Frontiers in Synaptic Neuroscience最新文献

Serotonin plays a crucial role in regulating hippocampal network dynamics, however, its effects on sharp wave-ripples (SPWs), a pattern fundamental for memory consolidation and emotional processing, remain incompletely understood, particularly along the dorsoventral axis. Using hippocampal slices from adult rats, we compared serotonergic modulation of SPWs and associated multiunit activity (MUA) in dorsal and ventral CA1 regions. Serotonin (1-100 μM) was applied to evaluate dose dependent and region-specific effects on SPW amplitude, duration, frequency, and neuronal firing. We found that serotonin reduces SPW amplitude in both hippocampal segments, decreases the rate of SPW occurrence in the dorsal hippocampus, and increases the rate of SPW occurrence in the ventral hippocampus, but only at relatively low concentrations. The suppressive effect on SPW amplitude is accompanied by a reduction in firing frequency during SPWs in both regions, whereas the enhancing effect of low serotonin concentrations on SPW rate in the ventral hippocampus is associated with an excitatory action on basal neuronal activity. These results reveal a region-specific, and dose-dependent serotonergic modulation of SPWs, reflecting distinct excitatory/inhibitory balances and receptor subtype distributions along the hippocampal axis. Functionally, serotonergic suppression of dorsal SPWs may regulate cognitive processes, whereas bidirectional modulation in the ventral hippocampus may fine-tune affective and stress-related responses. Our findings highlight dorsoventral specialization of serotonergic control over hippocampal network patterns, providing insights into the mechanisms of dorsoventral hippocampal specialization and the symptom heterogeneity of neuropsychiatric disorders involving serotonergic dysfunction.

Background: Synaptic pruning is a critical neurodevelopmental process that eliminates redundant or weak synaptic connections to optimize brain circuitry. In schizophrenia, converging evidence from imaging, genetic, and postmortem studies suggests that this process is pathologically accelerated, particularly in the prefrontal cortex during adolescence. The resulting reduction in synaptic density has been implicated in disrupted neural connectivity observed in psychosis, with the onset of cognitive impairment and negative symptoms.

Objective: This review explores whether modulating aberrant synaptic pruning could serve as a preventive or early intervention strategy for schizophrenia. We analyze domains with emerging therapeutic relevance: tetracycline antibiotics, the complement system and C4 gene, kynurenine pathway modulation, epigenetic therapies, neuroprotective strategies (e.g., BDNF, NF-κB, progranulin), genetic and transcriptional regulators of pruning, and other new, mostly hypothetical, options. We also discuss the limitations of the impact on pruning.

Methods: We conducted a structured review of the mechanisms involved in pruning, as well as clinical trials, preclinical studies, and mechanistic models that investigate molecular targets influencing synaptic pruning in schizophrenia.

Results: Several molecular pathways have been implicated in abnormal synaptic pruning in schizophrenia, including complement C4A overexpression, kynurenine pathway imbalance (KYNA/QUIN), and dysregulation of microglial and transcriptional modulators such as MEF2C and TCF4. While retrospective studies suggest minocycline or doxycycline may reduce psychosis risk, randomized trials remain inconclusive. Emerging interventions, including LSD1 inhibitors, BDNF/progranulin enhancers, and lifestyle-based epigenetic modulation, show promise but require further validation in clinical settings. We also discuss the limitations of these methods, including safety considerations.

Conclusion: Targeted modulation of synaptic pruning represents a promising but complex therapeutic strategy. The timing, specificity, and reversibility of interventions are crucial to avoid disrupting essential neurodevelopment. Future efforts should focus on identifying biomarkers for patient stratification and validating preventive strategies in high-risk populations.

Synapses, once considered static conduits for neuronal signals, are now recognized as dynamic, multifunctional structures critical to brain function, plasticity, and disease. This evolving understanding has highlighted the tripartite nature of synapses, including pre-synaptic terminals, post-synaptic compartments, and regulatory glial elements. Among excitatory synapses, glutamatergic transmission dominates, with AMPA receptors (AMPARs) playing a central role in fast synaptic signaling. AMPARs are tetrameric, ligand-gated ion channels that mediate rapid depolarization and are tightly regulated by subunit composition, trafficking, and interactions with scaffolding and signaling proteins. Their activity-dependent modulation underpins key processes such as long-term potentiation and depression, central to learning and memory. Importantly, dysfunctions in AMPAR expression, localization, or signaling are increasingly linked to neurological and psychiatric disorders including autism spectrum disorders, epilepsy, schizophrenia, and Alzheimer's disease. This review discusses AMPAR biology in the context of synaptic organization, highlighting recent advances and ongoing challenges in understanding their roles in health and disease.

The human brain's increased cognitive abilities are underpinned by evolutionary adaptations at the molecular, cellular, and circuit levels of neural structures. This perspective explores how protracted neuronal development and divergent cell intrinsic neuronal properties, including neuronal excitability, contribute to human neurobiological singularity. Those cellular aspects rely on molecular evolutionary innovations, including evolution of gene regulation and gene duplications that play critical roles in prolonging synaptogenesis and reducing neuronal excitability. These molecular evolutionary innovations are shown to interact with core neurodevelopmental molecular pathways linked to neurodevelopmental disorders. Furthermore, complementary multimodal and multiscale approaches offer promising platforms to study these processes and develop species-relevant therapeutic strategies. They include ex vivo acute brain slices and organotypic cultures which offer emerging tools for understanding human species-specificities and neural disorders.

