Wei Zhang

Objective: This study aimed to investigate the potential of ononin in alleviating mild cognitive impairment (MCI) and to determine whether its effects depend on the functional recovery of neurons in the nucleus tractus solitarius (NTS). Methods: Four-month-old APP/PS1 mice were treated with 30-mg/kg ononin via oral gavage for 8 consecutive days. Cognitive behavior was assessed using the novel object recognition test, Y-maze test, and open field test. Cortical perfusion was measured by laser speckle contrast imaging. The activation of NTS neurons was detected using c-Fos immunofluorescence staining, while dendritic complexity and neuronal firing frequency were evaluated via Golgi staining and patch-clamp electrophysiology, respectively. Results: Ononin treatment significantly improved the novel object recognition index and spontaneous alternation rate in the Y-maze test in APP/PS1 mice. It also enhanced cerebral blood flow perfusion and increased the number of c-Fos-positive cells in the NTS, hippocampal CA1 region, and cortex. Furthermore, ononin increased dendritic intersections and restored dendritic spine density in NTS neurons to normal levels, along with significantly elevating their firing frequency. Conclusion: Ononin may ameliorate MCI-like cognitive deficits in APP/PS1 mice by activating NTS neurons, restoring synaptic plasticity, and improving cerebral perfusion. These findings suggest that the NTS could serve as a potential target for early intervention in Alzheimer’s disease.

AMPA receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission throughout the central nervous system. Calcium-permeable AMPARs and GluA4-containing receptors are critical for cerebellar functions, such as motor learning, associative memory, auditory processing, and synaptic plasticity. In contrast to the well-characterized, predominantly GluA2-containing AMPARs of the hippocampus and cortex, cerebellar AMPARs contain a higher proportion of GluA4 and remain poorly understood. Here, we generated a highly GluA4-specific antibody. Using this antibody in combination with antibodies specifically recognizing GluA1 and GluA2, we purified native AMPARs and determined the subunit compositions of both calcium-impermeable and calcium-permeable native AMPARs in the cerebellum. The isolated cerebellar AMPARs that contained both GluA1 and GluA4 were calcium-permeable, with GluA4 occupying mainly the B/D positions, GluA1 occupying the A/C positions, and the complex associated primarily with cornichon 3 (CNIH3). We determined the structures of the complex in distinct functional states, including the resting, active, and desensitized states, and characterized the conformational transitions that underlie its activity. During desensitization, the receptor adopts a pseudo-4-fold configuration of the ligand-binding domain layer, which may be important for its functional properties. This study provides a blueprint for the subunit compositions of AMPARs in the cerebellum and clarifies the gating mechanism of the calcium-permeable native AMPAR^A1A4–CNIH3 complex, providing significant insight into AMPAR-mediated synaptic transmission in the cerebellum.

Attention-deficit/hyperactivity disorder (ADHD) is the most prevalent neurodevelopmental disorder in childhood and a common chronic condition among school-aged children. However, the pharmacological mechanisms and pathophysiology of ADHD remain incompletely elucidated. Transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor regulatory protein γ-8 (TARP γ-8, also known as calcium voltage-gated channel auxiliary subunit γ8) functions as an auxiliary subunit of AMPA receptors. Previous studies suggest that mice lacking the TARP γ-8 protein may display hyperactivity, impulsivity, and memory deficits, which are hallmarks of ADHD. The nootropic compound aniracetam effectively mitigates ADHD-like symptoms, including hyperactivity, impulsivity, anxiety, cognitive deficits, and memory impairment, observed in adolescent TARP γ-8 knockout (KO) mice. This investigation explored the therapeutic potential of aniracetam and its underlying molecular mechanisms using TARP γ-8 KO mice as an ADHD model. Through cerebral microdialysis coupled with liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis, we identified perturbations in neurotransmitter metabolism in the ADHD model of TARP γ-8 KO mice. Real-time quantitative PCR (RT-qPCR) was employed to detect alterations in the expression of key receptor and transporter genes. The results indicate that aniracetam can alleviate ADHD-related behavioral deficits by modulating the excitatory-inhibitory neurotransmitter systems through the modulation of glutamate receptor, γ-Aminobutyric Acid receptor, and monoamine neurotransmitter transporter expression. These findings in a TARP γ-8-deficient ADHD model support further investigation into aniracetam as a potential therapeutic intervention for ADHD, providing novel molecular targets and a theoretical framework for the pharmacological management of ADHD.

N-methyl-D-aspartate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) mediate the majority of excitatory synaptic transmission in central nervous system. Dysfunction of these receptors may result in various diseases, including epilepsy. In recent years, a growing number of studies have targeted NMDARs and AMPARs to screen for antiepileptic agents that are both efficacious and well-tolerated. This review summarizes compounds, herbal extracts, and herbal complexes of traditional Chinese medicine (TCM) that have demonstrated antiepileptic effects through their modulation of NMDARs and AMPARs over the past 25 years. Furthermore, this review also systematically synthesizes the molecular mechanisms underlying these drugs, with the aim of facilitating the rational design and translational development of future antiepileptic therapeutic agents.

The functional complexity of the mammalian brain is rooted in the diverse protein composition of synapses across distinct regions. To address the need for a detailed molecular understanding of this regional diversity, we generated the first comprehensive proteomic map of synaptosomes from six key rat brain regions: anterior cortex, posterior cortex, hippocampus, striatum, olfactory bulb, and cerebellum. Using high-resolution quantitative proteome and the Percoll density gradient ultracentrifugation, we identified 3,440 proteins and yielded high synaptic enrichment (60.11% synapse-unique proteins). In-depth functional analysis using the SynGO database revealed region-specific enrichments in the cellular components and biological processes. This study provides a valuable resource and foundational insights into the molecular architecture underlying regional synaptic diversity, paving the way for future investigations into brain function and neurological disorders.