Term Depression Research Articles

Modulation of acid sensing ion channel dependent protonergic neurotransmission at the mouse calyx of Held

Acid-sensing ion channels (ASICs) regulate synaptic activities and play important roles in neurodegenerative diseases. It has been reported that homomeric ASIC-1a channels are expressed in neurons of the medial nucleus of the trapezoid body (MNTB) of the auditory system in the CNS. During synaptic transmission, acidification of the synaptic cleft presumably due to the co-release of neurotransmitter and H+ from synaptic vesicles activates postsynaptic ASIC-1a channels in mice up to 3 weeks old. This generates synaptic currents (ASIC1a-SCs) that add to the glutamatergic excitatory postsynaptic currents (EPSCs). Here we report that neuromodulators like histamine and natural products like lactate and spermine potentiate ASIC1a-SCs in an additive form such that excitatory ASIC synaptic currents as well as the associated calcium influx become significantly large and physiologically relevant. We show that ASIC1a-SCs enhanced by endogenous neuromodulators are capable of supporting synaptic transmission in the absence of glutamatergic EPSCs. Furthermore, at high frequency stimulation (HFS), ASIC1a-SCs contribute to diminish short term depression (STD) and their contribution is even more relevant at early stages of development. Since ASIC channels are present in almost all types of neurons and synaptic vesicles content is acid, the participation of protons in synaptic transmission and its potentiation by endogenous substances could be a general phenomenon across the central nervous system. This article is part of a Special Issue entitled: Honoring Ricardo Miledi - outstanding neuroscientist of XX-XXI centuries.

Metabotropic Glutamate Receptor 5 and 8 Modulate the Ameliorative Effect of Ultramicronized Palmitoylethanolamide on Cognitive Decline Associated with Neuropathic Pain.

This study investigated whether metabotropic glutamate receptor (mGluR) 5 and 8 are involved in the effect of ultramicronizedpalmitoylethanolamide (um-PEA) on the cognitive behavior and long term potentiation (LTP) at entorhinal cortex (LEC)-dentate gyrus (DG) pathway in mice rendered neuropathic by the spare nerve injury (SNI). SNI reduced discriminative memory and LTP. Um-PEA treatment started after the development of neuropathic pain had no effects in sham mice, whereas it restored cognitive behavior and LTP in SNI mice. 2-Methyl-6-(phenylethynyl) pyridine (MPEP), a selective mGluR5 antagonist, improved cognition in SNI mice and produced a chemical long term depression of the field excitatory postsynaptic potentials (fEPSPs) in sham and SNI mice. After theta burst stimulation (TBS) MPEP restored LTP in SNI mice. In combination with PEA, MPEP antagonized the PEA effect on discriminative memory and decreased LTP in SNI mice. The (RS)-4-(1-amino-1-carboxyethyl)phthalic acid (MDCPG), a selective mGluR8 antagonist, did not affect discriminative memory, but it induced a chemical LTP and prevented the enhancement of fEPSPs after TBS in SNI mice which were treated or not treated with PEA. The effect of PEA on LTP and cognitive behavior was modulated by mGluR5 and mGluR8. In particular in the SNI conditions, the mGluR5 blockade facilitated memory and LTP, but prevented the beneficial effects of PEA on discriminative memory while the mGluR8 blockade, which was ineffective in itself, prevented the favorable action of the PEA on LTP. Thus, although their opposite roles (excitatory/inhibitory of the two receptor subtypes on the glutamatergic system), they appeared to be required for the neuroprotective effect of PEA in conditions of neuropathic pain.

