Long-term Potentiation Research Articles

The Physiological Mechanisms of Transcranial Direct Current Stimulation to Enhance Motor Performance: A Narrative Review.

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that applies a stable, low-intensity (1-2 mA) direct current to modulate neuronal activity in the cerebral cortex. This technique is effective, simple to operate, affordable, and widely employed across various fields. tDCS has been extensively used in clinical and translational research, with growing applications in military and competitive sports domains. In recent years, the use of tDCS in sports science has garnered significant attention from researchers. Numerous studies have demonstrated that tDCS can enhance muscle strength, explosive power, and aerobic metabolism, reduce fatigue, and improve cognition, thereby serving as a valuable tool for enhancing athletic performance. Additionally, recent research has shed light on the physiological mechanisms underlying tDCS, including its modulation of neuronal resting membrane potential to alter cortical excitability, enhancement of synaptic plasticity to regulate long-term potentiation, modulation of neurovascular coupling to improve regional cerebral blood flow, and improvement of cerebral network functional connectivity, which activates and reinforces specific brain regions. tDCS also enhances the release of excitatory neurotransmitters, further regulating brain function. This article, after outlining the role of tDCS in improving physical performance, delves into its mechanisms of action to provide a deeper understanding of how tDCS enhances athletic performance and offers novel approaches and perspectives for physical performance enhancement.

Rapid and local neuroestrogen synthesis supports long-term potentiation of hippocampal Schaffer collaterals-cornu ammonis 1 synapse in ovariectomized mice.

In aging women, cognitive decline and increased risk of dementia have been associated with the cessation of ovarian hormones production at menopause. In the brain, presence of the key enzyme aromatase required for the synthesis of 17-β-estradiol (E2) allows for local production of E2 in absence of functional ovaries. Understanding how aromatase activity is regulated could help alleviate the cognitive symptoms. In female rodents, genetic or pharmacological reduction of aromatase activity over extended periods of time impair memory formation, decreases spine density, and hinders long-term potentiation (LTP) in the hippocampus. Conversely, increased excitatory neurotransmission resulting in rapid N-methyl-d-aspartic acid (NMDA) receptor activation rapidly promotes neuroestrogen synthesis. This rapid modulation of aromatase activity led us to address the hypothesis that acute neuroestrogens synthesis is necessary for LTP at the Schaffer collateral-cornu ammonis 1 (CA1) synapse in absence of circulating ovarian estrogens. To test this hypothesis, we did electrophysiological recordings of field excitatory postsynaptic potential (fEPSPs) in hippocampal slices obtained from ovariectomized mice. To assess the impact of neuroestrogens synthesis on LTP, we applied the specific aromatase inhibitor, letrozole, before the induction of LTP with a theta burst stimulation protocol. We found that blocking aromatase activity prevented LTP. Interestingly, exogenous E2 application, while blocking aromatase activity, was not sufficient to recover LTP in our model. Our results indicate the critical importance of rapid, activity-dependent local neuroestrogens synthesis, independent of circulating hormones for hippocampal synaptic plasticity in female rodents.

Hippocampal dipeptidyl peptidase 9 bidirectionally regulates memory associated with synaptic plasticity

