GluN2D-containing NMDA receptors in parvalbumin neurons in the nucleus accumbens regulate nocifensive responses in neuropathic pain.

Neuropathic pain presents a significant challenge, with its underlying mechanisms still not fully understood. Here, we investigated the role of GluN2C- and GluN2D-containing NMDA receptors in the development of neuropathic pain induced by cisplatin, a widely used chemotherapeutic agent. Through genetic and pharmacological strategies, we found that GluN2D-containing NMDA receptors play a targeted role in regulating cisplatin-induced neuropathic pain (CINP), while sparing inflammatory or acute pain responses.

Local delivery of soluble fractalkine (CX3CL1) peptide restores ribbon synapses after noise-induced cochlear synaptopathy.

Cochlear ribbon synapses between sensory inner hair cells (IHCs) and spiral ganglion neurons (SGNs) are vulnerable to rapid and primary damage and/or loss due to noise overexposure. Such damaged ribbon synapses can repair spontaneously in mouse and guinea pig. However, the mechanisms for synaptic repair are unclear.

GluN2D subunit-containing NMDA receptors regulate reticular thalamic neuron function and seizure susceptibility.

Thalamic regulation of cortical function is important for several behavioral aspects including attention and sensorimotor control. This region has also been studied for its involvement in seizure activity. Among the NMDA receptor subunits GluN2C and GluN2D are particularly enriched in several thalamic nuclei including nucleus reticularis of the thalamus (nRT).

GluN2D Subunit in Parvalbumin Interneurons Regulates Prefrontal Cortex Feedforward Inhibitory Circuit and Molecular Networks Relevant to Schizophrenia.

Background: Parvalbumin interneuron (PVI) activity synchronizes the medial prefrontal cortex circuit for normal cognitive function, and its impairment may contribute to schizophrenia (SZ). NMDA receptors in PVIs participate in these activities and form the basis for the NMDA receptor hypofunction hypothesis of SZ. However, the role of the GluN2D subunit, which is enriched in PVIs, in regulating molecular networks relevant to SZ is unknown.

HIV-1 Tat induced microglial EVs leads to neuronal synaptodendritic injury: microglia-neuron cross-talk in NeuroHIV.

Aim: Activation of microglial NLRP3 inflammasome is an essential contributor to neuroinflammation underlying HIV-associated neurological disorders (HAND). Under pathological conditions, microglia-derived-EVs (MDEVs) can affect neuronal functions by delivering neurotoxic mediators to recipient cells. However, the role of microglial NLRP3 in mediating neuronal synaptodendritic injury has remained unexplored to date.

Macrophages Promote Repair of Inner Hair Cell Ribbon Synapses following Noise-Induced Cochlear Synaptopathy.

Resident cochlear macrophages rapidly migrate into the inner hair cell synaptic region and directly contact the damaged synaptic connections after noise-induced synaptopathy. Eventually, such damaged synapses are spontaneously repaired, but the precise role of macrophages in synaptic degeneration and repair remains unknown. To address this, cochlear macrophages were eliminated using colony stimulating factor 1 receptor (CSF1R) inhibitor, PLX5622.

ameliorates stress induced depression in mice by regulating neuroinflammatory cytokines.

Background And Aim: Linn. () (family: Amaranthaceae) is highly recognized in ethnomedicine and traditional systems of Indian medicine as a nervine restorative for several psychiatric disorders. Study presented here was designed to appraise the antidepressant-like effects of in murine model of chronic unpredictable mild stress (CUMS) induced depression.

Glutamate delta 1 receptor regulates autophagy mechanisms and affects excitatory synapse maturation in the somatosensory cortex.

The glutamate delta family of receptors is composed of GluD1 and GluD2 and serve as synaptic organizers. We have previously demonstrated several autism-like molecular and behavioral phenotypes including an increase in dendritic spines in GluD1 knockout mice. Based on previous reports we evaluated whether disruption of autophagy mechanisms may account for these phenotypes.

Dysfunction of Glutamate Delta-1 Receptor-Cerebellin 1 Trans-Synaptic Signaling in the Central Amygdala in Chronic Pain.

Chronic pain is a debilitating condition involving neuronal dysfunction, but the synaptic mechanisms underlying the persistence of pain are still poorly understood. We found that the synaptic organizer glutamate delta 1 receptor (GluD1) is expressed postsynaptically at parabrachio-central laterocapsular amygdala (PB-CeLC) glutamatergic synapses at axo-somatic and punctate locations on protein kinase C δ -positive (PKCδ) neurons. Deletion of GluD1 impairs excitatory neurotransmission at the PB-CeLC synapses.

Pharmacological characterization of a novel negative allosteric modulator of NMDA receptors, UBP792.

N-methyl-d-aspartate (NMDA) receptors (NMDARs) are a subtype of ionotropic glutamate receptor with important roles in CNS function. Since excessive NMDAR activity can lead to neuronal cell death and epilepsy, there is interest in developing NMDAR negative allosteric modulators (NAMs) as neuroprotective agents. In this study, we characterize the inhibitory properties of a novel NMDAR antagonist, UBP792.

Glutamate Delta-1 Receptor Regulates Inhibitory Neurotransmission in the Nucleus Accumbens Core and Anxiety-Like Behaviors.