Intermittent Hypoxia Disrupts Synaptic Long Term Depression

Long term potentiation (LTP), activity‐dependent synaptic strengthening, and long term depression (LTD), activity dependent synaptic attenuation, are two forms of synaptic plasticity whose underlying mechanisms permit flexibility in synaptic communication and serve as substrates for learning and memory. Intermittent hypoxia (IH), a hallmark of sleep apnea, is known to impair spatial learning and memory. The objective of this study is determine how LTP and LTD are affected by IH. We hypothesize that IH impedes efficacy of activity dependent synaptic plasticity in the hippocampus, a brain structure important to learning and memory. We examined in vitro LTP and LTD in hippocampal brain slices following IH exposure. Electrophysiological recordings showed that LTP in area CA1 could be evoked in control and IH exposed groups, yet the magnitude of LTP following IH was decreased (LTP: control 184.72±15.93% vs. IH 145.35±6.34% baseline) . While LTD could be elicited in the control group (63.31±3.03% baseline), LTD could not be evoked from the IH exposed group (104.18±3.44% baseline). Although IH impacted both forms of long term synaptic plasticity, this was not accompanied by differences in paired‐pulse facilitation, indicating that short‐term plasticity was unaffected by IH. These findings demonstrate that IH affects mechanisms of activity‐dependent regulation of synaptic efficacy, which may involve IH‐dependent changes in NMDA receptor contribution to these phenomena. Our findings further contribute to understanding potential neurophysiological changes that may decrease the threshold for cognitive decline associated with sleep apnea.Support or Funding InformationThis work was supported by NIH R01 NS10742101 (AJG).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Mechanism of Prenatal Cannabinoid Exposure Mediated Memory Loss in Adolescent Offspring: Opportunities for Identifying Therapeutic Target

Cannabis use during pregnancy has increased by 62% from 2002 through 2014 and is now the most commonly used illicit drug during pregnancy, in part due to its ability to reduce morning sickness during pregnancy. Several studies have demonstrated that neural network activity which underlies typical cognitive and behavioral processes can be altered by prenatal cannabinoid exposure (PCE) leading to a long lasting effects on adult behavior. Here, we have investigated the impact of PCE in adolescent offspring in hippocampus dependent learning and memory via performing a series of behavioral, electrophysiological and immunochemical studies. An osmotic pump filled with either vehicle or the cannabinoid receptor full agonist WIN55, 212–2 (2 mg/kg body weight/day) was implanted subcutaneously in gestational day 4, which delivered the drug at a constant rate until the pups were born. Contextual Fear Conditioning and Morris Water Maze test were performed to investigate the hippocampus based memory revealing significant learning deficits in the PCE group. To investigate the mechanisms behind observed behavioral deficits, electrophysiological experiments were performed on acute hippocampal slices. Reduced long‐term potentiation and enhanced and long term depression were observed in the PCE group demonstrating impaired synaptic plasticity. To identify alterations in the downstream signaling cascade involved in glutamatergic neurotransmission, immunoblotting experiment was performed. Immunoblotting data showed increased Cannabinoid Receptor Type 1(CB1) expression along with reduced Neural Cell Adhesion Molecule (NCAM) expression. NCAM is important for maintaining proper neuronal connections, and it modulates NMDA mediated glutamatergic neurotransmission. Based on our data, we hypothesize that a reduction in NCAM may be responsible for the learning and memory deficits observed in PCE animals and can be used as a therapeutic target to ameliorate the cognitive deficits in PCE offspring.Support or Funding InformationNo Available Funding SourceThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Abstract TP142: Post-Ischemic Cortical Excitability and Gene Expression are Modulated by Transplanted Human Neural Stem Cells