IntroductionSubtypes of the dipeptidyl peptidase (DPP) family, such as DPP4, are reportedly associated with memory impairment. DPP9 is widely distributed in cells throughout the body, including the brain. However, whether DPP9 regulates memory has not yet been elucidated. ObjectivesThis study aimed to elucidate the role of DPP9 in memory, as well as the underlying molecular mechanism. MethodsWe performed immunofluorescence on mouse brains to explore the distribution of DPP9 in different brain regions and used AAV vectors to construct knockdown and overexpression models. The effects of changing DPP9 expression on memory were demonstrated through behavioral experiments. Finally, we used electrophysiology, proteomics and affinity purification mass spectrometry (AP-MS) to study the molecular mechanism by which DPP9 affects memory. ResultsHere, we report that DPP9, which is found almost exclusively in neurons, is expressed and has enzyme activity in many brain regions, especially in the hippocampus. Hippocampal DPP9 expression increases after fear memory formation. Fear memory was impaired by DPP9 knockdown and enhanced by DPP9 protein overexpression in the hippocampus. According to subsequent hippocampal proteomics, multiple pathways, including the peptidase pathway, which can be bidirectionally regulated by DPP9. DPP9 directly interacts with its enzymatic substrate neuropeptide Y (NPY) in neurons. Hippocampal long-term potentiation (LTP) is also bidirectionally regulated by DPP9. Moreover, inhibiting DPP enzyme activity impaired both LTP and memory. In addition, AP-MS revealed that DPP9-interacting proteins are involved in the functions of dendritic spines and axons. By combining AP-MS and proteomics, DPP9 was shown to play a role in regulating actin functions. ConclusionTaken together, our findings reveal that DPP9 affects the CNS not only through enzymatic activity but also through protein–protein interactions. This study provides new insights into the molecular mechanisms of memory and DPP family functions.

Quantitative analysis of the interaction between NMDA and AMPA receptors in glutamatergic synapses based on mathematical model

NMDA and AMPA receptors are co-localized at most glutamatergic synapses, where their numbers and distribution undergo dynamic changes. Glutamate binds to both the NMDA and AMPA receptors. Initially, I investigated whether there is competition between AMPA receptors and N-methyl-D-aspartic acid (NMDA) receptors for glutamate. Subsequently, I examined how these dynamic receptor changes affect synaptic response. To test the hypothesis, a synaptic model incorporating coexisting NMDA and AMPA receptors within the postsynaptic density (PSD) was developed. During long-term potentiation (LTP) induction, the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the PSD increase. If there is competition for glutamate between AMPA receptors and NMDA receptors, the number of activated NMDA receptor channels will decrease. Since LTP induction relies on the activation of NMDA receptors, reducing their activation will raise the threshold for LTP induction. Consequently, the LTP of the synapse itself can establish negative feedback, preventing excessive dynamics and maintaining the stability of the neural network.

Reliable resistive switching and synaptic simulation behaviors in ammonium polyphosphate-based memristor with non-inert Al electrode

Abstract Memristive devices that integrate storage and computing capabilities are highly promising candidates for artificial synapses in neuromorphic systems. However, achieving both cost-effectiveness and high-performance in memristors remains a substantial challenge. Ammonium polyphosphate (APP), an all-inorganic ionic polymer, has been utilized in the fabrication of memristive devices due to its distinctive poly-ionic properties and exceptional ion mobility. In this study, a two-terminal APP-based memristor with an Al/APP/ITO structure was fabricated. The experimental results revealed improved bipolar resistive switching behavior, characterized by lower operating voltages, enhanced endurance performance, and extended retention time. Detailed data fitting and chemical bonding analysis suggest that the physical mechanism underlying resistive switching involves a combination of interfacial Schottky barrier and conductive filaments. Furthermore, adjustable device conductance is achieved by applying consecutive positive and negative voltage sweeps. Various synaptic functions, including excitatory postsynaptic current, short-term paired-pulse facilitation, long-term potentiation /depression, and spike-timing-dependent plasticity, are effectively emulated. This study presents an effective approach to enhancing the memristive characteristics of APP-based devices and positions APP as a viable candidate for innovative neuromorphic architectures.

Alterations of synaptic plasticity in Angelman syndrome model mice are rescued by 5-HT7R stimulation.

