Modulation Of Synaptic Plasticity Research Articles

Insulin potential in preventing brain damage after traumatic brain injury: What we know.

Traumatic brain injury (TBI) is a major global cause of disability and mortality. TBI results in a spectrum of primary and secondary injuries that impact neural function and overall survival. Insulin, beyond its well-known role in regulating blood glucose levels, plays critical roles in the central nervous system (CNS). These roles include the modulation of synaptic plasticity, neurotransmitter levels, neurogenesis, and neuroprotection. Central insulin resistance, a reduced sensitivity to insulin in the brain, has been observed in TBI patients. This insulin resistance impairs insulin function in the brain and increases the risk of neurodegenerative processes. This review will delve into the central role of insulin resistance in the pathological changes observed after TBI and explore the potential benefits of insulin therapy as a treatment approach for TBI.

Exploring the role of Cdk5 on striatal synaptic plasticity in a 3-NP-induced model of early stages of Huntington’s disease

Impaired mitochondrial function has been associated with the onset of neurodegenerative diseases. Specifically, certain mitochondrial toxins, such as 3-nitropropionic acid (3-NP), initiate cellular changes within the striatum that closely resemble the pathology observed in Huntington’s disease (HD). Among the pivotal signaling molecules contributing to neurodegeneration, cyclin-dependent kinase 5 (Cdk5) stands out. In particular, Cdk5 has been implicated not only in cellular pathology but also in the modulation of synaptic plasticity. Given its widespread presence in the striatum, this study seeks to elucidate the potential role of Cdk5 in the induction of corticostriatal synaptic plasticity in murine striatal cells subjected to subchronic doses of 3-NP in vivo, aiming to mimic the early stages of HD. Immunostaining analyses revealed an increase in Cdk5 in tissues from animals treated with 3-NP, without a significant change in protein levels. Regarding striatal plasticity, long-term depression (LTD) was induced in both control and 3-NP cells when recorded in voltage clamp mode. The Cdk5 inhibitor roscovitine-reduced LTD in most cells. A minority subset of cells exhibited long-term potentiation (LTP) generation in the presence of roscovitine. The inhibitor of D1 receptors SCH23390 prevented LTP in three of nine cells, implying that MSN cells lacking D1/PKA activation were capable of LTP induction when Cdk5 was also blocked. Nevertheless, the co-administration of H89, a PKA inhibitor, along with roscovitine, prevented the generation of any type of plasticity in all recorded cells. These findings show the impact of 3-NP treatment on striatal plasticity and suggest that Cdk5 during early neurodegeneration may attenuate signaling pathways that lead neurons to increase their activity.

Paraventricular hypothalamic RUVBL2 neurons suppress appetite by enhancing excitatory synaptic transmission in distinct neurocircuits

The paraventricular hypothalamus (PVH) is crucial for food intake control, yet the presynaptic mechanisms underlying PVH neurons remain unclear. Here, we show that RUVBL2 in the PVH is significantly reduced during energy deficit, and knockout (KO) of PVH RUVBL2 results in hyperphagic obesity in mice. RUVBL2-expressing neurons in the PVH (PVHRUVBL2) exert the anorexigenic effect by projecting to the arcuate hypothalamus, the dorsomedial hypothalamus, and the parabrachial complex. We further demonstrate that PVHRUVBL2 neurons form the synaptic connections with POMC and AgRP neurons in the ARC. PVH RUVBL2 KO impairs the excitatory synaptic transmission by reducing presynaptic boutons and synaptic vesicles near active zone. Finally, RUVBL2 overexpression in the PVH suppresses food intake and protects against diet induced obesity. Together, this study demonstrates an essential role for PVH RUVBL2 in food intake control, and suggests that modulation of synaptic plasticity could be an effective way to curb appetite and obesity.

Organic heterojunction memristors with enhanced tunable resistive states for artificial synapses

Tunable and uniform evolution of conductance is the key performance metric for neuromorphic computing leveraging memristors. Nonetheless, the stochastic conductance update associated with limited material composition and uncontrollable filament distribution has restricted the tunability that can be customized for targeted synaptic properties. Here, we introduce organic heterojunction memristors utilizing the C60/P3HT bilayer, demonstrating analog switching characteristics with multilevel conductance states. We demonstrate that both conventional bipolar and unipolar voltages can achieve synaptic plasticity modulation for potentiation and depression, offering enhanced tunability. Through in situ Raman spectroscopy and impedance spectroscopy, we directly observe the dynamic alterations within the active layers during switching processes. The reversible migration of ions diminishes the barrier within the polymer layer, leading to highly uniform resistive switching behavior. The C60 layer functions as a confined transport medium, mitigating critical current variability issues. Moreover, we introduce a shunt resistor approach, furnishing analog memristors with selectively adjustable uniformity, enhanced linearity, and expanded dynamic conductance range, providing a general solution adaptable to various memristive hardware architectures.

