Cortical Long-term Potentiation Research Articles

A functional aged human iPSC-cortical neuron model recapitulates Alzheimer's disease, senescence, and the response to therapeutics.

The degeneration of cortical layers is associated with cognitive decline in Alzheimer's disease (AD). Current therapies for AD are not disease-modifying, and, despite substantial efforts, research and development for AD has faced formidable challenges. In addition, cellular senescence has emerged as a significant contributor to therapy resistance. Human iPSC-derived cortical neurons were cultured on microelectrode arrays to measure long-term potentiation (LTP) noninvasively. Neurons were treated with pathogenic amyloid-β (Aβ) to analyze senescence and response to therapeutic molecules. Microphysiological recordings revealed Aβ dampened cortical LTP activity and accelerated neuronal senescence. Aging neurons secreted inflammatory factors previously detected in brain, plasma, and cerebral spinal fluid of AD patients, in which drugs modulated senescence-related factors. This platform measures and records neuronal LTP activity in response to Aβ and therapeutic molecules in real-time. Efficacy data from similar platforms have been accepted by the FDA for neurodegenerative diseases, expediting regulatory submissions. This work developed a progerontic model of amyloid-β (Aβ)-driven cortical degeneration. This work measured neuronal LTP and correlated function with aging biomarkers. Aβ is a driver of neuronal senescence and cortical degeneration. Molecules rescued neuronal function but did not halt Aβ-driven senescence. Therapeutic molecules modulated secretion of inflammatory factors by aging neurons.

Inhibition of calcium-stimulated adenylyl cyclase subtype 1 (AC1) for the treatment of pain and anxiety symptoms in Parkinson's disease mice model.

Pain and anxiety are two common and undertreated non-motor symptoms in Parkinson's disease (PD), which affect the life quality of PD patients, and the underlying mechanisms remain unclear. As an important subtype of adenylyl cyclases (ACs), adenylyl cyclase subtype 1 (AC1) is critical for the induction of cortical long-term potentiation (LTP) and injury induced synaptic potentiation in the cortical areas including anterior cingulate cortex (ACC) and insular cortex (IC). Genetic deletion of AC1 or pharmacological inhibition of AC1 improved chronic pain and anxiety in different animal models. In this study, we proved the motor deficit, pain and anxiety symptoms of PD in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice model. As a lead candidate AC1 inhibitor, oral administration (1 dose and seven doses) of NB001 (20 and 40mg/kg) showed significant analgesic effect in MPTP-treated mice, and the anxiety behavior was also reduced (40mg/kg). By using genetic knockout mice, we found that AC1 knockout mice showed reduced pain and anxiety symptoms after MPTP administration, but not AC8 knockout mice. In summary, genetic deletion of AC1 or pharmacological inhibition of AC1 improved pain and anxiety symptoms in PD model mice, but didn't affect motor function. These results suggest that NB001 is a potential drug for the treatment of pain and anxiety symptoms in PD patients by inhibiting AC1 target.

Recruitment of cortical silent responses by forskolin in the anterior cingulate cortex of adult mice.

Recent studies using different experimental approaches demonstrate that silent synapses may exist in the adult cortex including the sensory cortex and anterior cingulate cortex (ACC). The postsynaptic form of long-term potentiation (LTP) in the ACC recruits some of these silent synapses and the activity of calcium-stimulated adenylyl cyclases (ACs) is required for such recruitment. It is unknown if the chemical activation of ACs may recruit silent synapses. In this study, we found that activation of ACs contributed to synaptic potentiation in the ACC of adult mice. Forskolin, a selective activator of ACs, recruited silent responses in the ACC of adult mice. The recruitment was long-lasting. Interestingly, the effect of forskolin was not universal, some silent synapses did not undergo potentiation or recruitment. These findings suggest that these adult cortical synapses are not homogenous. The application of a selective calcium-permeable AMPA receptor inhibitor 1-naphthyl acetyl spermine (NASPM) reversed the potentiation and the recruitment of silent responses, indicating that the AMPA receptor is required. Our results strongly suggest that the AC-dependent postsynaptic AMPA receptor contributes to the recruitment of silent responses at cortical LTP.