Non-reinforced reactivation destabilizes spatial memory in the Morris water maze (MWM), triggering reconsolidation, a protein synthesis-dependent process that restabilizes reactivated memories. PKMζ is a constitutively active, atypical PKC isoform implicated in memory storage. However, the potential involvement of this kinase in spatial memory reconsolidation remains unexplored. We found that intra-dorsal CA1 infusion of the PKMζ inhibitor myristoylated ζ-inhibitory peptide (ZIP), but not its inactive scrambled analog scZIP, following non-reinforced spatial memory reactivation in the MWM, induced time-dependent, long-lasting amnesia in adult male Wistar rats. This effect was replicated by silencing PKMζ mRNA translation with phosphorothioated antisense oligonucleotides, but not by inhibiting the related PKCι/λ with ICAP, and was prevented by disrupting hippocampal GluN2B-NMDAR signaling with RO25-6981, proteasome activity with clasto-lactacystin β-lactone, and AMPAR endocytosis with dynasore hydrate. ZIP had no effect on retention when given without reactivation or after reinforced reactivation. These findings suggest hippocampal PKMζ is necessary for spatial memory reconsolidation in the MWM, but not for its passive maintenance.

Introduction: Non-invasive brain stimulation techniques, widely used to manipulate neural excitability and behavior, are well studied at the meso- and macroscopic scales. However, less is known about their specificity at the level of individual cells.

Methods: Models based on real pyramidal and parvalbumin neuron morphologies created by the Allen Institute for Brain Science were characterized using metrics we devised to quantify various aspects of cellular morphology, ranging from whole cell attributes to net compartment length, branching, diameter and orientation. The models were simulated to quantify the single-cell variability and evoked response susceptibility to uniform electric fields.

Results and discussion: No physical traits yielded layer- or cell-type-specific responses passing statistical significance tests. While uniform electric fields reliably modulated somatic, dendritic and axonal compartments, and subtype-specific responses were observed, specificity was blurred by the variability in cellular morphology. These null results suggest morphology alone may not account for the reported subtype specificity to electric field stimulation, and question the extent to which non-invasive techniques can control specific components of neural circuitry.

Mitochondria regulate intracellular calcium ion (Ca²⁺) signaling by a fine-tuned process of mitochondrial matrix (m) Ca²⁺ influx, mCa²⁺ buffering (sequestration) and mCa²⁺ release (Ca²⁺ efflux). This process is critically important in the neurosynaptic terminal, where there is a simultaneous high demand for ATP utilization, cytosolic (c) Ca²⁺ regulation, and maintenance of ionic gradients across the cell membrane. Brain synaptic and non-synaptic mitochondria display marked differences in Ca²⁺ retention capacity. We hypothesized that mitochondrial Ca²⁺ handling in these two mitochondrial populations is determined by the net effects of Ca²⁺ uptake, buffering or efflux with increasing CaCl₂ boluses. We found first that synaptic mitochondria have a more coupled respiration than non-synaptic mitochondria; this may correlate with the higher local energy demand in synapses to support neurotransmission. When both mitochondrial fractions were exposed to increasing mCa²⁺ loads we observed decreased mCa²⁺ sequestration in synaptic mitochondria as assessed by a significant increase in the steady-state free extra matrix Ca²⁺ (ss[Ca²⁺]_e) compared to non-synaptic mitochondria. Since, non-synaptic mitochondria displayed a significantly reduced ss[Ca²⁺]_e, this suggested a larger mCa²⁺ buffering capacity to maintain [Ca²⁺]_m with increasing mCa²⁺ loads. There were no differences in the magnitude of the transient depolarizations and repolarizations of the membrane potential (ΔΨ_m) and both fractions exhibited similar gradual depolarization of the baseline ΔΨ_m during additional CaCl₂ boluses. Adding the mitochondrial Na⁺/Ca²⁺ exchanger (mNCE) inhibitor CGP37157 to the mitochondrial suspensions unmasked the mCa²⁺ sequestration and concomitantly lowered ss[Ca²⁺]_e in synaptic vs. non-synaptic mitochondria. Adding complex V inhibitor oligomycin plus ADP (OMN + ADP) bolstered the matrix Ca²⁺ buffering capacity in synaptic mitochondria, as did Cyclosporin A (CsA), in non-synaptic. Our results display distinct differences in regulation of the free [Ca²⁺]_m to prevent collapse of ΔΨ_m during mCa²⁺ overload in the two populations of mitochondria. Synaptic mitochondria appear to rely mainly on mCa²⁺ efflux via mNCE, while non-synaptic mitochondria rely mainly on P_i-dependent mCa²⁺ sequestration. The functional implications of differential mCa²⁺ handling at neuronal synapses may be adaptations to cope with the higher metabolic activity and larger mCa²⁺ transients at synaptosomes, reflecting a distinct role they play in brain function.