Angelman syndrome (AS) is a severe neurodevelopmental disorder characterized by motor disfunction, seizures, intellectual disability, speech deficits, and autism-like behavior, showing high comorbidity with Autism Spectrum Disorders (ASD). It is known that stimulation of the serotonin receptor 7 (5-HT7R) can rescue some of the behavioral and neuroplasticity dysfunctions in animal models of Fragile X and Rett syndrome, two pathologies associated with ASD. In view of these observations, we hypothesised that alterations of 5-HT7R signalling might also be involved in AS. To test this hypothesis, we stimulated 5-HT7R with the selective agonist LP-211 to investigate its possible beneficial effects on synaptic dysfunctions and altered behavior in the AS mice model. In mutant mice, we observed impairment of the synaptic machinery of protein synthesis, which was reversed by 5-HT7R activation. Moreover, stimulation of 5-HT7R was able to: i) enhance dendritic spine density in hippocampal neurons, which was reduced in AS mice; ii) restore impaired long-term potentiation (LTP) in hippocampal slices of the AS mice; iii) improve cognitive performance of the mutant animals subjected to the fear conditioning paradigm. Altogether, our results, showing beneficial effects of 5-HT7R stimulation in restoring molecular and cognitive deficits associated with AS, suggest that targeting 5-HT7R could be a promising therapeutic approach for the pathology.

Ion-migration-induced synaptic plasticity in high ion-storable fluorine graphdiyne for information processing

Neuromorphic devices encounter constraints associated with complementary metal–oxide–semiconductor technology, such as intricate electronics and high power consumption. Recently, solid polymer electrolytes (SPE) have gained attraction in electronic devices for constructing artificial synapses, primarily due to their low-voltage operation enabled by ion-assisted signal transmission. This study presents a two-terminal artificial synapse fabricated using fluorine graphdiyne (F-GDY) synthesized through chemical vapor deposition and ion-doped SPE. The device architecture consists of Au/SPE/F-GDY/Si, which operates by ion migration induced by external potential pulses. Electrical measurements are conducted to depict the synaptic plasticity of the devices. Among devices employing different ion-doped SPEs (Li-SPE, Na-SPE, K-SPE, and Ca-SPE), the one utilizing Li-SPE demonstrates the highest synaptic weight. This is attributed to the superior Li+ ion storage capacity of F-GDY; hence, Li-SPE/F-GDY was chosen for in-depth examinations of synaptic activity presenting long-term potentiation, short-term depression, and pair-pulse facilitation. The device has good durability and stability and can respond to low action potential with power consumption at the pJ level. Furthermore, Modified National Institute of Standards and Technology simulations reveal its learning and pattern recognition capability with 91.3 % accuracy after 10 training epochs. Finally, flexible substrate-based SPE/F-GDY devices integrated with gate electrodes were fabricated to record physiological signals, showing promise for in-sensing applications. This work shows the potential of F-GDY/Li-SPE devices for low-power neuromorphic computing, though real-time parallel processing and multimodal integration (e.g., visual, auditory) remain unexplored. However, the biocompatibility and efficient ion-assisted transmission of F-GDY suggest promising future applications in these areas.

Desipramine reverses remote memory deficits by activating calmodulin-CaMKII pathway in a UTX knockout mouse model of Kabuki syndrome.

Kabuki syndrome (KS) is a rare developmental disorder characterised by multiple congenital anomalies and intellectual disability. UTX (ubiquitously transcribed tetratricopeptide repeat, X chromosome), which encodes a histone demethylase, is one of the two major pathogenic risk genes for KS. Although intellectual disability is a key phenotype of KS, the role of UTX in cognitive function remains unclear. Currently, no targeted therapies are available for KS. This study aimed to investigate how UTX regulates cognition, to explore the mechanisms underlying UTX dysfunction and to identify potential molecular targets for treatment. We generated UTX conditional knockout mice and found that UTX deletion downregulated calmodulin transcription by disrupting H3K27me3 (trimethylated histone H3 at lysine 27) demethylation. UTX-knockout mice showed decreased phosphorylation of calcium / calmodulin-dependent protein kinase II, impaired long-term potentiation and deficit in remote contextual fear memory. These effects were reversed by an Food and Drug Administration-approved drug desipramine. Our results reveal an epigenetic mechanism underlying the important role of UTX in synaptic plasticity and cognitive function, and suggest that desipramine could be a potential treatment for KS.