Glutamate delta-1 receptor (GluD1) is a member of the ionotropic glutamate receptor family expressed at excitatory synapses and functions as a synaptogenic protein by interacting with presynaptic neurexin. We have previously shown that GluD1 plays a role in the maintenance of excitatory synapses in a region-specific manner. Loss of GluD1 leads to reduced excitatory neurotransmission in medium spiny neurons (MSNs) in the dorsal striatum, but not in the ventral striatum (both core and shell of the nucleus accumbens (NAc)).

Facilitation of GluN2C-containing NMDA receptors in the external globus pallidus increases firing of fast spiking neurons and improves motor function in a hemiparkinsonian mouse model.

Globus pallidus externa (GPe) is a nucleus in the basal ganglia circuitry involved in the control of movement. Recent studies have demonstrated a critical role of GPe cell types in Parkinsonism. Specifically increasing the function of parvalbumin (PV) neurons in the GPe has been found to facilitate motor function in a mouse model of Parkinson's disease (PD).

Striatal glutamate delta-1 receptor regulates behavioral flexibility and thalamostriatal connectivity.

Impaired behavioral flexibility and repetitive behavior is a common phenotype in autism and other neuropsychiatric disorders, but the underlying synaptic mechanisms are poorly understood. The trans-synaptic glutamate delta (GluD)-Cerebellin 1-Neurexin complex, critical for synapse formation/maintenance, represents a vulnerable axis for neuropsychiatric diseases. We have previously found that GluD1 deletion results in reversal learning deficit and repetitive behavior.

Differential effect of NMDA receptor GluN2C and GluN2D subunit ablation on behavior and channel blocker-induced schizophrenia phenotypes.

The GluN2C- and GluN2D-containing NMDA receptors are distinct from GluN2A- and GluN2B-containing receptors in many aspects including lower sensitivity to Mg block and lack of desensitization. Recent studies have highlighted the unique contribution of GluN2C and GluN2D subunits in various aspects of neuronal and circuit function and behavior, however a direct comparison of the effect of ablation of these subunits in mice on pure background strain has not been conducted. Using knockout-first strains for the GRIN2C and GRIN2D produced on pure C57BL/6N strain, we compared the effect of partial or complete ablation of GluN2C and GluN2D subunit on various behaviors relevant to mental disorders.

Pharmacological repositioning of Achyranthes aspera as an antidepressant using pharmacoinformatic tools PASS and PharmaExpert: a case study with wet lab validation.

Traditional knowledge guides the use of plants for restricted therapeutic indications, but their pharmacological actions may be found beyond their ethnic therapeutic indications employing emerging computational tools. In this context, the present study was envisaged to explore the novel pharmacological effect of Achyranthes aspera (A. aspera) using PASS and PharmaExpert software tools.

Acute orexigenic effect of agmatine involves interaction between central α-adrenergic and GABAergic receptors.

Agmatine and GABA have been abundantly expressed in brain nuclei involved in regulation of energy homeostasis and promoting stimulation of food intake in rodents. However, their mutual interaction, if any, in the elicitation of feeding behavior is largely remains unclear. The current study provides experimental evidence for the possible interaction of agmatine, adrenergic and GABAergic systems in stimulation of feeding in satiated rats.

Agmatine for combined treatment of epilepsy, depression and cognitive impairment in chronic epileptic animals.

Epilepsy is fourth most common neurological disorders associated with depression and cognitive deficits. As per present scenario, none of the antiseizure drugs have been reported successful to have ameliorative effect on epilepsy associated depression and cognitive deficits. Thus, the study was envisioned to assess an ameliorative potential of agmatine on epilepsy and its efficacy and safety for management of associated depression and cognitive deficits.

Anticonvulsant activity and acute neurotoxic profile of Achyranthes aspera Linn.

Ethnopharmacological Relevance: Root powder of Achyranthes aspera Linn. (A. aspera) belongs to family Amaranthaceae is used in Indian traditional medicine for the management of epilepsy and its efficacy is widely acclaimed among the different rural communities.

Agmatine ameliorates adjuvant induced arthritis and inflammatory cachexia in rats.

The present study investigated the pharmacological effect of agmatine in Complete Freud Adjuvant (CFA) induced arthritis and cachexia in rats. The rats were injected with CFA (0.1ml/rat) to induced symptoms of arthritis.

Pharmacological validation of in-silico guided novel nootropic potential of Achyranthes aspera L.

Ethnopharmacological Relevance: Achyranthes aspera (A. aspera) has been used as a brain tonic in folk medicine. Although, ethnic use of medicinal plant has been basis for drug discovery from medicinal plants, but the available in-silico tools can be useful to find novel pharmacological uses of medicinal plants beyond their ethnic use.

[Computer evaluation of hidden potential of phytochemicals of medicinal plants of the traditional Indian ayurvedic medicine].

Applicability of our computer programs PASS and PharmaExpert to prediction of biological activity spectra of rather complex and structurally diverse phytocomponents of medicinal plants, both separately and in combinations has been evaluated. The web-resource on phytochemicals of 50 medicinal plants used in Ayurveda was created for the study of hidden therapeutic potential of Traditional Indian Medicine (TIM) (http://ayurveda.pharmaexpert.

Revealing Medicinal Plants That Are Useful for the Comprehensive Management of Epilepsy and Associated Comorbidities through In Silico Mining of Their Phytochemical Diversity.

In silico techniques in drug discovery may rationalise and speed up the identification of lead molecules from nature. Drug discovery from medicinal plants has mostly been confined to indications in accordance with their ethnical use only. However, the availability of multiple phytoconstituents in medicinal plants suggests that these may be much more useful beyond their traditional uses and in the management of chronic diseases, along with their comorbidities.