Effects of voltage schemes on the conductance modulation of artificial synaptic device based on 2D hBN memristor: Its applications for pattern classifications

Artificial synaptic devices utilizing nonvolatile memristors with 2D materials show potential for neuromorphic computing systems due to their intriguing electrical properties, simple structure, and capability to emulate biological synaptic behaviors. Here, we fabricated nonvolatile memristors based on 2D multilayer hBN film and demonstrated their analog memory performance along with biological synaptic characteristics, including paired-pulse facilitation and depression (PPF and PPD), and synaptic plasticity. We utilized different voltage scheme algorithms to analyze the impact of synaptic functions on image classification tasks across various pattern datasets through simulations. Our findings reveal that pattern recognition outcomes varied due to the modulation of synaptic plasticity by the applied voltage schemes. We also investigated the relationship between conductance update variations and classification accuracy to highlight the significance of optimized synaptic plasticity in improving image recognition capabilities in large-scale neural networks. Our experimental results contribute to the development of high-performance neuromorphic computing for diverse pattern classification tasks using artificial synaptic devices based on 2D hBN.

Caprylic acid promotes synaptic plasticity potentially through enhancing Leptin/NM2B signaling

Synaptic plasticity is crucial for memory formation and can be impaired in metabolic diseases. Insulin and insulin-like growth factors play important roles in synaptic plasticity, while leptin protects neurons and stimulates growth. Diets can affect synaptic plasticity through macronutrients and appetite signals, highlighting the need for deeper research and interventions for synaptic dysfunction in metabolic diseases. Recent research suggests that while saturated fatty acids (SFA) have been viewed as unhealthy for cognition, they may benefit memory and learning in certain conditions. High levels of SFA were found to improve recollection in young people. In specific, low-level intake of caprylic acid may reduce neuroinflammation and protect against neural degeneration. This anti-neuroinflammatory effect of caprylic acid may be mediated through the JAK2/STAT3 signaling pathway, which is a crucial part in the modulation of synaptic plasticity by leptin/NM2B signaling. Therefore, this work hypothesized that caprylic acid can enhance leptin/NM2B signaling pathway by increasing the expression of JAK2/STAT3 signaling pathway. In this proposal, a 12-week mice experiment is proposed with fEPSP measurements, immunoblotting, and immunoprecipitation to test the long-term potentiation (LTP) and the expression level as well as regions of the signaling molecules. This work may offer another perspective on the complex role of SFA in brain health.

The dose-dependent effect of the D2R agonist quinpirole microinjected into the ventral pallidum on information flow in the limbic system

The ventral pallidum (VP) receives its primary inputs from the nucleus accumbens (NAC) and the basolateral amygdala (BLA). We demonstrated recently that in the VP, the D2 DA receptor (D2R) agonist quinpirole dose-dependently facilitates memory consolidation in inhibitory avoidance and spatial learning. In the VP, D2R can be found both on NAC and BLA terminals. According to our hypothesis, quinpirole microinjected into the VP can facilitate memory consolidation via modulation of synaptic plasticity on NAC and/or BLA terminals.The effect of intra-VP quinpirole on BLA-VP and NAC shell-VP synapses was investigated via a high frequency stimulation (HFS) protocol. Quinpirole was administered in three doses into the VP of male Sprague-Dawley rats after HFS; controls received vehicle. To examine whether an interaction between the NAC shell and the BLA at the level of the VP was involved, tetrodotoxin (TTX) was microinjected into one of the nuclei while stimulating the other nucleus.Our results showed that quinpirole dose-dependently modulates BLA-VP and NAC shell-VP synapses, similar to those observed in inhibitory avoidance and spatial learning, respectively. The lower dose inhibits BLA inputs, while the larger doses facilitates NAC shell inputs. The experiments with TTX demonstrates that the two nuclei do not influence each others' evoked responses in the VP.Power spectral density analysis demonstrated that independent from the synaptic facilitation, intra-VP quinpirole increases the amplitude of gamma frequency band after NAC HFS, and BLA tonically suppresses the NAC's HFS-induced gamma facilitation. In contrast, HFS of the BLA results in a delayed, transient increase in the amplitude of the gamma frequency band correlating with the LTP of the P1 component of the VP response to BLA stimulation.Furthermore, our results demonstrate that the BLA plays a prominent role in the generation of the delta oscillations: HFS of the BLA leads to a gradually increasing delta frequency band facilitation over time, while BLA inhibition blocks the NAC's HFS induced strong delta facilitation.These findings demonstrate that there is a complex interaction between the NAC shell region and the VP, as well as the BLA and the VP, and support the important role of VP D2Rs in the regulation of limbic information flow.

