments for multiple sclerosis (MS) focus on autoimmune reactions causing demyelination, it is possible that neurodegeneration precedes the autoimmune response. Hence, glutamate receptor antagonists preventing excitotoxicity showed promise in MS animal models, though blocking glutamate signaling prevents critical neuronal functions. This study reports the discovery of a small molecule that prevents AMPA-mediated excitotoxicity by targeting an allosteric binding site.

Universal, label-free, single-molecule visualization of DNA origami nanodevices across biological samples using origamiFISH.

Structural DNA nanotechnology enables the fabrication of user-defined DNA origami nanostructures (DNs) for biological applications. However, the role of DN design during cellular interactions and subsequent biodistribution remain poorly understood. Current methods for tracking DN fates in situ, including fluorescent-dye labelling, suffer from low sensitivity and dye-induced artifacts.

Inhibition of Rac1 in ventral hippocampal excitatory neurons improves social recognition memory and synaptic plasticity.

Rac1 is critically involved in the regulation of the actin cytoskeleton, neuronal structure, synaptic plasticity, and memory. Rac1 overactivation is reported in human patients and animal models of Alzheimer's disease (AD) and contributes to their spatial memory deficits, but whether Rac1 dysregulation is also important in other forms of memory deficits is unknown. In addition, the cell types and synaptic mechanisms involved remain unclear.

The omega-3 hydroxy fatty acid 7()-HDHA is a high-affinity PPARα ligand that regulates brain neuronal morphology.

The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα) is emerging as an important target in the brain for the treatment or prevention of cognitive disorders. The identification of high-affinity ligands for brain PPARα may reveal the mechanisms underlying the synaptic effects of this receptor and facilitate drug development. Here, using an affinity purification-untargeted mass spectrometry (AP-UMS) approach, we identified an endogenous, selective PPARα ligand, 7()-hydroxy-docosahexaenoic acid [7()-HDHA].

The GR-FKBP51 interaction modulates fear memory but not spatial or recognition memory.

The glucocorticoid receptor (GR) forms a protein complex with FKBP51 that is increased in post-traumatic stress disorder (PTSD) and by fear conditioned learning. Disrupting the GR-FKBP51 complex with a synthetic peptide can block the storage or retrieval of fear conditioned memories, which could be a novel approach to the alleviate fear associated memory in PTSD. However, a potential unacceptable side effect could be the impairment of other types of memory.

Characterizing neurotrophic factor-induced synaptic growth in primary mouse neuronal cultures.

Neurotrophic factors and their signaling cascades play important roles in synaptic growth, which can be investigated in cultured primary neurons to better control the concentrations and timing of neurotrophic factor treatment. Here, we provide a protocol detailing the preparation of cultured primary mouse neurons and the neurotrophic factor treatment. We then describe electrophysiological recording of synaptic transmission, immunocytochemistry of AMPA receptor expression, and imaging analysis of dendritic spines.

Disruption of PAK3 Signaling in Social Interaction Induced cFos Positive Cells Impairs Social Recognition Memory.

P21-activated kinase 3 (PAK3) gene mutations are linked to several neurodevelopmental disorders, but the underlying mechanisms remain unclear. In this study, we used a tetracycline-inducible system to control the expression of a mutant PAK3 (mPAK3) protein in immediate early gene, namely cFos, positive cells to disrupt PAK signaling, specifically in cells activated by social interaction in transgenic mice. We show that the expression of mPAK3-GFP proteins was in cFos-expressing excitatory and inhibitory neurons in various brain regions, such as the cortex and hippocampus, commonly activated during learning and memory.

Rho Signaling in Synaptic Plasticity, Memory, and Brain Disorders.

Memory impairments are associated with many brain disorders such as autism, Alzheimer's disease, and depression. Forming memories involves modifications of synaptic transmission and spine morphology. The Rho family small GTPases are key regulators of synaptic plasticity by affecting various downstream molecules to remodel the actin cytoskeleton.

LIM-Kinases in Synaptic Plasticity, Memory, and Brain Diseases.

Learning and memory require structural and functional modifications of synaptic connections, and synaptic deficits are believed to underlie many brain disorders. The LIM-domain-containing protein kinases (LIMK1 and LIMK2) are key regulators of the actin cytoskeleton by affecting the actin-binding protein, cofilin. In addition, LIMK1 is implicated in the regulation of gene expression by interacting with the cAMP-response element-binding protein.