Impaired long-term potentiation-like motor cortical plasticity in progressive supranuclear palsy

ObjectiveTo elucidate long-term potentiation (LTP)-like effects on the primary motor cortical (M1) in progressive supranuclear palsy (PSP) and its relationships with clinical features. MethodsParticipants were 18 probable/possible PSP Richardson syndrome (PSP-RS) patients and 17 healthy controls (HC). We used quadripulse stimulation (QPS) over the M1 with an interstimulus interval of 5 ms (QPS-5) to induce LTP-like effect and analyzed the correlations between the degree of LTP-like effect and clinical features. We also evaluated cortical excitability using short interval intracortical inhibition (SICI), intracortical facilitation (ICF) and short interval intracortical facilitation (SICF) in 15 PSP patients and 17 HC. ResultsLTP-like effect after QPS in PSP was smaller than HC and negatively correlated with Unified Parkinson’s Disease Rating Scale Part III (UPDRS-III) score, especially bradykinesia, but not with either age or any scores of cognitive functions. The SICI was abnormally reduced in PSP, but neither ICF nor SICF differed from those of normal subjects. None of these cortical excitability parameters correlated with any clinical features. ConclusionsLTP induction was impaired in PSP. The degree of LTP could reflect the severity of bradykinesia. The bradykinesia may partly relate with the motor cortical dysfunction. SignificanceThe degree of motor cortical LTP could relate with the severity of motor symptoms in PSP.

Inhibiting neuronal AC1 for treating anxiety and headache in the animal model of migraine

Migraines are a common medical condition. From a basic science point of view, the central mechanism for migraine and headache is largely unknown. In the present study, we demonstrate that cortical excitatory transmission is significantly enhanced in the anterior cingulate cortex (ACC)-a brain region which is critical for pain perception. Biochemical studies found that the phosphorylation levels of both the NMDA receptor GluN2B and AMPA receptor GluA1 were enhanced in ACC of migraine rats. Both the presynaptic release of glutamate and postsynaptic responses of AMPA receptors and NMDA receptors were enhanced. Synaptic long-term potentiation (LTP) was occluded. Furthermore, behavioral anxiety and nociceptive responses were increased, which were reversed by application of AC1 inhibitor NB001 within ACC. Our results provide strong evidence that cortical LTPs contribute to migraine-related pain and anxiety. Drugs that inhibit cortical excitation such as NB001 may serve as potential medicines for treating migraine in the future.

Interhemispheric cortical long-term potentiation in the auditory cortex requires heterosynaptic activation of entorhinal projection

Long-term potentiation (LTP), which underlies learning and memory, can beinduced by high-frequency electrical stimulation (HFS or HFES) and is thought to occur at the synapses of efferent projection. Here, the contralateral connectivity in mice auditory cortex was investigated to reveal the fundamental corticocortical connection properties. After HFES, plasticity was not observed at the terminal synapses at the recording site. The optogenetic HFS at the recording site of the interhemispheric cortical projections could not induce LTP, but HFES at the recording site could induce the interhemispheric cortical LTP. Our subsequent results uncovered that it is the cholecystokinin (CCK) released from the entorhino-neocortical pathway induced by HEFS that modulates the neuroplasticity of the afferent projections, including interhemispheric auditory cortical afferents. Our study illustrates a heterosynaptic mechanism as the basis for cortical plasticity. This regulation might contribute new spots for the understanding and treatment of neurological disorders.

A Novel CCK Receptor GPR173 Mediates Potentiation of GABAergic Inhibition.