Human neural stem cell (hNSC) transplantation improves recovery in preclinical stroke models. However their effects on surviving sensorimotor circuits are not well understood. Here we performed a comprehensive electrophysiological assessment and RNA-seq analysis of the stroke-injured rat cortex after transplantation of two hNSC lines, G010 (fetal-derived) and NR1 (hES-derived). Vehicle, G010, or NR1 cells were transplanted into the ischemic cortex of Nude rats 1 wk after distal middle cerebral artery occlusion. Neurological recovery was accessed by the Whisker-paw test. Acute brain slices were prepared 1 wk post-transplantation for electrophysiological recording. A linear multichannel recording probe was placed in the peri-infarct motor cortex and local field potentials (LFPs) recorded simultaneously from all cortical layers following circuit activation in layer 2/3. For RNA-seq analysis, the transplantation area was dissected, RNA extracted and cDNA libraries prepared for RNA-seq. G010 and NR1 cells enhanced post-stroke behavioral recovery starting 1 or 3 wks post-transplantation, respectively. Current source density (CSD) analysis of evoked LFPs, a method used to more accurately localize synaptic currents, revealed that both G010 and NR1 cells restored circuit excitability in layer 2/3, through reduction in inhibitory/excitatory (I/E) balance. However, the mechanisms driving the I/E balance shift were different, with NR1 cells enhancing excitation while G010 cells reduced inhibition. RNA-seq analysis of the cortex revealed that stem cell- versus vehicle-treated animals had different gene expression patterns in all cortical layers. Moreover, NR1 and G010 cells affected different genes. Layer 2/3-specific genes significantly affected by G010 grafts include Arpp21, Enpp2, Gbe1, Mylk, Pea15, Pkig, Rcn1, Slit3, Uchl1 and Wfs1; while NR1 grafts altered expression of Hapln4, Kcnc1, Ppp1r1b, Scn1a, Slit3 and Slitrk1. GO analysis revealed that both stem cell treatments activated critical canonical pathways e.g. Actin Cytoskeleton Signaling and Synaptic Long Term Depression. Stem cell transplantation modulates host gene expression and this is associated with increased circuit excitability and motor-sensory function.

Hypothesis on Remote Memory Forming from Heterosynaptic LTD-Mediated Neuronal Degeneration

In this article, it is hypothesized a new mechanism for the formation of stable remote memory in brain comprising the important memory acquired during childhood and the common words in language. It has been demonstrated that the memory forms concurrently at both homosynaptic long term potentiation (LTP) and heterosynaptic long term depression (LTD). It is pointed out that the repeated LTD may result in neuronal degeneration as evidenced at molecular and cellular level, becoming long lasting throughout the lifespan. Besides, it is further supported by the consequent storage of remote memory directly on the information pathway, as evidenced by the degenerative ocular dominance plasticity and the storage of common words/grammar within the linguistic areas of brain. Accordingly, it is herein completed the hypothesis on the formation of remote memory from the heterosynaptic LTD-mediated neuronal degeneration in brain so long as the homosynaptic pathway does not degenerate from such causes as aging and so on, while supplementing a new form of neuronal plasticity for memory in addition to the contemporary LTP and LTD.

Frequency driven organic memristive devices for neuromorphic short term and long term plasticity

The concomitant and concurrent presence of cellular mechanisms, such as the activity-dependent Long Term Potentiation (LTP) and Depression (LTD), and the Short Term Plasticity (STP) is believed to be at the basis of encoding memories in brains. Thus, the best possible emulation of these fundamental brain activities is essential for developing bioinspired circuits and novel adaptive technologies, and, looking in perspective, an efficient brain-machine interface. In this framework, memristive devices are increasingly considered as key elements in the emerging fields of neuromorphic engineering and computing because of their synaptic-like plasticity properties. Here we demonstrate the realization of organic memristive devices (OMDs), based on polyaniline (PANI), mimicking controlled neuromorphic functions. In particular our OMDs exhibit LTD or LTP by varying the polarity or, more interestingly, by varying the frequency of the incoming stimuli, according to the typical biological patterns. In both cases, OMDs show also an effect analogous to the transition between short term to long term memory, as a function of the total number of received pulses. We validate that organic memristors represent an important step toward an “intelligent” neuroprosthetics demonstrating through the hardware implementation of OMDs neuromorphic functionalities, the possibility of pairing the frequency dependence of synaptic signals with the non-volatile evolution of the internal memory states of the device.

Activation of Serotonin 5-HT7 Receptors Modulates Hippocampal Synaptic Plasticity by Stimulation of Adenylate Cyclases and Rescues Learning and Behavior in a Mouse Model of Fragile X Syndrome.