Overexpression of LIMK1 in hippocampal excitatory neurons improves synaptic plasticity and social recognition memory in APP/PS1 mice.

Accumulating evidence indicates that the actin regulator cofilin is overactivated in Alzheimer's Disease (AD), but whether this abnormality contributes to synaptic and cognitive impairments in AD is unclear. In addition, the brain region and cell types involved remain unknown. In this study, we specifically manipulate LIMK1, the key protein kinase that phosphorylates and inactivates cofilin, in the hippocampus of APP/PS1 transgenic mice.

Genetic manipulations of AMPA glutamate receptors in hippocampal synaptic plasticity.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are the principal mediators of fast excitatory synaptic transmission and they are required for various forms of synaptic plasticity, including long-term potentiation (LTP) and depression (LTD), which are key mechanisms of learning and memory. AMPARs are tetrameric complexes assembled from four subunits (GluA1-4), however, the lack of subunit-specific pharmacological tools has made the assessment of individual subunits difficult. The application of genetic techniques, particularly gene targeting, allows for precise manipulation and dissection of each subunit in the regulation of neuronal function and behaviour.

Disruption of the autism-related gene Pak1 causes stereocilia disorganization, hair cell loss, and deafness in mice.

Several clinical studies have reported that hearing loss is correlated with autism in children. However, little is known about the underlying mechanism between hearing loss and autism. p21-activated kinases (PAKs) are a family of serine/threonine kinases that can be activated by multiple signaling molecules, particularly the Rho family of small GTPases.

Transcriptome Regulation by Oncogenic ALK Pathway in Mammalian Cortical Development Revealed by Single-Cell RNA Sequencing.

Precise regulation of embryonic neurodevelopment is crucial for proper structural organization and functioning of the adult brain. The key molecular machinery orchestrating this process remains unclear. Anaplastic lymphoma kinase (ALK) is an oncogenic receptor-type protein tyrosine kinase that is specifically and transiently expressed in developing nervous system.

PQBP1 promotes translational elongation and regulates hippocampal mGluR-LTD by suppressing eEF2 phosphorylation.

Eukaryotic elongation factor 2 (eEF2) mediates translocation of peptidyl-tRNA from the ribosomal A site to the P site to promote translational elongation. Its phosphorylation on Thr56 by its single known kinase eEF2K inactivates it and inhibits translational elongation. Extensive studies have revealed that different signal cascades modulate eEF2K activity, but whether additional factors regulate phosphorylation of eEF2 remains unclear.

Norwogonin attenuates hypoxia-induced oxidative stress and apoptosis in PC12 cells.

Background: Norwogonin is a natural flavone with three phenolic hydroxyl groups in skeletal structure and has excellent antioxidant activity. However, the neuroprotective effect of norwogonin remains unclear. Here, we investigated the protective capacity of norwogonin against oxidative damage elicited by hypoxia in PC12 cells.

The Role of ADF/Cofilin in Synaptic Physiology and Alzheimer's Disease.

Actin-depolymerization factor (ADF)/cofilin, a family of actin-binding proteins, are critical for the regulation of actin reorganization in response to various signals. Accumulating evidence indicates that ADF/cofilin also play important roles in neuronal structure and function, including long-term potentiation and depression. These are the most extensively studied forms of long-lasting synaptic plasticity and are widely regarded as cellular mechanisms underlying learning and memory.

The Requirement of the C-Terminal Domain of GluA1 in Different Forms of Long-Term Potentiation in the Hippocampus Is Age-Dependent.

Long-term potentiation (LTP) at glutamatergic synapses is an extensively studied form of long-lasting synaptic plasticity widely regarded as the cellular basis for learning and memory. At the CA1 synapse, there are multiple forms of LTP with distinct properties. Although AMPA glutamate receptors (AMPARs) are a key target of LTP expression, whether they are required in all forms of LTP remains unclear.

Neuroligin 2 regulates absence seizures and behavioral arrests through GABAergic transmission within the thalamocortical circuitry.

Epilepsy and autism spectrum disorders (ASD) are two distinct brain disorders but have a high rate of co-occurrence, suggesting shared pathogenic mechanisms. Neuroligins are cell adhesion molecules important in synaptic function and ASD, but their role in epilepsy remains unknown. In this study, we show that Neuroligin 2 (NLG2) knockout mice exhibit abnormal spike and wave discharges (SWDs) and behavioral arrests characteristic of absence seizures.