Short-term plasticity is an important feature in the brain for shaping neural dynamics and for information processing. Short-term plasticity is known to depend on many factors including brain region, cortical layer, and cell type. Here we focus on vasoactive-intestinal peptide (VIP) interneurons (INs). VIP INs play a key disinhibitory role in cortical circuits by inhibiting other IN types, including Martinotti cells (MCs) and basket cells (BCs). Despite this prominent role, short-term plasticity at synapses to and from VIP INs is not well described. In this study, we therefore characterized the short-term plasticity at inputs and outputs of genetically targeted VIP INs in mouse motor cortex. To explore inhibitory to inhibitory (I → I) short-term plasticity at layer 2/3 (L2/3) VIP IN outputs onto L5 MCs and BCs, we relied on a combination of whole-cell recording, 2-photon microscopy, and optogenetics, which revealed that VIP IN→MC/BC synapses were consistently short-term depressing. To explore excitatory (E) → I short-term plasticity at inputs to VIP INs, we used extracellular stimulation. Surprisingly, unlike VIP IN outputs, E → VIP IN synapses exhibited heterogeneous short-term dynamics, which we attributed to the target VIP IN cell rather than the input. Computational modeling furthermore linked the diversity in short-term dynamics at VIP IN inputs to a wide variability in probability of release. Taken together, our findings highlight how short-term plasticity at VIP IN inputs and outputs is specific to synapse type. We propose that the broad diversity in short-term plasticity of VIP IN inputs forms a basis to code for a broad range of contrasting signal dynamics.

Long-term plasticity at pyramidal cell to basket cell (PC → BC) synapses is important for the functioning of cortical microcircuits. It is well known that at neocortical PC → PC synapses, dendritic calcium (Ca) dynamics signal coincident pre-and postsynaptic spiking which in turn triggers long-term potentiation (LTP). However, the link between dendritic Ca dynamics and long-term plasticity at PC → BC synapses of primary visual cortex (V1) is not as well known. Here, we explored if PC → BC synaptic plasticity in developing V1 is sensitive to postsynaptic spiking. Two-photon (2P) Ca imaging revealed that action potentials (APs) in dendrites of V1 layer-5 (L5) BCs back-propagated decrementally but actively to the location of PC → BC putative synaptic contacts. Pairing excitatory inputs with postsynaptic APs elicited dendritic Ca supralinearities for pre-before-postsynaptic but not post-before-presynaptic temporal ordering, suggesting that APs could impact synaptic plasticity. In agreement, extracellular stimulation as well as high-throughput 2P optogenetic mapping of plasticity both revealed that pre-before-postsynaptic but not post-before-presynaptic pairing resulted in anti-Hebbian long-term depression (LTD). Our results demonstrate that V1 BC dendritic Ca nonlinearities and synaptic plasticity at PC → BC connections are both sensitive to somatic spiking.

β-adrenergic receptors (β-ARs) play a critical role in modulating learning, memory, emotionality, and long-term synaptic plasticity. Recent studies indicate that β-ARs are necessary for long-term potentiation (LTP) induction in the ventral hippocampus under moderate synaptic activation conditions that do not typically induce LTP. To explore potential dorsoventral differences in β-AR-mediated effects, we applied the β-AR agonist isoproterenol (10 μM, 30 min) to dorsal and ventral hippocampal slices, recording field excitatory postsynaptic potentials (fEPSPs) and population spikes (PSs) from the CA1 region. Isoproterenol induced robust, long-lasting PS increases, with effects three times greater in the dorsal compared to the ventral hippocampus. Isoproterenol did not significantly affect fEPSP in either segment of the hippocampus, leading to strong excitatory-to-spike (E-S) potentiation-twice as large as that in the ventral hippocampus. E-S potentiation was not associated with significant paired-pulse inhibition changes in either hippocampal segment. These differences do not appear to result from β1-AR expression levels, as they are comparable across dorsal and ventral hippocampal regions. Overall, the findings suggest that β-AR activation enhances the dorsal hippocampus's role during stress, facilitating heightened alertness, rapid spatial information processing, and effective navigation necessary for "fight-or-flight" responses.