TDCS and local scalp cooling do not change corticomotor and intracortical excitability in healthy humans

ObjectiveScalp cooling might increase the long-term potentiation (LTP)-like effect of transcranial direct current stimulation (tDCS) by reducing the threshold for after-effects according to metaplasticity and increasing electrical current density reaching the cortical neurons. We aimed to investigate whether priming scalp cooling potentiates the tDCS after-effect on motor cortex excitability. MethodsThis study had a randomized, parallel-arms, sham-controlled, double-blinded design with an adequately powered sample of 105 healthy subjects. Corticomotor and intracortical excitability were assessed with motor evoked potentials (MEP) from transcranial magnetic stimulation (TMS) in short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) paradigms. Subjects were randomly allocated into six intervention groups, including anodal and cathodal tDCS (1-mA/20-min), scalp cooling, and sham. MEPs were recorded before, immediately, and 15 min after the interventions. ResultsWe did not observe changes in MEP amplitude from single-pulse TMS, SICI, and ICF with any intervention protocol. ConclusionAnodal and cathodal tDCS did not have an LTP-like neuromodulatory effect on corticospinal and did not provide detectable GABAergic and glutamatergic neurotransmission changes, which were not influenced by priming scalp cooling. SignificanceWe provide strong evidence that tDCS (1-mA/20-min) does not alter corticomotor and intracortical excitability with or without priming scalp cooling.

Impaired hippocampal plasticity associated with loss of recycling endosomal SLC9A6/NHE6 is ameliorated by the TrkB agonist 7,8-dihydroxyflavone

Proper maintenance of intracellular vesicular pH is essential for cargo trafficking during synaptic function and plasticity. Mutations in the SLC9A6 gene encoding the recycling endosomal pH regulator (Na+, K+)/H+ exchanger isoform 6 (NHE6) are causal for Christianson syndrome (CS), a severe form of X-linked intellectual disability. NHE6 expression is also downregulated in other neurodevelopmental and neurodegenerative disorders, such as autism spectrum disorder and Alzheimer's disease, suggesting its dysfunction could contribute more broadly to the pathophysiology of other neurological conditions. To understand how ablation of NHE6 function leads to severe learning impairments, we assessed synaptic structure, function, and cellular mechanisms of learning in a novel line of Nhe6 knockout (KO) mice expressing a plasma membrane-tethered green fluorescent protein within hippocampal neurons. We uncovered significant reductions in dendritic spines density, AMPA receptor (AMPAR) expression, and AMPAR-mediated neurotransmission in CA1 pyramidal neurons. The neurons also failed to undergo functional and structural enhancement during long-term potentiation (LTP). Significantly, the selective TrkB agonist 7,8-dihydroxyflavone restored spine density as well as functional and structural LTP in KO neurons. TrkB activation thus may act as a potential clinical intervention to ameliorate cognitive deficits in CS and other neurodegenerative disorders.

Neuroprotective Properties of Rutin Hydrate against Scopolamine-Induced Deficits in BDNF/TrkB/ERK/CREB/Bcl2 Pathways.