Astrocyte modulation of synaptic plasticity mediated by activity-dependent Sonic hedgehog signaling.

The influence of neural activity on astrocytes and their reciprocal interactions with neurons has emerged as an important modulator of synapse function. Astrocytes exhibit activity-dependent changes in gene expression, yet the molecular mechanisms by which they accomplish this have remained largely unknown. The molecular signaling pathway, Sonic hedgehog (Shh), mediates neuron-astrocyte communication and regulates the organization of cortical synapses. Here, we demonstrate that neural activity stimulates Shh signaling in cortical astrocytes and upregulates expression of Hevin and SPARC, astrocyte derived molecules that modify synapses. Whisker stimulation and chemogenetic activation both increase Shh activity in deep layers of the somatosensory cortex, where neuron-astrocyte Shh signaling is predominantly found. Experience-dependent Hevin and SPARC require intact Shh signaling and selective loss of pathway activity in astrocytes occludes experience-dependent structural plasticity. Taken together, these data identify Shh signaling as an activity-dependent, neuronal derived cue that stimulates astrocyte interactions with synapses and promotes synaptic plasticity.

Bidirectional modulation of synaptic transmission by insulin-like growth factor-I.

Insulin-like growth factor-I (IGF-I) plays a key role in the modulation of synaptic plasticity and is an essential factor in learning and memory processes. However, during aging, IGF-I levels are decreased, and the effect of this decrease in the induction of synaptic plasticity remains unknown. Here we show that the induction of N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) at layer 2/3 pyramidal neurons (PNs) of the mouse barrel cortex is favored or prevented by IGF-I (10 nM) or IGF-I (7 nM), respectively, when IGF-I is applied 1 h before the induction of Hebbian LTP. Analyzing the cellular basis of this bidirectional control of synaptic plasticity, we observed that while 10 nM IGF-I generates LTP (LTPIGF-I) of the post-synaptic potentials (PSPs) by inducing long-term depression (LTD) of the inhibitory post-synaptic currents (IPSCs), 7 nM IGF-I generates LTD of the PSPs (LTDIGF-I) by inducing LTD of the excitatory post-synaptic currents (EPSCs). This bidirectional effect of IGF-I is supported by the observation of IGF-IR immunoreactivity at both excitatory and inhibitory synapses. Therefore, IGF-I controls the induction of Hebbian NMDAR-dependent plasticity depending on its concentration, revealing novel cellular mechanisms of IGF-I on synaptic plasticity and in the learning and memory machinery of the brain.

Study on the Role of Physical Fields in TMAS to Modulate Synaptic Plasticity in Mice.

Transcranial magneto-acoustic stimulation (TMAS) is a composite technique combining static magnetic and coupled electric fields with transcranial ultrasound stimulation (TUS) and has shown advantages in neuromodulation. However, the role of these physical fields in neuromodulation is unclear. Synaptic plasticity is the cellular basis for learning and memory. In this paper, we varied the intensity of static magnetic, electric and ultrasonic fields respectively to investigate the modulation of synaptic plasticity by these physical fields. There are control, static magnetic field (0.1 T/0.2 T), TUS (0.15/0.3 MPa), and TMAS (0.15 MPa + 0.2 V/m, 0.3 MPa + 0.2 V/m, 0.3 MPa + 0.4 V/m) groups. Hippocampal areas were stimulated at 5 min daily for 7 days and in vivo electrophysiological experiments were performed. TMAS induced greater LTP, LTD, and paired-pulse ratio (PPR) than TUS, reflecting that TMAS has a more significant modulation in both long- and short- term synaptic plasticity. In TMAS, a doubling of the electric field amplitude increases LTP, LTD and PPR to a greater extent than a doubling of the acoustic pressure. Increasing the static magnetic field intensity has no significant effect on the modulation of synaptic plasticity. This paper argues that electric fields should be the main reason for the difference in modulation between TMAS and TUS and that changing the amplitude of the electric field affected the modulation of TMAS more than changing the acoustic pressure. This study elucidates the roles of the physical fields in TMAS and provides a parameterisation way to guide TMAS applications based on the dominant roles of the physical fields.

