Open research questions in Neuroscience and Neuropharmacology Research

What the literature leaves open

• The exact mechanisms of action of some antiseizure drugs remain incompletely understood. The functional effects of antiseizure drugs on peripheral neuronal populations are not well characterized.

  Comparative Neuropharmacological Effects of Antiseizure Drugs on Cultured Myenteric and Dorsal Root Ganglion Neurons · 2026 · DOI

• Investigate the local relationship between ISs and dendritic spines in the same neurons, - Track ISs and dendritic spines in the same neurons to higher level of detail, - Explore the role of AIS-projecting INs in other brain areas

  Learning reorganizes dendritic and stabilizes axon initial segment inhibitory synapses in CA1 pyramidal neurons · 2026 · DOI

• The lack of understanding of how structural plasticity of inhibitory synapses supports their functions and emerging properties like memory. The limited knowledge of inhibitory synapses in the hippocampus, with most previous work focusing on neocortical areas.

  Learning reorganizes dendritic and stabilizes axon initial segment inhibitory synapses in CA1 pyramidal neurons · 2026 · DOI

• Further research is needed to investigate the effects of aging on the electrophysiology of SG in other species. The study of age-related changes in the electrophysiology of SG could be extended to other age ranges. Investigating the effects of aging on the electrophysiology of SG in female mice could provide additional insights.

  Age‐dependent reduction in voltage‐gated inward sodium current and Scn8a gene expression in murine stellate ganglia · 2025 · DOI

• However, the turnover mechanisms that maintain this spatial pattern remain unclear.

  Asymmetric turnover dynamics of Nav1.6 voltage-gated sodium channels at the axon initial segment · 2026 · DOI

• Although the dependence of glutamatergic plasticity on protein synthesis is well established, the role of translation in inhibitory plasticity remains unclear.

  Distinct protein synthesis requirements for coupled excitatory and inhibitory long-term co-plasticity in mouse hippocampus · 2026 · DOI

• This paradoxical response to an AMPA antagonist underscores the need for further study of GRIA2 ‐related phenotypes and targeted therapies.

  GRIA2 Variant Associated With Paradoxical Response to Perampanel Expanding the Spectrum of GRIA2 ‐Related Epileptic Encephalopathy: Case Report and Literature Review · 2026 · DOI

• Research indicates that high-intensity interval training (HIIT) enhances cognitive functions reliant on the hippocampus in mice, although the specific receptor-mediated molecular pathways involved are not fully elucidated.

  HIIT-induced lactate/GPR81 signaling with dual branches converging on ERK1/2 contributes to hippocampal synaptic remodeling and memory improvement · 2026 · DOI

• Although astrocytic calcium (Ca 2+ ) signaling has been widely studied in relation to neurovascular coupling, the role of cyclic adenosine monophosphate (cAMP), another key second messenger of GPCRs, on CBF has not been established.

  Cerebral blood flow is modulated by astrocytic cAMP elevation independently of IP 3 R2-mediated Ca 2+ signaling in mice · 2025 · DOI

• While saccades initially rotated the eyes in the same direction as the head turn, saccades were followed by eye rotations countering the ongoing head rotation, which reduced image blur and limited information loss across the visual field during head turns.

  Eye saccades align optic flow with retinal specializations during object pursuit in freely moving ferrets · 2025 · DOI

• The characteristics of neural circuitry that permit this experience-dependent plasticity are poorly understood.

  Representational drift gates critical-period plasticity in mouse visual cortex · 2025 · DOI

• Approximately 75% of epilepsy cases emerge in childhood, and 10%-30% of these pediatric epilepsy cases are resistant to standard drug therapies; however, the underlying causes of resistance remain poorly understood.

  Critical contributions of neuronal subtypes to pediatric drug-resistant focal dysplasia · 2025 · DOI

• Although siramesine (Sira) has demonstrated antitumor activity in various cancers, its potential therapeutic effect in gliomas remains uncertain.

  Siramesine induced cell death of glioblastoma through inactivating the STAT3-MGMT signaling pathway · 2025 · DOI

• However, with limited observations of synaptic activity and plasticity in vivo, the features of synapses subjected to elimination remain poorly understood.

  Local and global predictors of synapse elimination during motor learning · 2024 · DOI

• How these cortical engrams acquire stability during systems-level memory consolidation without compromising their dynamic nature remains unclear.

  Synaptic rearrangement of NMDA receptors controls memory engram formation and malleability in the cortex · 2024 · DOI

• Due to the complexity of synaptic transmissions and input-output connections in the VTA, the structure and function of this crucial brain region are still not fully understood.

  The Formation and Function of the VTA Dopamine System · 2024 · DOI

• However, the underlying synaptic and computational mechanisms of this network are not well understood.

  Structure and function of the hippocampal CA3 module · 2024 · DOI

• However, how the actions of ketamine at the subcellular level give rise to the oscillatory dynamics observed at the network level remains unknown.