Background/Objectives: Alzheimer's disease (AD) is an age-related degenerative brain disorder characterized by a progressive decline in cognitive function and memory. This study aimed to evaluate whether rutin hydrate (RH) has neuroprotective effects in an AD-like learning and memory impairment rat model induced by scopolamine (SCO). Methods: The rats were administered with RH (100 mg/kg) and SCO (1.5 mg/kg) and underwent behavioral tests, including the Morris water maze test, Y-maze test, and passive avoidance test, to evaluate their learning and memory abilities. Additionally, long-term potentiation (LTP) was induced to observe changes in the field excitatory postsynaptic potential (fEPSP) activity. Results: RH treatment attenuated the SCO-induced shortening of step-through latency in the passive avoidance (PA) test, increased the percentage of alternation in the Y-maze, and increased the time spent in the target zone in the Morris water maze (MWM). Moreover, RH increased the total activity of fEPSP following theta burst stimulation and attenuated the SCO-induced blockade of fEPSP. RH also ameliorated the SCO-induced decrease in the expression levels of the BDNF, TrkB, ERK, CREB, and Bcl-2 proteins and the increase in the Bax protein level in the rat hippocampus. This demonstrates that RH has beneficial neuroprotective effects in the brain, improving learning, memory, and synaptic plasticity in rats. Conclusions: Our results highlight the molecular and cellular mechanisms through which RH exerts its neuroprotective effects in the prevention and treatment of learning and memory deficit disorders. RH could potentially be used as a therapeutic strategy for the restoration of learning and memory function and the prevention of the progression of AD.

Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE

APOE is a major genetic factor in late-onset Alzheimer’s disease (LOAD), with APOE4 increasing risk, APOE3 acting as neutral, and APOE2 offering protection. APOE also plays key role in lipid metabolism, affecting both peripheral and central systems, particularly in lipoprotein metabolism in triglyceride and cholesterol regulation. APOE2 is linked to Hyperlipoproteinemia type III (HLP), characterized by mixed hypercholesterolemia and hypertriglyceridemia due to impaired binding to Low-Density Lipoproteins receptors. To explore the impact of human APOE isoforms on LOAD and lipid metabolism, we developed Long-Evans rats with human APOE2, APOE3, or APOE4 in place of rat Apoe. These rats were crossed with those carrying a humanized App allele to express human Aβ, which is more aggregation-prone than rodent Aβ, enabling the study of human APOE-human Aβ interactions. In this study, we focused on 80-day-old adolescent rats to analyze early changes that may be associated with the later development of LOAD. We found that APOE2hAβ rats had the highest levels of APOE in serum and brain, with no significant transcriptional differences among isoforms, suggesting variations in protein translation or stability. Aβ43 levels were significantly higher in male APOE4hAβ rats compared to APOE2hAβ rats. However, no differences in Tau or phosphorylated Tau levels were observed across the APOE isoforms. Neuroinflammation analysis revealed lower levels of IL13, IL4 and IL5 in APOE2hAβ males compared to APOE4hAβ males. Neuronal transmission and plasticity tests using field Input-Output (I/O) and long-term potentiation (LTP) recordings showed increased excitability in all APOE-carrying rats, with LTP deficits in APOE2hAβand APOE4hAβ rats compared to ApoehAβ and APOE3hAβ rats. Additionally, a lipidomic analysis of 222 lipid molecular species in serum samples showed that APOE2hAβ rats displayed elevated triglycerides and cholesterol, making them a valuable model for studying HLP. These rats also exhibited elevated levels of phosphatidylglycerol, phosphatidylserine, phosphatidylethanolamine, sphingomyelin, and lysophosphatidylcholine. Minimal differences in lipid profiles between APOE3hAβ and APOE4hAβ rats reflect findings from mouse models. Future studies will include comprehensive lipidomic analyses in various CNS regions and at older ages to further validate these models and explore the effects of APOE isoforms on lipid metabolism in relation to AD pathology.

Object Motion Detection Enabled by Reconfigurable Neuromorphic Vision Sensor under Ferroelectric Modulation.