Broadband Artificial Tetrachromatic Synaptic Devices Composed of 2D/3D Integrated WSe2‐GaN‐based Dual‐Channel Floating Gate Transistors

AbstractThe development of artificial tetrachromatic vision holds great potential to enhance human color perception and discrimination, thereby enabling more effective navigation in diverse environments. Herein, an artificial tetrachromatic synaptic device is presented built upon 2D‐3D vertically stacked semiconductors composed of tungsten diselenide (WSe2)‐gallium nitride (GaN) configuration, forming a dual‐channel floating gate transistor (FGT). Under the concerted influence of electrical and optical stimulation, the device successfully mimics fundamental tetrachromatic synaptic behaviors, including short‐term potentiation (STP), weak long‐term potentiation (wLTP), long‐term potentiation (LTP), paired‐pulse facilitation (PPF), spike number‐dependent plasticity (SNDP), and spike rate‐dependent plasticity (SRDP). Notably, the plasticity of the device can be further modulated under ultraviolet (UV) stimulation, providing insights into the modulation of synaptic plasticity through the photogenerated carrier dynamics in the GaN channel. These results imply that WSe2‐GaN‐based FGT architecture with dual‐channel characteristics seamlessly integrates optical sensing and synaptic simulation functionalities, representing a promising avenue for the development of next‐generation artificial visual perception systems (AVPS), with a particular advantage for the pursuit of high‐performance artificial tetrachromatic neuromorphic computing applications of the future.

Synaptic Plasticity Modulation of Neuromorphic Transistors through Phosphorus Concentration in Phosphosilicate Glass Electrolyte Gate.

This study proposes a phosphosilicate glass (PSG)-based electrolyte gate synaptic transistor with varying phosphorus (P) concentrations. A metal oxide semiconductor capacitor structure device was employed to measure the frequency-dependent (C-f) capacitance curve, demonstrating that the PSG electric double-layer capacitance increased at 103 Hz with rising P concentration. Fourier transform infrared spectroscopy spectra analysis facilitated a theoretical understanding of the C-f curve results, examining peak differences in the P-OH structure based on P concentration. Using the proposed synaptic transistors with different P concentrations, changes in the hysteresis window were investigated by measuring the double-sweep transfer curves. Subsequently, alterations in proton movement within the PSG and charge characteristics at the channel/PSG electrolyte interface were observed through excitatory post-synaptic currents, paired-pulse facilitation, signal-filtering functions, resting current levels, and potentiation and depression characteristics. Finally, we demonstrated the proposed neuromorphic system's feasibility based on P concentration using the Modified National Institute of Standards and Technology learning simulations. The study findings suggest that, by adjusting the PSG film's P concentration for the same electrical stimulus, it is possible to selectively mimic the synaptic signal strength of human synapses. Therefore, this approach can positively contribute to the implementation of various neuromorphic systems.

Astrocyte ryanodine receptors facilitate gliotransmission and astroglial modulation of synaptic plasticity.

Intracellular Ca2+-signaling in astrocytes is instrumental for their brain "housekeeping" role and astroglial control of synaptic plasticity. An important source for elevating the cytosolic Ca2+ level in astrocytes is a release from endoplasmic reticulum which can be triggered via two fundamental pathways: IP3 receptors and calcium-induced calcium release (CICR) mediated by Ca2+-sensitive ryanodine receptors (RyRs). While the physiological role for glial IP3 became a focus of intensive research and debate, ryanodine receptors received much less attention. We explored the role for ryanodine receptors in the modulation of cytosolic Ca2+-signaling in the cortical and hippocampal astrocytes, astrocyte-neuron communication and astroglia modulation of synaptic plasticity. Our data show that RyR-mediated Ca2+-induced Ca2+-release from ER brings substantial contribution into signaling in the functional microdomains hippocampal and neocortical astrocytes. Furthermore, RyR-mediated CICR activated the release of ATP and glutamate from hippocampal and neocortical astrocytes which, in turn, elicited transient purinergic and tonic glutamatergic currents in the neighboring pyramidal neurons. The CICR-facilitated release of ATP and glutamate was inhibited after intracellular perfusion of astrocytes with ryanodine and BAPTA and in the transgenic dnSNARE mice with impaired astroglial exocytosis. We also found out that RyR-mediated amplification of astrocytic Ca2+-signaling enhanced the long-term synaptic potentiation in the hippocampus and neocortex of aged mice. Combined, our data demonstrate that ryanodine receptors are essential for astrocytic Ca2+-signaling and efficient astrocyte-neuron communications. The RyR-mediated CICR contributes to astrocytic control of synaptic plasticity and can underlie, at least partially, neuroprotective and cognitive effects of caffein.