  Ketamine can produce oscillatory dynamics by engaging mechanisms dependent on the kinetics of NMDA receptors · 2024 · DOI

• However, the molecular mechanism underlying this transsynaptic nanostructure in inhibitory synapses still remains unclear and its impact on synapse function in physiological or pathological contexts has not been demonstrated.

  Structural and functional reorganization of inhibitory synapses by activity-dependent cleavage of neuroligin-2 · 2024 · DOI

• Yet, how specifically astrocytes and their neuroactive transmitters control learning and memory is currently an open question.

  Astrocytes enhance plasticity response during reversal learning · 2024 · DOI

• Intriguingly, loss of Nlgn2 differentially affects subsets of GABAergic synapses, indicating that synapse-specific interactors and redundancies define its function, but the nature of these interactions remain poorly understood.

  Functional Neuroligin-2-MDGA1 interactions differentially regulate synaptic GABAARs and cytosolic gephyrin aggregation · 2024 · DOI

• Berberine has been found to be able to cross the blood-brain barrier to treat psychiatric disorders, but its neurocirculatory mechanisms remain unclear.

  Berberine alleviates chronic pain-induced anxiety-like behaviors by inhibiting the activation of VLT-projecting cACC (Cg2) neurons · 2024 · DOI

• Nevertheless, the mechanisms underlying this phenomenon remain poorly understood.

  Acute activation of hemichannels by ethanol leads to Ca2+-dependent gliotransmitter release in astrocytes · 2024 · DOI

• The ability to limit neuronal hyperactivity relies on the localization and diffusion of GLT-1 on the astrocytic surface, however, little is known about the underlying mechanisms.

  GLT-1a glutamate transporter nanocluster localization is associated with astrocytic actin and neuronal Kv2 clusters at sites of neuron-astrocyte contact · 2024 · DOI

• Further studies are needed to elucidate the molecular mechanisms underlying the neuroprotective effects of dexmedetomidine. The development of therapeutic interventions targeting the AMPK/mTOR signaling pathway may be a promising approach for the treatment of CIRI. Additional research is needed to confirm the findings of this study and to explore the potential of dexmedetomidine as a therapeutic agent for CIRI.

  Exploring the molecular mechanism of dexmedetomidine in alleviating blood–brain barrier disruption in rats with cerebral ischemia reperfusion injury based on network pharmacology · 2026 · DOI

Most-cited papers in Neuroscience and Neuropharmacology Research

• Magnesium gates glutamate-activated channels in mouse central neurones · Nature · 1984 · 3,129 citations
• Oxidative Stress, Glutamate, and Neurodegenerative Disorders · Science · 1993 · 3,092 citations
• A mesoscale connectome of the mouse brain · Nature · 2014 · 2,678 citations
• Glycine potentiates the NMDA response in cultured mouse brain neurons · Nature · 1987 · 2,501 citations
• Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones · Nature · 1984 · 2,291 citations
• Long-Term Potentiation--A Decade of Progress? · Science · 1999 · 2,170 citations
• Excitatory Amino Acids as a Final Common Pathway for Neurologic Disorders · New England Journal of Medicine · 1994 · 2,140 citations
• Molecular Diversity of Glutamate Receptors and Implications for Brain Function · Science · 1992 · 2,099 citations
• Heteromeric NMDA Receptors: Molecular and Functional Distinction of Subtypes · Science · 1992 · 2,098 citations
• Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain · Nature · 1988 · 2,063 citations

Most recent work

• Cortical astrocytes extend phasic norepinephrine signals and critically mediate learned behavior · bioRxiv · 2026
• Ten3-Lphn2-mediated target selection across the extended hippocampal network demonstrates a repeated strategy for circuit assembly · Current Biology · 2026
• Substrate Self-Architects a Neurogenesis Module: Activity-vs-Phi Distinction and Cross-Module Coupling in a Bio-Inspired Computational System · Zenodo (CERN European Organization for Nuclear Research) · 2026
• Clustered Inputs Maximize Efficiency for Stable Place Field Encoding in Hippocampal Pyramidal Neurons · bioRxiv · 2026
• Striatal lateral inhibition regulates action selection in a mouse model of levodopa-induced dyskinesia · bioRxiv · 2026
• ATP13A4 gates extracellular polyamine levels to control excitatory synaptogenesis · medRxiv · 2026
• Efficacy and Tolerability of RAP-219, a Potential First-in-class Negative Allosteric Modulator of γ8 Transmembrane AMPA Receptor Regulatory Protein: Impact on RNS Long Episodes and Clinical Seizures (S29.003) · Neurology · 2026
• Genetic Activation of Locus Coeruleus Noradrenergic Neurons Modulates Cerebellar MF-GrC Synaptic Plasticity via Presynaptic α2-AR/PKA Signaling in Mice · Biology · 2026
• Persistent Firing Neurons in the Medial Septum Drive Arousal and Locomotion · bioRxiv · 2026
• CO2-sensitive Cx26 hemichannels in dorsal raphe-ventral tegmental area pathway mediate hypercapnic arousal · bioRxiv · 2026

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