Increasing the demand for object motion detection (OMD) requires shifts of reducing redundancy, heightened power efficiency, and precise programming capabilities to ensure consistency and accuracy. Drawing inspiration from object motion-sensitive ganglion cells, we propose an OMD vision sensor with a simple device structure of a WSe2 homojunction modulated by a ferroelectric copolymer. Under optical mode and intermediate ferroelectric modulation, the vision sensor can generate progressive and bidirectional photocurrents with discrete multistates under zero power consumption. This design enables reconfigurable devices to emulate long-term potentiation and depression for synaptic weights updating, which exhibit 82 states (more than 6 bits) with a uniform step of 6 pA. Such OMD devices also demonstrate nonvolatility, reversibility, symmetry, and ultrahigh linearity, achieving a fitted R2 of 0.999 and nonlinearity values of 0.01/-0.01. Thus, a vision sensor could implement motion detection by sensing only dynamic information based on the brightness difference between frames, while eliminating redundant data from static scenes. Additionally, the neural network utilizing a linear result can recognize the essential moving information with a high recognition accuracy of 96.8%. We also present the scalable potential via a uniform 3 × 3 neuromorphic vision sensor array. Our work offers a platform to achieve motion detection based on controllable and energy-efficient ferroelectric programmability.

Treadmill Exercise Facilitates Synaptic Plasticity in APP/PS1 Mice by Regulating Hippocampal AMPAR Activity.

Accumulating evidence underscores exercise as a straightforward and cost-effective lifestyle intervention capable of mitigating the risk and slowing the emergence and progression of Alzheimer's disease (AD). However, the intricate cellular and molecular mechanisms mediating these exercise-induced benefits in AD remain elusive. The present study delved into the impact of treadmill exercise on memory retrieval performance, hippocampal synaptic plasticity, synaptic morphology, and the expression and activity of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptors (AMPARs) in 6-month-old APP/PS1 mice. APP/PS1 mice (4-month-old males) were randomly assigned to either a treadmill exercise group or a sedentary group, with C57BL/6J mice (4-month-old males) as the control group (both exercise and sedentary). The exercise regimen spanned 8 weeks. Our findings revealed that 8-week treadmill exercise reversed memory retrieval impairment in step-down fear conditioning in 6-month-old APP/PS1 mice. Additionally, treadmill exercise enhanced basic synaptic strength, short-term potentiation (STP), and long-term potentiation (LTP) of the hippocampus in these mice. Moreover, treadmill exercise correlated with an augmentation in synapse numbers, refinement of synaptic structures, and heightened expression and activity of AMPARs. Our findings suggest that treadmill exercise improves behavioral performance and facilitates synaptic transmission by increasing structural synaptic plasticity and the activity of AMPARs in the hippocampus of 6-month-old APP/PS1 mice, which is involved in pre- and postsynaptic processes.

Increased protein kinase Mζ expression by Minocycline and N-acetylcysteine restores late-phase long-term potentiation and spatial learning after closed head injury in mice.

Cognitive deficits frequently arise after traumatic brain injury. The murine closed head injury (CHI) models these deficits since injured mice cannot acquire Barnes maze. Dosing of minocycline plus N-acetylcysteine beginning 12 hours post-CHI (MN12) restores Barnes maze acquisition by an unknown mechanism. Increased hippocampal synaptic efficacy is needed to acquire Barnes maze, synaptic long-term potentiation (LTP) models this increased synaptic efficacy in vitro . LTP has an early phase (E-LTP) lasting up to one hour that is mediated by second messengers that is followed by a late phase (L-LTP) that needs new synthesis of protein kinase M zeta (PKMζ). PKMζ has constitutive kinase activity because it lacks the autoinhibitory regulatory domain found in other PKCs. Due to its constitutive activity, the amount of PKMζ kinase activity is determined by PKMζ protein levels. We report that CHI bilaterally decreases PKMζ levels in the CA3 and CA1 hippocampus. MN12 increases CA1 PKMζ expression. CHI inhibits E-LTP in slices from the ipsilesional hippocampus and inhibits L-LTP in slices from both hippocamppi. MN12 treatment reestablishes both E-LTP and L-LTP in slices from the injured MN12-treated hippocampus. The restoration of L-LTP from injured MN12-treated hippocampus is mediated by PKMζ because L-LTP is blocked by the specific PKMζ inhibitor, ζ-stat. Hippocampal ζ-stat infusions also prevents Barnes maze acquisition in injured, MN12-treated mice. These data suggest that post-injury minocycline plus N-acetylcysteine targets PKMζ to improve synaptic plasticity and cognition in mice with closed-head injury.