Impact of (Co–Fe–B)x(LiNbO3)100–x Nanocomposite Memristors Characteristics Dispersion on Dopamine-Like Modulation of Synaptic Plasticity

Impact of (Co–Fe–B)x(LiNbO3)100–x Nanocomposite Memristors Characteristics Dispersion on Dopamine-Like Modulation of Synaptic Plasticity

Piezo-phototronic effect modulated optoelectronic artificial synapse based on a-Ga2O3/ZnO heterojunction

Amorphous gallium oxide (a-Ga2O3) based optoelectronic devices responds to deep ultraviolet (DUV), which triggers their potential applications for simulating biological vision system. However, there is still lack of research on the influence of multiple stimuli on regulating synaptic plasticity in artificial synapse. Herein, we reported a flexible a-Ga2O3/ZnO film heterostructure with tunable DUV photoresponse, serving as a promising platform for artificial optoelectronic synapse. Based on persistent photoconductivity effect under 265 nm illumination, basic synaptic functions have been mimicked. Notably, the strain-induced piezo-phototronic effect of the heterojunction enables the modulation of synaptic plasticity, playing a role analogous to neuromodulator interaction with biological synapse activity. Strain-evoked an additional degree of freedom controls synapse weight-update rate during learning process and synapse weight-decay during forgetting process. The underlying mechanism is attributed to energy band bending tailored by strain-induced piezo-potential that determines carrier separation/transport and the recombination reaction of ionized oxygen vacancy. The recognition accuracy of MNIST images is as high as 92.31% in the artificial neural network constructed by the heterojunction devices. This work not only exhibits the application prospect of ultra-wide bandgap semiconductor-based heterojunction in artificial optoelectronic synapse, but also opens up a new avenue for multiple stimuli modulating synaptic plasticity.

Light-Stimulated IGZO Transistors with Tunable Synaptic Plasticity Based on Casein Electrolyte Electric Double Layer for Neuromorphic Systems.

In this study, optoelectronic synaptic transistors based on indium-gallium-zinc oxide (IGZO) with a casein electrolyte-based electric double layer (EDL) were examined. The casein electrolyte played a crucial role in modulating synaptic plasticity through an internal proton-induced EDL effect. Thus, important synaptic behaviors, such as excitatory post-synaptic current, paired-pulse facilitation, and spike rate-dependent and spike number-dependent plasticity, were successfully implemented by utilizing the persistent photoconductivity effect of the IGZO channel stimulated by light. The synergy between the light stimulation and the EDL effect allowed the effective modulation of synaptic plasticity, enabling the control of memory levels, including the conversion of short-term memory to long-term memory. Furthermore, a Modified National Institute of Standards and Technology digit recognition simulation was performed using a three-layer artificial neural network model, achieving a high recognition rate of 90.5%. These results demonstrated a high application potential of the proposed optoelectronic synaptic transistors in neuromorphic visual systems.

The Importance of α-Klotho in Depression and Cognitive Impairment and Its Connection to Glutamate Neurotransmission-An Up-to-Date Review.

Depression is a serious neuropsychiatric disease affecting an increasing number of people worldwide. Cognitive deficits (including inattention, poor memory, and decision-making difficulties) are common in the clinical picture of depression. Cognitive impairment has been hypothesized to be one of the most important components of major depressive disorder (MDD; referred to as clinical depression), although typical cognitive symptoms are less frequent in people with depression than in people with schizophrenia or bipolar disorder (BD; sometimes referred to as manic-depressive disorder). The importance of α-Klotho in the aging process has been well-documented. Growing evidence points to the role of α-Klotho in regulating other biological functions, including responses to oxidative stress and the modulation of synaptic plasticity. It has been proven that a Klotho deficit may contribute to the development of various nervous system pathologies, such as behavioral disorders or neurodegeneration. Given the growing evidence of the role of α-Klotho in depression and cognitive impairment, it is assumed that this protein may be a molecular link between them. Here, we provide a research review of the role of α-Klotho in depression and cognitive impairment. Furthermore, we propose potential mechanisms (related to oxidative stress and glutamatergic transmission) that may be important in α-Klotho-mediated regulation of mental and cognitive function.