We have previously demonstrated that activation of serotonin 5-HT7 receptors (5-HT7R) reverses metabotropic glutamate receptor-mediated long term depression (mGluR-LTD) in the hippocampus of wild-type (WT) and Fmr1 Knockout (KO) mice, a model of Fragile X Syndrome (FXS) in which mGluR-LTD is abnormally enhanced. Here, we have investigated intracellular mechanisms underlying the effect of 5-HT7R activation using patch clamp on hippocampal slices. Furthermore, we have tested whether in vivo administration of LP-211, a selective 5-HT7R agonist, can rescue learning and behavior in Fmr1 KO mice. In the presence of an adenylate cyclase blocker, mGluR-LTD was slightly enhanced in WT and therefore the difference between mGluR-LTD in WT and Fmr1 KO slices was no longer present. Conversely, activation of adenylate cyclase by either forskolin or Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) completely reversed mGluR-LTD in WT and Fmr1 KO. 5-HT7R activation reversed mGluR-LTD in WT and corrected exaggerated mGluR-LTD in Fmr1 KO; this effect was abolished by blockade of either adenylate cyclase or protein kinase A (PKA). Exposure of hippocampal slices to LP-211 caused an increased phosphorylation of extracellular signal regulated kinase (ERK), an intracellular effector involved in mGluR-LTD, in WT mice. Conversely, this effect was barely detectable in Fmr1 KO mice, suggesting that 5-HT7R-mediated reversal of mGluR-LTD does not require ERK stimulation. Finally, an acute in vivo administration of LP-211 improved novel object recognition (NOR) performance in WT and Fmr1 KO mice and reduced stereotyped behavior in Fmr1 KO mice. Our results indicate that mGluR-LTD in WT and Fmr1 KO slices is bidirectionally modulated in conditions of either reduced or enhanced cAMP formation. Activation of 5-HT7 receptors reverses mGluR-LTD by activation of the cAMP/PKA intracellular pathway. Importantly, a systemic administration of a 5-HT7R agonist to Fmr1 KO mice corrected learning deficits and repetitive behavior. We suggest that selective 5-HT7R agonists might become novel pharmacological tools for FXS therapy.

MGluR1-Dependent Long Term Depression in Rodent Midbrain Dopamine Neurons Is Regulated by Neuregulin 1/ErbB Signaling.

Increasing evidence demonstrates that the neurotrophic factor Neuregulin 1 (NRG1) and its receptors, ErbB tyrosine kinases, modulate midbrain dopamine (DA) transmission. We have previously reported that NRG1/ErbB signaling is essential for proper metabotropic glutamate receptors 1 (mGluR1) functioning in midbrain DA neurons, thus the functional interaction between ErbB receptors and mGluR1 regulates neuronal excitation and in vivo striatal DA release. While it is widely recognized that mGluR1 play a pivotal role in long-term modifications of synaptic transmission in several brain areas, specific mGluR1-dependent forms of synaptic plasticity in substantia nigra pars compacta (SNpc) DA neurons have not been described yet. Here, first we aimed to detect and characterize mGluR1-dependent glutamatergic long-term depression (LTD) in SNpc DA neurons. Second, we tested the hypothesis that endogenous ErbB signaling, by affecting mGluR1, fine-tunes glutamatergic synaptic plasticity in DA cells. We found that either pharmacological or synaptic activation of mGluR1 causes an LTD of AMPAR-mediated transmission in SNpc DA neurons from mice and rat slices, which is reliant on endogenous NRG1/ErbB signaling. Indeed, LTD is counteracted by a broad spectrum ErbB inhibitor. Moreover, the intracellular injection of pan-ErbB- or ErbB2 inhibitors inside DA neurons reduces mGluR1-dependent LTD, suggesting an involvement of ErbB2/ErbB4-containing receptors. Interestingly, exogenous NRG1 fosters LTD expression during minimal mGluRI activation. These results enlarge our cognizance on mGluR1 relevance in the induction of a novel form of long-term synaptic plasticity in SNpc DA neurons and describe a new NRG1/ErbB-dependent mechanism shaping glutamatergic transmission in DA cells. This might have important implications either in DA-dependent behaviors and learning/memory processes or in DA-linked diseases.