Cholecystokinin (CCK) enables excitatory circuit long-term potentiation (LTP). Here, we investigated its involvement in the enhancement of inhibitory synapses. Activation of GABA neurons suppressed neuronal responses in the neocortex to a forthcoming auditory stimulus in mice of both sexes. High-frequency laser stimulation (HFLS) of GABAergic neurons potentiated this suppression. HFLS of CCK interneurons could induce the LTP of their inhibition toward pyramidal neurons. This potentiation was abolished in CCK knock-out mice but intact in mice with both CCK1R and 2R knockout of both sexes. Next, we combined bioinformatics analysis, multiple unbiased cell-based assays, and histology examinations to identify a novel CCK receptor, GPR173. We propose GPR173 as CCK3R, which mediates the relationship between cortical CCK interneuron signaling and inhibitory LTP in the mice of either sex. Thus, GPR173 might represent a promising therapeutic target for brain disorders related to excitation and inhibition imbalance in the cortex.SIGNIFICANCE STATEMENT CCK, the most abundant and widely distributed neuropeptide in the CNS, colocalizes with many neurotransmitters and modulators. GABA is one of the important inhibitory neurotransmitters, and much evidence shows that CCK may be involved in modulating GABA signaling in many brain areas. However, the role of CCK-GABA neurons in the cortical microcircuits is still unclear. We identified a novel CCK receptor, GPR173, localized in the CCK-GABA synapses and mediated the enhancement of the GABA inhibition effect, which might represent a promising therapeutic target for brain disorders related to excitation and inhibition imbalance in the cortex.

Age-related attenuation of cortical synaptic tagging in the ACC is rescued by BDNF or a TrkB receptor agonist in both sex of mice

Long-term potentiation (LTP) is a key cellular mechanism for learning and memory, and recent studies in the hippocampus found that LTP was impaired in aged animals. Previous studies of cortical LTP have focused primarily on the homosynaptic plasticity in adult mice, while fewer studies have looked at heterosynaptic plasticity—such as synaptic tagging in aged mice. In the present study, we investigated synaptic tagging in adult and middle-aged mice's anterior cingulate cortex (ACC) using the 64-channel multielectrode dish (MED64) recording system. We found that synaptic tagging was impaired in the ACC of middle-aged male mice as compared to adult mice. Both the network late-phase LTP (L-LTP) and the recruitment of inactive responses were reduced in the ACC of middle-aged male mice. Similar results were found in female middle-aged mice, indicating that there is no gender difference. Furthermore, bath application of brain-derived neurotrophic factor (BDNF) or systemic treatment with newly developed TrkB receptor agonists R13, was shown to rescue both synaptic tagging, and L-LTP, in middle-aged mice. To determine the distribution of synaptic LTP within the ACC, a new visualization method was developed to map the Spatio-temporal variation of LTP in the ACC. Our results provide strong evidence that cortical potentiation and synaptic tagging show an age-dependent reduction, and point to the TrkB receptor as a potential drug target for the treatment of memory decline.

Synaptic Plasticity in the Pain-Related Cingulate and Insular Cortex.

Cumulative animal and human studies have consistently demonstrated that two major cortical regions in the brain, namely the anterior cingulate cortex (ACC) and insular cortex (IC), play critical roles in pain perception and chronic pain. Neuronal synapses in these cortical regions of adult animals are highly plastic and can undergo long-term potentiation (LTP), a phenomenon that is also reported in brain areas for learning and memory (such as the hippocampus). Genetic and pharmacological studies show that inhibiting such cortical LTP can help to reduce behavioral sensitization caused by injury as well as injury-induced emotional changes. In this review, we will summarize recent progress related to synaptic mechanisms for different forms of cortical LTP and their possible contribution to behavioral pain and emotional changes.

Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing

Perineuronal nets (PNNs) are chondroitin sulphate proteoglycan-containing structures on the neuronal surface that have been implicated in the control of neuroplasticity and memory. Age-related reduction of chondroitin 6-sulphates (C6S) leads to PNNs becoming more inhibitory. Here, we investigated whether manipulation of the chondroitin sulphate (CS) composition of the PNNs could restore neuroplasticity and alleviate memory deficits in aged mice. We first confirmed that aged mice (20-months) showed memory and plasticity deficits. They were able to retain or regain their cognitive ability when CSs were digested or PNNs were attenuated. We then explored the role of C6S in memory and neuroplasticity. Transgenic deletion of chondroitin 6-sulfotransferase (chst3) led to a reduction of permissive C6S, simulating aged brains. These animals showed very early memory loss at 11 weeks old. Importantly, restoring C6S levels in aged animals rescued the memory deficits and restored cortical long-term potentiation, suggesting a strategy to improve age-related memory impairment.

Blockade of Motor Cortical Long-Term Potentiation Induction by Glutamatergic Dysfunction Causes Abnormal Neurobehavior in an Experimental Subarachnoid Hemorrhage Model.

