Glutamatergic dysregulation

Parkinson's disease involves multiple neurotransmitter systems beyond the classical dopaminergic circuit, but their influence on structural and functional alterations is not well understood. Here, we use patient-specific causal brain modeling to identify latent neurotransmitter receptor-mediated mechanisms contributing to Parkinson's disease progression. Combining the spatial distribution of 15 receptors from post-mortem autoradiography with 6 neuroimaging-derived pathological factors, we detect a diverse set of receptors influencing gray matter atrophy, functional activity dysregulation, microstructural degeneration, and dendrite and dopaminergic transporter loss...

Involvement of the glutamate system, particularly N-methyl-D-aspartate (NMDA) receptor hypofunction, has long been postulated to be part of the pathophysiology of schizophrenia. An important development is provided by recent data that strongly implicate GRIN2A, the gene encoding the NR2A (GluN2A) NMDA receptor subunit, in the aetiology of the disorder. Rare variants and common variants are both robustly associated with genetic risk for schizophrenia. Some of the rare variants are point mutations likely affecting channel function, but most are predicted to cause protein truncation and thence result, like the common variants, in reduced gene expression...

BACKGROUND: Internalising disorders are highly prevalent emotional dysregulations during preadolescence but clinical decision-making is hampered by high heterogeneity. During this period impulsivity represents a major risk factor for psychopathological trajectories and may act on this heterogeneity given the controversial anxiety-impulsivity relationships. However, how impulsivity contributes to the heterogeneous symptomatology, neurobiology, neurocognition and clinical trajectories in preadolescent internalising disorders remains unclear...

In mouse primary visual cortex (V1), familiar stimuli evoke significantly altered responses when compared to novel stimuli. This stimulus-selective response plasticity (SRP) was described originally as an increase in the magnitude of visual evoked potentials (VEPs) elicited in layer 4 (L4) by familiar phase-reversing grating stimuli. SRP is dependent on NMDA receptors (NMDAR) and has been hypothesized to reflect potentiation of thalamocortical synapses in L4. However, recent evidence indicates that the synaptic modifications that manifest as SRP do not occur on L4 principal cells...

Glucocorticoids administered early in infancy can affect the architectonic organization of brain structures, particularly those with a postnatal development and resulting in long-term deficits of neuromotor function and cognition. The present study was undertaken to study the effects of daily corticosterone (CORT) injections at a pharmacological dose from postnatal days 8-15 on cerebellar and hippocampal development in mouse pups. Gene expression status for trophic factors involved in synaptic development and function as well as measures of layer thickness associated with cytochrome oxidase labelling were analyzed in the hippocampus, hypothalamus, and specific cerebellar lobules involved in motor control...

The Par3 polarity protein is critical for subcellular compartmentalization in different developmental processes. Variants of PARD3 , which encodes PAR3, are associated with intelligence and neurodevelopmental disorders. However, the role of Par3 in glutamatergic synapse formation and cognitive functions in vivo remains unknown. Here, we show that forebrain conditional knockout of Par3 leads to an increase in long, thin dendritic spines without significantly impacting mushroom spines in vivo . In addition, we observed a decrease in the amplitude of miniature excitatory postsynaptic currents...

Multimodal astrocyte-neuron communications govern brain circuitry assembly and function1 . For example, through rapid glutamate release, astrocytes can control excitability, plasticity and synchronous activity2,3 of synaptic networks, while also contributing to their dysregulation in neuropsychiatric conditions4-7 . For astrocytes to communicate through fast focal glutamate release, they should possess an apparatus for Ca2+ -dependent exocytosis similar to neurons8-10 . However, the existence of this mechanism has been questioned11-13 owing to inconsistent data14-17 and a lack of direct supporting evidence...

A genetically valid animal model could transform our understanding of schizophrenia (SCZ) disease mechanisms. Rare heterozygous loss-of-function (LoF) mutations in GRIN2A, encoding a subunit of the NMDA receptor, greatly increase the risk of SCZ. By transcriptomic, proteomic, and behavioral analyses, we report that heterozygous Grin2a mutant mice show (1) large-scale gene expression changes across multiple brain regions and in neuronal (excitatory and inhibitory) and non-neuronal cells (astrocytes and oligodendrocytes), (2) evidence of hypoactivity in the prefrontal cortex (PFC) and hyperactivity in the hippocampus and striatum, (3) an elevated dopamine signaling in the striatum and hypersensitivity to amphetamine-induced hyperlocomotion (AIH), (4) altered cholesterol biosynthesis in astrocytes, (5) a reduction in glutamatergic receptor signaling proteins in the synapse, and (6) an aberrant locomotor pattern opposite of that induced by antipsychotic drugs...

Genome-wide association studies indicate that allele variants in MIR137, the host gene of microRNA-137 (miR137), confer an increased risk of schizophrenia (SCZ). Aberrant expression of miR137 and its targets, many of which regulate synaptic functioning, are also associated with an increased risk of SCZ. Thus, miR137 represents an attractive target aimed at correcting the molecular basis for synaptic dysfunction in individuals with high genetic risk for SCZ. Advancements in nanotechnology utilize lipid nanoparticles (LNPs) to transport and deliver therapeutic RNA...

Obsessive-compulsive disorder (OCD) is characterised by excessive intrusive thoughts that may cause an individual to engage in compulsive behaviours. Frontline pharmacological treatments (i.e., selective serotonin reuptake inhibitors (SSRIs)) leave approximately 40% of patients refractory to treatment. To investigate the possibility of novel pharmacological therapies for OCD, as well as the potential mechanisms underlying its pathology, we used the Sapap3 knockout (KO) mouse model of OCD, which exhibits increased anxiety and compulsive grooming behaviours...