Regulation of hippocampal long term depression by Neuroligin 1

Neuroligins (NLGs) are postsynaptic adhesion molecules known to play essential roles in synapse development and maturation, but their effects on synaptic plasticity at mature synapses remain unclear. In this study, we investigate the involvement of NLG1 in hippocampal long-term depression (LTD), a key form of long lasting synaptic plasticity, critical for memory formation and brain disorders, by using mice deficient in the expression of NLG1. We find that although NLG1 homozygous (NLG1−/−) mice show no impairments in either NMDA receptor- (NMDAR-LTD) or metabotropic glutamate receptor-dependent LTD (mGluR-LTD), the heterozygous (NLG1+/−) mice are significantly altered in both forms of LTD characterized by the absence of NMDAR-LTD but enhanced mGluR-LTD. Accordingly, the NLG1+/−, but not the NLG1−/− mice are altered in synaptic proteins, including PSD95, GluA2 and phosphorylated GluA1 at serine 845, all of which are involved in the expression of LTD. The NLG1+/− mice also exhibit autistic-like behaviors including increased grooming and impaired recognition memory. We further show that the expression of NLG3, a close family member of NLG1, is elevated in the NLG1−/−, but not in NLG1+/− mice, suggesting that the lack of LTD deficits in the NLG1−/− mice might be due to the increased NLG3. Our results reveal a gene dosage dependent role for NLG1 in the regulation of LTD and suggest that moderate changes in NLG1 protein level may be sufficient to cause synaptic and behavior deficits in brain disorders where copy number variants and hemizygosity of gene mutations are common.

Prenatal immune activation potentiates endocannabinoid-related plasticity of inhibitory synapses in the hippocampus of adolescent rat offspring

There is strong evidence that immune activation from prenatal infection increases the risk for offspring to develop schizophrenia. The endocannabinoid (eCB) system has been implicated in the pathophysiology of schizophrenia while models of cortical dysfunction postulate an imbalance between neuronal excitation and inhibition in the disorder. The current study examined the impact of prenatal immune activation on eCB-mediated inhibitory mechanisms. We compared two forms of eCB-related plasticity of evoked inhibitory postsynaptic currents, namely depolarization-induced suppression of inhibition (DSI) and metabotropic glutamate receptor-induced long term depression (mGluR-iLTD), in both the dorsal and ventral hippocampus between adolescent offspring from rat dams that received either saline or bacterial lipopolysaccharide (LPS) during pregnancy. Compared to prenatal saline offspring, prenatal LPS offspring displayed prolonged DSI and stronger mGluR-iLTD in the dorsal and ventral hippocampus, respectively. The sensitivity of mGluR-iLTD to the CB1 receptor antagonist AM251 was also lower in the dorsal hippocampus of prenatal LPS compared to prenatal saline offspring. Testing whether changes in eCB receptor signaling or levels could contribute to these changes in inhibitory transmission, we found region specific increases in 2-arachidonoylglycerol-stimulated signaling and in basal and mGluR-induced levels of anandamide in prenatal LPS offspring when compared to prenatal saline offspring. Our findings indicate that prenatal immune activation can lead to long-term changes in eCB-related plasticity of hippocampal inhibitory synaptic transmission in adolescent rat offspring. Perturbation of the eCB system resulting from prenatal immune activation could represent a mechanism linking early life immune events to the development of psychopathology in adolescence.