Subarachnoid hemorrhage (SAH) is a life-threatening condition that can also lead to permanent paralysis. However, the mechanisms that underlying neurobehavioral deficits after SAH have not been fully elucidated. As theta burst stimulation (TBS) can induce long-term potentiation (LTP) in the motor cortex, we tested its potential as a functional evaluation tool after experimentally induced SAH. Motor cortical inter-neuronal excitability was evaluated in anesthetized rats after 200 Hz-quadripulse TBS (QTS5), 200 Hz-quadripulse stimulation (QPS5), and 400 Hz-octapulse stimulation (OPS2.5). Furthermore, correlation between motor cortical LTP and N-methyl-D-aspartate-receptor activation was evaluated using MK-801, a NMDA-receptor antagonist. We evaluated inhibition-facilitation configurations [interstimulus interval: 3 ms; short-latency intracortical inhibition (SICI) and 11 ms; intracortical facilitation (ICF)] with paired electrical stimulation protocols and the effect of TBS paradigm on continuous recording of motor-evoked potentials (MEPs) for quantitative parameters. SAH and MK-801 completely blocked ICF, while SICI was preserved. QTS5, QPS5, and OPS2.5 facilitated continuous MEPs, persisting for 180 min. Both SAH and MK-801 completely blocked MEP facilitations after QPS5 and OPS2.5, while MEP facilitations after QTS5 were preserved. Significant correlations were found among neurological scores and 3 ms-SICI rates, 11 ms-ICF rates, and MEP facilitation rates after 200 Hz-QTS5, 7 days after SAH (R2 = 0.6236; r = −0.79, R2 = 0.6053; r = −0.77 and R2 = 0.9071; r = 0.95, p < 0.05, respectively). Although these findings need to be verified in humans, our study demonstrates that the neurophysiological parameters 3 ms-SICI, 11 ms-ICF, and 200 Hz-QTS5-MEPs may be useful surrogate quantitative biomarkers for assessing inter-neuronal function after SAH.

Cortical plasticity is correlated with cognitive improvement in Alzheimer’s disease patients after rTMS treatment

ObjectiveRepetitive transcranial magnetic stimulation (rTMS) has been widely used in non-invasive treatments for different neurological disorders. Few biomarkers are available for treatment response prediction. This study aims to analyze the correlation between changes in long-term potentiation (LTP)-like cortical plasticity and cognitive function in patients with Alzheimer’s disease (AD) that underwent rTMS treatment. MethodsA total of 75 AD patients were randomized into either 20 Hz rTMS treatment at the dorsolateral prefrontal cortex (DLPFC) group (n = 37) or a sham treatment group (n = 38) for 30 sessions over six weeks (five days per week) with a three-month follow-up. Neuropsychological assessments were conducted using the Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment-Cognitive Component (ADAS-Cog). The cortical plasticity reflected by the motor-evoked potential (MEP) before and after high-frequency repetitive TMS to the primary motor cortex (M1) was also examined prior to and after the treatment period. ResultsThe results showed that the cognitive ability of patients who underwent the MMSE and ADAS-Cog assessments showed small but significant improvement after six weeks of rTMS treatment compared with the sham group. The cortical plasticity improvement correlated to the observed cognition change. ConclusionsCortical LTP-like plasticity could predict the treatment responses of cognitive improvements in AD patients receiving rTMS intervention. This warrants future clinical trials using cortical LTP as a predictive marker.

Inhibition of calcium-stimulated adenylyl cyclase subtype 1 (AC1) for the treatment of neuropathic and inflammatory pain in adult female mice.

Cortical long-term potentiation (LTP) serves as a cellular model for chronic pain. As an important subtype of adenylyl cyclases (ACs), adenylyl cyclase subtype 1 (AC1) is critical for the induction of cortical LTP in the anterior cingulate cortex (ACC). Genetic deletion of AC1 or pharmacological inhibition of AC1 blocked behavioral allodynia in animal models of neuropathic and inflammatory pain. Our previous experiments have identified a lead candidate AC1 inhibitor, NB001, which is highly selective for AC1 over other AC isoforms, and found that NB001 is effective in inhibiting behavioral allodynia in animal models of chronic neuropathic and inflammatory pain. However, previous experiments were carried out in adult male animals. Considering the potential gender difference as an important issue in researches of pain and analgesia, we investigated the effect of NB001 in female chronic pain animal models. We found that NB001, when administered orally, has an analgesic effect in female animal models of neuropathic and inflammatory pain without any observable side effect. Genetic deletion of AC1 also reduced allodynia responses in models of neuropathic pain and chronic inflammation pain in adult female mice. In brain slices of adult female mice, bath application of NB001(20 μM) blocked the induction of LTP in ACC. Our results indicate that calcium-stimulated AC1 is required for injury-related cortical LTP and behavioral allodynia in both sexes of adult animals, and NB001 can be used as a potential therapeutic drug for treating neuropathic and inflammatory pain in man and woman.