BACKGROUND: Striatal medium spiny neurons (MSNs) are preferentially lost in Huntington's disease. Genomic studies also implicate a direct role for MSNs in schizophrenia, a psychiatric disorder known to involve cortical neuron dysfunction. It remains unknown whether the two diseases share similar MSN pathogenesis or if neuronal deficits can be attributed to cell type-dependent biological pathways. Transcription factor BCL11B, which is expressed by all MSNs and deep layer cortical neurons, was recently proposed to drive selective neurodegeneration in Huntington's disease and identified as a candidate risk gene in schizophrenia...

AIMS: The basolateral amygdala (BLA) plays an integral role in anxiety disorders (such as post traumatic stress disorder) stem from dysregulated fear memory. The excitability of glutamatergic neurons in the BLA correlates with fear memory, and the afterhyperpolarization current (IAHP ) mediated by small-conductance calcium-activated potassium channel subtype 2 (SK2) dominates the excitability of glutamatergicneurons. This study aimed to explore the effect of MPP2 interacts with SK2 in the excitability of glutamatergic neurons in the BLA and the extinction of conditioned fear in mice...

The role of astrocytes in Alzheimer's disease is often disregarded. Hence, characterization of astrocytes along their early evolution toward Alzheimer would be greatly beneficial. However, due to their exquisite responsiveness, in vivo studies are difficult. So public microarray data of hippocampal homogenates from (healthy) young, (healthy) elder and elder with mild cognitive impairment (MCI) were subjected to re-analysis by a multi-step computational pipeline. Ontologies and pathway analyses were compared after determining the differential genes that, belonging to astrocytes, have splice forms...

Learning and memory mainly rely on correct synaptic function in the hippocampus and other brain regions. In Parkinson's disease, subtle cognitive deficits may even precede motor signs early in the disease. Hence, we set out to unravel the earliest hippocampal synaptic alterations associated with human α-synuclein overexpression prior to and soon after the appearance of cognitive deficits in a parkinsonism model. We bilaterally injected adeno-associated viral vectors encoding A53T-mutated human α-synuclein into the substantia nigra of rats, and evaluated them 1, 2, 4 and 16 weeks post-inoculation by immunohistochemistry and immunofluorescence to study degeneration and distribution of α-synuclein in the midbrain and hippocampus...

While most of the efforts to uncover mechanisms contributing to bipolar disorder (BD) focused on phenotypes at the mature neuron stage, little research has considered events that may occur during earlier timepoints of neurodevelopment. Further, although aberrant calcium (Ca2+ ) signaling has been implicated in the etiology of this condition, the possible contribution of store-operated Ca2+ entry (SOCE) is not well understood. Here, we report Ca2+ and developmental dysregulations related to SOCE in BD patient induced pluripotent stem cell (iPSC)-derived neural progenitor cells (BD-NPCs) and cortical-like glutamatergic neurons...

Stroke and late-onset Alzheimer's disease (AD) are risk factors for each other; the comorbidity of these brain disorders in aging individuals represents a significant challenge in basic research and clinical practice. The similarities and differences between stroke and AD in terms of pathogenesis and pathophysiology, however, have rarely been comparably reviewed. Here, we discuss the research background and recent progresses that are important and informative for the comorbidity of stroke and late-onset AD and related dementia (ADRD)...

Neurotransmitters serve as chemical messengers playing a crucial role in information processing throughout the nervous system, and are essential for healthy physiological and behavioural functions in the body. Neurotransmitter systems are classified as cholinergic, glutamatergic, GABAergic, dopaminergic, serotonergic, histaminergic, or aminergic systems, depending on the type of neurotransmitter secreted by the neuron, allowing effector organs to carry out specific functions by sending nerve impulses. Dysregulation of a neurotransmitter system is typically linked to a specific neurological disorder...

Major depression disorder (MDD) is one of the most common psychiatric disorders and one of the leading causes of disability in worldwide. Both inflammation and GABAergic dysfunction have been implicated in the pathophysiology of MDD. Caspase-1, a classic inflammatory caspase, regulates AMPARs-mediated glutamatergic neurotransmission. However, the role of caspase-1 in chronic stress-induced GABAergic dysfunction remains largely unknown. In this study, we found that serum and hippocampal caspase-1-IL-1β levels increased significantly in chronic restraint stress (CRS) mice, and a significant negative correlation occurred between levels of caspase-1 and depression-like behaviors...

Retrotrapezoid nucleus (RTN) neurons in the brainstem regulate the ventilatory response to hypercarbia. It is unclear how PHOX2B-polyalanine repeat mutations (PHOX2B-PARMs) alter the function of PHOX2B and perturb the formation of RTN neurons. Here, we generated human brainstem organoids (HBSOs) with RTN-like neurons from human pluripotent stem cells. Single-cell transcriptomics revealed that expression of PHOX2B+7Ala PARM alters the differentiation trajectories of the hindbrain neurons and hampers the formation of the RTN-like neurons in HBSOs...

Background: Gestational sleep apnea affects 8-26% of pregnancies and can increase the risk for autism spectrum disorder (ASD) in offspring. ASD is a neurodevelopmental disorder associated with social dysfunction, repetitive behaviors, anxiety, and cognitive impairment. To examine the relationship between gestational sleep apnea and ASD-associated behaviors, we used a chronic intermittent hypoxia (CIH) protocol between gestational days (GD) 15-19 in pregnant rats to model late gestational sleep apnea. We hypothesized that late gestational CIH would produce sex- and age-specific social, mood, and cognitive impairments in offspring...