Increased neuronal expression of the early endosomal adaptor APPL1 leads to endosomal and synaptic dysfunction with cholinergic neurodegeneration.

Dysfunction in the endolysosomal system within neurons is a key feature of Alzheimer's disease (AD). Multiple AD risk factors lead to hyperactivity of the early-endosome GTPase rab5, disrupting neuronal pathways including the cholinergic circuits involved early in memory decline. APPL1, a crucial rab5 effector, connects endosomal and neuronal functions through its interaction with a specific amyloid precursor protein (APP) fragment generated within endosomes. To understand APPL1's role, a transgenic mouse model over-expressing human APPL1 in neurons (Thy1-APPL1 mice) was developed. These mice show enlarged early endosomes and increased synaptic endocytosis due to rab5 activation, resulting in impaired hippocampal long-term potentiation and depression, the degeneration of basal forebrain cholinergic neurons, and memory deficits, highlighting a pathological cascade mediated through APPL1 at the early endosome.

Inducing Long-Term Plasticity of Intrinsic Neuronal Excitability in Neurons of the Dorsal Lateral Geniculate Nucleus.

The dorsal lateral geniculate nucleus (dLGN) has long been held to act as a basic relay for visual information traveling from the retina to cortical areas, but recent findings suggest largely underestimated functional plasticity of dLGN principal cells. However, the cellular mechanisms supporting these changes have not been fully explored. Here, we report a protocol to induce long-term potentiation of intrinsic neuronal excitability (LTP-IE) in dorsal dLGN relay cells from acute brain slices of young rats. Intrinsic plasticity is generally induced in parallel with synaptic plasticity. However, in dLGN neurons, LTP-IE is reliably induced by spiking activity at a frequency of 40 Hz for 10 min. LTP-IE in dLGN relay neurons is long-lasting as it can be followed up to 40 min after the induction protocol. In conclusion, the results of this study provide the first evidence for the induction of intrinsic plasticity in dLGN relay cells, thus further pointing to the role of thalamic neurons in activity-dependent visual plasticity.

Median raphe glutamatergic neuron-mediated enhancement of GABAergic transmission and suppression of long-term potentiation in the hippocampus

The ascending neuromodulatory pathway from the median raphe nucleus (MRN) extends widely throughout midline/para-midline regions and robustly innervates the hippocampus. This neuromodulatory pathway is believed to be critical for regulating emotional and affective behaviors. Although the MRN primarily contains serotoninergic (5-HTergic), GABAergic, and glutamatergic neurons, glutamatergic neurons expressing vesicular glutamate transporter 3 (VGLUT3) form the primary MRN input to the hippocampus. Despite the earlier demonstration of the robust MRN VGLUT3 innervation of the hippocampus, little is known about how this MRN glutamatergic input modulates synaptic transmission and plasticity in the hippocampus. Our studies show that MRN VGLUT3 neurons activate serotonin 3a receptor (5-HT3aR)-expressing GABAergic neurons, including VGLUT3-expressing neurons, at the stratum radiatum (SR)/stratum lacunosum moleculare (SLM) border. This MRN VGLUT3 neuron-mediated glutamatergic transmission onto SR/SLM 5-HT3aR neurons is negatively regulated by 5-HT through 5-HT1B receptors. In agreement with the MRN VGLUT3 neuron-mediated activation of the 5-HT3aR GABAergic neurons, activation of MRN VGLUT3 projections induces a long-lasting increase in GABAergic transmission but not glutamatergic transmission in CA1 pyramidal neurons from male but not female mice. Consistent with the MRN VGLUT3 neuron-mediated enhancement of GABAergic transmission in male mice, activation of MRN VGLUT3 projections suppresses Schaffer collateral (SC)-CA1 long-term potentiation (LTP) in male but not female mice. Thus, our results show that MRN VGLUT3 neurons modulate the dorsal hippocampus by augmenting synaptic inhibition of CA1 pyramidal neurons and by suppressing SC-CA1 LTP in a sex-specific manner.