Cortical plasticity as synaptic mechanism for chronic pain.

Adult brain structures such as the hippocampus are highly plastic to learning and gaining new experiences. Recent studies reveal that cortical areas that respond to sensory noxious stimuli (stimuli that cause pain in humans) are also highly plastic, like the learning-related hippocampus. Long-term potentiation (LTP), a key cellular model for learning and memory, is reported in the anterior cingulate cortex (ACC) and insular cortex (IC), two key cortical areas for pain perception. ACC and IC LTP exist in at least two major forms: presynaptically expressed LTP, and postsynaptically expressed LTP (post-LTP). In this short review, I will review, recent progress made in cortical LTPs, and explore potential roles of other forms of LTPs such as synaptic tagging. Their contribution to chronic pain as well as emotional changes caused by injury will be discussed.

New Concerns for Neurocognitive Function during Deep Space Exposures to Chronic, Low Dose-Rate, Neutron Radiation.

As NASA prepares for a mission to Mars, concerns regarding the health risks associated with deep space radiation exposure have emerged. Until now, the impacts of such exposures have only been studied in animals after acute exposures, using dose rates ∼1.5×105 higher than those actually encountered in space. Using a new, low dose-rate neutron irradiation facility, we have uncovered that realistic, low dose-rate exposures produce serious neurocognitive complications associated with impaired neurotransmission. Chronic (6 month) low-dose (18 cGy) and dose rate (1 mGy/d) exposures of mice to a mixed field of neutrons and photons result in diminished hippocampal neuronal excitability and disrupted hippocampal and cortical long-term potentiation. Furthermore, mice displayed severe impairments in learning and memory, and the emergence of distress behaviors. Behavioral analyses showed an alarming increase in risk associated with these realistic simulations, revealing for the first time, some unexpected potential problems associated with deep space travel on all levels of neurological function.

Early postnatal environmental enrichment restores neurochemical and functional plasticities of the cerebral cortex and improves learning performance in hidden-prenatally-malnourished young-adult rats

Moderate reduction of dietary protein (from 25% to 8% casein) in pregnant rats, calorically compensated by carbohydrates, gives rise to ‘hidden prenatal malnutrition’ (HPM) in the offspring since it does not alter body and brain weights of pups at birth. However, this dietary treatment leads to decreased β-adrenoceptor signaling and brain derived neurotrophic factor (BDNF) levels in the pup' brain, altogether with defective cortical long-term potentiation (LTP) and lowered visuospatial memory performance. Since early postnatal environmental enrichment (EE) has been shown to exert plastic effects on the developing brain and neuroprotection both on cognition and on structural properties of the neocortex, in the present study we addressed the question of whether early postnatal EE during the lactation period could exert compensatory changes in the expression of ®-adrenergic receptors and BDNF in the neocortex of HPM rats, and if these effects are associated with an improvement or even a restore of both neocortical LTP in vivo and cognitive performance induced by HPM. The results obtained show that EE restored β-adrenoceptor density, BDNF expression and the ability to support LTP at prefrontal and occipital cortices of HPM rats. Besides, EE improved learning performance in visuospatial and operant conditioning tasks. The latter support the notion that adequate maternal protein nutrition during pregnancy is required for proper brain development and function. Further, the results highlight the role of environmental enrichment during early postnatal life in increasing later brain plasticity and exerting neuroprotection against brain deficits induced by prenatal malnutrition.