Neuron-derived extracellular vesicles contain synaptic proteins, promote spine formation, activate TrkB-mediated signalling and preserve neuronal complexity.

Extracellular vesicles (EVs) play an important role in intercellular communication as carriers of signalling molecules such as bioactive miRNAs, proteins and lipids. EVs are key players in the functioning of the central nervous system (CNS) by influencing synaptic events and modulating recipient neurons. However, the specific role of neuron-to-neuron communication via EVs is still not well understood.Here, we provide evidence that primary neurons uptake neuron-derived EVs in the soma, dendrites, and even in the dendritic spines, and carry synaptic proteins. Neuron-derived EVs increased spine density and promoted the phosphorylation of Akt and ribosomal protein S6 (RPS6), via TrkB-signalling, without impairing the neuronal network activity. Strikingly, EVs exerted a trophic effect on challenged nutrient-deprived neurons. Altogether, our results place EVs in the spotlight for synaptic plasticity modulation as well as a possible therapeutic tool to fight neurodegeneration.

Tailoring Neuroplasticity in a Ferroelectric‐Gated Multi‐Terminal Synaptic Transistor by Bi‐Directional Modulation for Improved Pattern Edge Recognition

AbstractThe dynamic modulation of the plasticity of artificial neuromorphic devices facilitates a wide range of neuromorphic functions. However, integrating diverse plasticity modulation techniques into a single device presents a challenge due to limitations in the device structure design. Here, a multiterminal artificial synaptic device capable of bi‐directional modulation on its plasticity is proposed. Significantly, the conversion of inhibitory and excitatory synaptic plasticity can be achieved not only by modifying the polarity of the presynaptic voltage spike but also by exchanging its input terminal between top and bottom gate while maintaining the same presynaptic stimuli. This unique bi‐directional modulation of synaptic plasticity has been attributed to two distinct physical mechanisms: nonvolatile ferroelectric polarization and interface charge trap‐induced memory characteristics. Additionally, the effective dynamic modulation of the synaptic behaviors is quantified under different back‐gate bias and verified in the constructed neural network perceptron. Further, a visual simulation demonstrates the enhanced clarity and precision of edge recognition through the back‐gate modulation in the artificial synapses. This study provides a strategy to fulfill diversified modulation on synaptic plasticity in ferroelectric‐gated transistors, thereby prompting efficient and controllable neuromorphic visual systems.

Insulin-induced long-term potentiation in the dentate gyrus of hippocampal formation

The discovery that brain areas involving in learning and memory express receptors for insulin hormone, led to the idea that insulin signaling may have a role in regulating cognitive function. Although previous studies have shown a role for insulin in regulation of the threshold of plasticity induction, no study has addressed whether insulin can induce a chemical plasticity per se. Young-adult male rats that are fed with standard diets with or without carbohydrate syrup (sucrose or high-fructose corn syrups) were enrolled in this study. Extracellular field potentials were recorded from the dentate gyrus in response to perforant pathway stimulation at 0.033 Hz in anesthetized rats. The slope of field excitatory postsynaptic potentials (fEPSPs) and the amplitude of population spike (PS) were measured 15 min after a 60-min infusion of insulin (500 nM), NT157 (an IRS inhibitor, 6 μM), alone or together, or physiological saline. mRNA expressions of insulin signaling proteins were measured by rt-PCR in the whole hippocampus. We did not observe any appreciable change in the fEPSP slope and the PS amplitude before and after saline infusion. However, intra-hippocampal insulin application results in the induction of LTP of fEPSP and of PS in the dentate gyrus. Insulin infusion together with NT157 inhibited fEPSP-LTP, but not PS-LTP, and rats that are fed with carbohydrate syrup did not express synaptic LTP. In rats that additional carbohydrate syrup is not given, insulin-induced LTP was accompanied with an increase in PI3K-mRNA, AKT-mRNA, and GSK-3β-mRNA which was not observed when co-administered with NT157. The GSK-3β-mRNA and IRS1-mRNA levels were found to be lower in rats that received supplemental carbohydrate and that not express insulin-induced synaptic LTP, compared to the rats expressing synaptic LTP and fed by standard diet. The results obtained provide a mechanistic link between insulin and synaptic plasticity. We concluded that insulin not only functions as a modulator of synaptic plasticity but also acts as a chemical inducer of LTP.