Palmitoylation and depalmitoylation represent dichotomic processes by which a labile posttranslational lipid modification regulates protein trafficking and degradation. The depalmitoylating enzyme, palmitoyl-protein thioesterase 1 (PPT1), is associated with the devastating pediatric neurodegenerative condition, infantile neuronal ceroid lipofuscinosis (CLN1). CLN1 is characterized by the accumulation of autofluorescent lysosomal storage material (AFSM) in neurons and robust neuroinflammation. Converging lines of evidence suggest that in addition to cellular waste accumulation, the symptomology of CLN1 corresponds with disruption of synaptic processes. Indeed, loss of Ppt1 function in cortical neurons dysregulates the synaptic incorporation of the GluA1 AMPA receptor (AMPAR) subunit during a type of synaptic plasticity called synaptic scaling. However, the mechanisms causing this aberration are unknown. Here, we used the mouse model (both sexes) to further investigate how Ppt1 regulates synaptic plasticity and how its disruption affects downstream signaling pathways. To this end, we performed a palmitoyl-proteomic screen, which provoked the discovery that Akap5 is excessively palmitoylated at synapses. Extending our previous data, induction of synaptic scaling, which is regulated by Akap5, caused an excessive upregulation of GluA1 in mice. This synaptic change was associated with exacerbated disease pathology. Furthermore, the Akap5- and inflammation-associated transcriptional regulator, nuclear factor of activated T cells (NFAT), was sensitized in cortical neurons. Suppressing the upstream regulator of NFAT activation, calcineurin, with the FDA-approved therapeutic FK506 (Tacrolimus) modestly improved neuroinflammation in mice. These findings indicate that the absence of depalmitoylation stifles synaptic protein trafficking and contributes to neuroinflammation via an Akap5-associated mechanism.

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.

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

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/ 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.

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.

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 acute brain slices and organotypic cultures which offer emerging tools for understanding human species-specificities and neural disorders.

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.

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.

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.

As a crucial player in excitatory synaptic transmission, AMPA receptors (AMPARs) contribute to the formation, regulation, and expression of social behaviors. AMPAR modifications have been associated with naturalistic social behaviors, such as aggression, sociability, and social memory, but are also noted in brain diseases featuring impaired social behavior. Understanding the role of AMPARs in social behaviors is timely to reveal therapeutic targets for treating social impairment in disorders, such as autism spectrum disorder and schizophrenia. In this review, we will discuss the contribution of the molecular composition, function, and plasticity of AMPARs to social behaviors. The impact of targeting AMPARs in treating brain disorders will also be discussed.

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 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.

Age-related hearing difficulties have a complex etiology that includes degenerative processes in the sensory cochlea. The cochlea comprises the start of the afferent, ascending auditory pathway, but also receives efferent feedback innervation by two separate populations of brainstem neurons: the medial olivocochlear and lateral olivocochlear pathways, innervating the outer hair cells and auditory-nerve fibers synapsing on inner hair cells, respectively. Efferents are believed to improve hearing under difficult conditions, such as high background noise. Here, we compare olivocochlear efferent innervation density along the tonotopic axis in young-adult and aged gerbils (at ~50% of their maximum lifespan potential), a classic animal model for age-related hearing loss.

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, Ca/calmodulin-dependent protein kinase II (CaMKII). Autophosphorylation is initiated by Ca 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 Ca 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 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 . We examine the effects of "CaM-trapping," a process in which the affinity for Ca/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 Ca/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.

Rapid, synapse-specific neurotransmission requires the precise alignment of presynaptic neurotransmitter release and postsynaptic receptors. How postsynaptic glutamate receptor accumulation is induced during maturation is not well understood. We find that in cultures of dissociated hippocampal neurons at 11 days (DIV) numerous synaptic contacts already exhibit pronounced accumulations of the pre- and postsynaptic markers synaptotagmin, synaptophysin, synapsin, bassoon, VGluT1, PSD-95, and Shank. The presence of an initial set of AMPARs and NMDARs is indicated by miniature excitatory postsynaptic currents (mEPSCs). However, AMPAR and NMDAR immunostainings reveal rather smooth distributions throughout dendrites and synaptic enrichment is not obvious. We found that brief periods of Ca influx through NMDARs induced a surprisingly rapid accumulation of NMDARs within 1 min, followed by accumulation of CaMKII and then AMPARs within 2-5 min. Postsynaptic clustering of NMDARs and AMPARs was paralleled by an increase in their mEPSC amplitudes. A peptide that blocked the interaction of NMDAR subunits with PSD-95 prevented the NMDAR clustering. NMDAR clustering persisted for 3 days indicating that brief periods of elevated glutamate fosters permanent accumulation of NMDARs at postsynaptic sites in maturing synapses. These data support the model that strong glutamatergic stimulation of immature glutamatergic synapses results in a fast and substantial increase in postsynaptic NMDAR content that required NMDAR binding to PSD-95 or its homologues and is followed by recruitment of CaMKII and subsequently AMPARs.

GABA receptors (GABARs) are important modulators of neuronal excitability, synaptic transmission and plasticity in principal cells (PCs). While at the cellular level they can inhibit synaptic transmission directly, at the network level, due to a net disinhibitory effect, they promote plasticity in PCs. However, their effect on plasticity in GABAergic interneurons (INs) is less well-understood.