Traumatic Brain Injury (TBI) is a leading cause of mortality and morbidity in adults and can lead to long-term disability, including cognitive and motor deficits. Despite advances in research, there are currently no pharmacological interventions to improve outcomes after TBI. Studies suggest that non-selective transient receptor potential melastatin 2 (TRPM2) channels contribute to brain injury in models of ischemia, however TRPM2 remains understudied following TBI. Thus, we utilized TRPM2 KO mice and a novel TRPM2 inhibiting peptide, tatM2NX, to assess the role of TRPM2 in TBI-induced injury and functional recovery. This study used histological analysis of injury, neurobehavior and electrophysiology to assess the role of TRPM2 on injury and cognitive recovery (memory) impairments using the controlled cortical impact (CCI) model to induce TBI in mice. Histological analysis used to investigate brain injury volume at 7 days after TBI showed sex differences in response to injury in TRPM2 KO mice but no pharmacological effects in our WT mice. A contextual fear-conditioning task was used to study memory function 7 or 30 days after TBI and demonstrates that sham-operated mice exhibited significant freezing behavior compared to TBI-operated mice, indicating impaired memory function. Mice administered tat-M2NX 2 h after TBI exhibited a significant reduction of freezing behavior compared to control tat-scrambled (tat-SCR)-treated mice, suggesting improvement in memory function after TBI. To test the effect of TBI on hippocampal long-term potentiation (LTP), a well-established cellular model of synaptic plasticity associated with changes in learning and memory, extracellular field recordings of CA1 neurons were performed in hippocampal slices prepared 7 days after TBI. Consistent with our behavioral testing, we observed impaired hippocampal LTP in mice following TBI (tat-SCR), compared to sham control mice. However, mice treated with tat-M2NX after TBI exhibited preserved LTP, consistent with the improved memory function observed in our behavioral studies. While this data implicates TRPM2 in brain pathology following TBI, the improvement in memory function without providing histological protection suggests that administration of tatM2NX at an acute time point differentially affects hippocampal regions compared to cortical regions.

Neuronal transmitters are released at the morphological specializations known as active zones (AZs). Transmitters can be released either in response to a stimulus or spontaneously, and spontaneous transmission is a vital component of neuronal communication. Employing postsynaptically tethered calcium sensor GCaMP, we investigated how nerve stimulation affects spontaneous transmission at individual AZs at the Drosophila neuromuscular synapse. Optical monitoring of spontaneous transmission at individual AZs revealed that prolonged high-frequency stimulation (HFS, 30 Hz for 1 min) selectively activates the hot spots of spontaneous transmission, including the individual AZs with elevated activities as well as AZ clusters. In contrast, a brief tetanus (2 s) activated numerous low-activity AZs. We employed Monte-Carlo simulations of spontaneous transmission based on a three-state model of AZ preparedness, which incorporated longer-lasting (minutes) and shorter-lasting (sub-seconds to seconds) high-activity states of AZs. The simulations produced an accurate quantitative description of the variability and time-course of spontaneous transmission at individual AZs before and after the stimulation and suggested that HFS activates both longer-lasting and shorter-lasting states of AZ preparedness.

Long-term potentiation (LTP) is a biochemical process that underlies learning in excitatory glutamatergic synapses in the Central Nervous System (CNS). A critical early driver of LTP is autophosphorylation of the abundant postsynaptic enzyme, Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). Autophosphorylation is initiated by Ca²⁺ flowing through NMDA receptors activated by strong synaptic activity. Its lifetime is ultimately determined by the balance of the rates of autophosphorylation and of dephosphorylation by protein phosphatase 1 (PP1). Here we have modeled the autophosphorylation and dephosphorylation of CaMKII during synaptic activity in a spine synapse using MCell4, an open source computer program for creating particle-based stochastic, and spatially realistic models of cellular microchemistry. The model integrates four earlier detailed models of separate aspects of regulation of spine Ca²⁺ and CaMKII activity, each of which incorporate experimentally measured biochemical parameters and have been validated against experimental data. We validate the composite model by showing that it accurately predicts previous experimental measurements of effects of NMDA receptor activation, including high sensitivity of induction of LTP to phosphatase activity in vivo, and persistence of autophosphorylation for a period of minutes after the end of synaptic stimulation. We then use the model to probe aspects of the mechanism of regulation of autophosphorylation of CaMKII that are difficult to measure in vivo. We examine the effects of "CaM-trapping," a process in which the affinity for Ca²⁺/CaM increases several hundred-fold after autophosphorylation. We find that CaM-trapping does not increase the proportion of autophosphorylated subunits in holoenzymes after a complex stimulus, as previously hypothesized. Instead, CaM-trapping may dramatically prolong the lifetime of autophosphorylated CaMKII through steric hindrance of dephosphorylation by protein phosphatase 1. The results provide motivation for experimental measurement of the extent of suppression of dephosphorylation of CaMKII by bound Ca²⁺/CaM. The composite MCell4 model of biochemical effects of complex stimuli in synaptic spines is a powerful new tool for realistic, detailed dissection of mechanisms of synaptic plasticity.