Higher-Order Thalamocortical Inputs Gate Synaptic Long-Term Potentiation via Disinhibition

Sensory experience and perceptual learning changes receptive field properties of cortical pyramidal neurons (PNs), largely mediated by synaptic long-term potentiation (LTP). The circuit mechanisms underlying cortical LTP remain unclear. In the mouse somatosensory cortex, LTP can be elicited in layer 2/3PNs by rhythmic whisker stimulation. We dissected the synaptic circuitry underlying this typeof plasticity in thalamocortical slices. We found that projections from higher-order, posterior medial thalamic complex (POm) are key to eliciting N-methyl-D-aspartate receptor (NMDAR)-dependent LTP of intracortical synapses. Paired activation of cortical and higher-order thalamocortical inputs increased vasoactive intestinal peptide (VIP) and parvalbumin (PV) interneuron (IN) activity and decreased somatostatin (SST) IN activity, which together disinhibited the PNs. VIP IN-mediated disinhibition was critical for inducing LTP. This study reveals a circuit motif in which higher-order thalamic inputs gate synaptic plasticity via disinhibition. This motif may allow contextual feedback to shape synaptic circuits that process first-order sensory information.

Lithium modulates the muscarinic facilitation of synaptic plasticity and theta-gamma coupling in the hippocampal-prefrontal pathway

Mood disorders are associated to functional unbalance in mesolimbic and frontal cortical circuits. As a commonly used mood stabilizer, lithium acts through multiple biochemical pathways, including those activated by muscarinic cholinergic receptors crucial for hippocampal-prefrontal communication. Therefore, here we investigated the effects of lithium on prefrontal cortex responses under cholinergic drive. Lithium-treated rats were anesthetized with urethane and implanted with a ventricular cannula for muscarinic activation, a recording electrode in the medial prefrontal cortex (mPFC), and a stimulating electrode in the intermediate hippocampal CA1. Either of two forms of synaptic plasticity, long-term potentiation (LTP) or depression (LTD), were induced during pilocarpine effects, which were monitored in real time through local field potentials. We found that lithium attenuates the muscarinic potentiation of cortical LTP (<20 min) but enhances the muscarinic potentiation of LTD maintenance (>80 min). Moreover, lithium treatment promoted significant cross-frequency coupling between CA1 theta (3–5 Hz) and mPFC low-gamma (30–55 Hz) oscillations. Interestingly, lithium by itself did not affect any of these measures. Thus, lithium pretreatment and muscarinic activation synergistically modulate the hippocampal-prefrontal connectivity. Because these alterations varied with time, oscillatory parameters, and type of synaptic plasticity, our study suggests that lithium influences prefrontal-related circuits through intricate dynamics, informing future experiments on mood disorders.

Cortical LTP: A Synaptic Model for Chronic Pain.

Cumulative evidence indicates that cortical synapses not only play important roles in pain perception and related emotional functions but also undergo long-term potentiation (LTP) and contribute to chronic pain. LTP is found at two key cortical regions such as the anterior cingulate cortex (ACC) and insular cortex (IC), and inhibition of cortical LTP produces analgesic effects as well as anxiolytic effects. In this chapter, I will summarize our work on ACC and IC and provide evidence for calcium-stimulated AC1 as a key molecule for cortical LTP and chronic pain.

A method to induce human cortical long-term potentiation by acoustic stimulation

Object: Acoustic stimulation induced LTP in the human auditory cortex was successfully recorded for the first time by electroencephalography (EEG) using a stimulus of 1 kHz pure-tone in 2005. However, it was barely reproduced, given considerable challenges to reliably elicit and accurately record the enhanced potentials in vivo. The purpose of this paper was to explore whether acoustic stimuli other than 1 kHz pure-tone could generate LTP or not.Measures: To answer this question, we proposed a tetanic-stimulation paradigm of pure-tones, narrow-band noises (NBNs) and white noise (WN) to elicit LTP in human subjects.Results: The results showed that pure-tones with different frequency could elicit LTP in human auditory cortex, and proved for the first time that NBNs and WN could also achieve the same goal. Interestingly, it was also shown that the noises with certain bandwidth induced the greatest LTP and the WN induced LTP had the least variation over time and across subjects in comparison with pure-tones and NBNs.Conclusions: In light of the results, we suggested to use the paradigm for broader studies of human in vivo cortical plasticity.