GnRH protective effects against long-term potentiation impairment induced by AANAT-siRNA

There is an interplay between the gonadotropin-releasing hormone (GnRH) and melatoninergic systems. The key enzyme of melatonin synthesis (arylalkylamine N-acetyltransferase, AANAT), and GnRH receptors are expressed in the hippocampus. While it has been shown that hippocampal AANAT enzyme activity is necessary for proper hippocampal cognitive function, their role in long-term potentiation (LTP) induction is not fully understood. In current study, the impact of GnRH on LTP induction was investigated, while hippocampal melatonin synthesis had been inhibited. The melatonin synthesis was inhibited by AANAT-siRNA administration, and LTP was induced using in vivo field potential electrophysiological recording.Animals were divided into 5 groups: Intact, vehicle, siRNA, GnRH and siRNA+GnRH. All animals, except intact group, experienced the stereotaxic surgery and intra-hippocampal cannulation to receive vehicle agent, AANAT siRNA (0.5 μg/hip), GnRH (1 ng/rat), and AANAT siRNA+GnRH. The recognition memory was assessed by Novel object recognition test. The field potential electrophysiology experiment was conducted by stimulating the Schaffer collateral pathway, and LTP induction was carried out through high-frequency stimulation (HFS). After recording, animals' brain was isolated and quickly frozen for further hippocampal melatonin levels measurement by LC-MS and AANAT mRNA levels by qRT-PCR.GnRH injection in the hippocampus increased local AANAT-mRNA expression and melatonin levels. GnRH-treated animals displayed higher LTP amplitude compared to intact, vehicle and siRNA groups. While the reduction in hippocampal melatonin levels by AANAT-siRNA inhibited LTP and impaired recognition memory, the GnRH prevented these adverse effects. The data suggests that GnRH have protective effects against AANAT-siRNA-induced LTP decline. The protective mechanism at least partially, may be related to the increased expression of local AANAT-mRNA.

Lasting effects of transcranial direct current stimulation on the inducibility of synaptic plasticity by paired-associative stimulation in humans

BackgroundTranscranial direct current stimulation (tDCS) is capable of eliciting changes in cortical neuroplasticity. Increasing duration or repetition of tDCS during the after-effects of a first stimulation has been hypothesized to enhance efficacy. Computational models suggest sequential stimulation patterns with changing polarities to further enhance effects. Lasting tDCS effects on neural plasticity are of great importance for clinical applications.ObjectiveThe study systematically examined the influence of different tDCS paradigms on long term potentiation (LTP)-like plasticity in humans, focusing on stimulation duration, repetition frequency and sequential combinations of changing polarities as the underlying characteristics.MethodsAmplitude changes of motor evoked potentials (MEP) were measured in response to paired associative stimulation (PAS) 6 h after application of different tDCS protocols. In total, 36 healthy participants completed the study, randomised into three groups with different stimulation protocols (N = 12 each).ResultstDCS was able to display lasting modulatory effects on the inducibility of LTP-like plasticity in the human motor cortex 6 h after stimulation. TDCS with the anode on primary motor cortex significantly increased MEP amplitudes following PAS induction. Further analyses highlighted single stimulation block duration to be of higher importance than repetitive protocols for efficacy of effects.ConclusionstDCS is capable of inducing lasting changes in the brain’s capability to interact with future stimuli. Especially, effects on the inducibility of LTP-like plasticity might only be detectable with specific tests such as PAS and might otherwise be overlooked. Refined tDCS protocols should focus on higher current and duration of single stimulations instead of implementing complex repetitive schedules.