Potent PDZ-Domain PICK1 Inhibitors that Modulate Amyloid Beta-Mediated Synaptic Dysfunction

Protein interacting with C kinase (PICK1) is a scaffolding protein that is present in dendritic spines and interacts with a wide array of proteins through its PDZ domain. The best understood function of PICK1 is regulation of trafficking of AMPA receptors at neuronal synapses via its specific interaction with the AMPA GluA2 subunit. Disrupting the PICK1-GluA2 interaction has been shown to alter synaptic plasticity, a molecular mechanism of learning and memory. Lack of potent, selective inhibitors of the PICK1 PDZ domain has hindered efforts at exploring the PICK1-GluA2 interaction as a therapeutic target for neurological diseases. Here, we report the discovery of PICK1 small molecule inhibitors using a structure-based drug design strategy. The inhibitors stabilized surface GluA2, reduced Aβ-induced rise in intracellular calcium concentrations in cultured neurons, and blocked long term depression in brain slices. These findings demonstrate that it is possible to identify potent, selective PICK1-GluA2 inhibitors which may prove useful for treatment of neurodegenerative disorders.

Eco-Friendly All-Inorganic Perovskite Memristors and Artificial Synapses

Artificial Synapse has been an emerging research field as emulating the functions of biological synapse. It is regarded as a basic building block for neuromorphic computing. Organic lead-based perovskites including CH3NH3PbI3 and CH3NH3PbBr3 have been researched as materials for synaptic devices based on Resistive Random Access Memory(RRAM). They have shown gradual increase and decrease of conductivity that represent the synaptic plasticity such as STP (Short Term Potentiation), LTP (Long Term Potentiation), and LTD (Long Term Depression) which imitate learning and forgetting in human brain. However, there have been some environmental concerns about using lead-based materials in large-scale applications because of the possibility of lead contamination. Also, it is still required to increase perovskites’ air-stability. All-inorganic halide perovskites are considered as promising alternatives for RRAM and synaptic devices because of their remarkable stability. Therefore, this study focused on fully inorganic CsPb(1-x)BixI3 perovskite to achieve lower lead content and better stability. Optimized bismuth content was discovered according to their morphology, grain size, and synaptic performances. CsPb(1-x)BixI3 emulates synapse by showing similar functions such as STP and LTP by different current change rate depending on the intensities and frequencies of pulses. Also, STD and LTD can be obtained by applying opposite pulses. Therefore, based on these synaptic functions that optimized CsPb(1-x)BixI3 achieves, it can be applied as a single synapse with low energy consumption for neuromorphic computing which works by parallel operation to connect and store information.

PB11. Long term GABA alterations induced by anodal Transcranial Direct Current Stimulation (tDCS) in motor cortex: A proton magnetic resonance spectroscopy study

Background Transcranial direct current stimulation (tDCS) is a non-invasive technique that modulates excitability of neurons in the motor cortex. In particular, anodal tDCS leads to cortical facilitation and overall increase in excitability ( Nitsche et al., 2000 ). Objective Although the effects of anodal tDCS on modulating motor cortex activation have been reported, there is little evidence of long term reduction of GABA concentration following anodal stimulation. Therefore, to characterize the duration of after effects of primary motor cortex (M1) excitability following anodal stimulation, we performed repeated magnetic resonance spectroscopy (MRS) measurements of GABA for 60 min after the stimulation. Materials and methods Thirty-two right-handed healthy volunteers were recruited in RWTH Aachen University. GABA-edited spectra were acquired using 3 T Siemens scanner from a volume of interest of 3 × 3 × 3 cm (27 mL) carefully placed on the hand motor area of the left primary motor cortex [ Fig. 1 ]. MEGA-PRESS J-editing ( Mescher et al., 1998 ), was used for GABA detection. Data processing and quantification of spectra was performed with TARQUIN ( Wilson et al., 2011 ). Results An ANOVA was performed on percentage of GABA concentrations with stimulation (sham vs. anodal) and measurement (12 measurements: 2 pre-stimulation and 10 post-stimulation measurements taken every 6 min) as between- and within-participants factors. The main effects of stimulation was not significant F(1, 30) = 1.157, p = .291. However, main effect of measurement was significant F(11, 330) = 2.378 p = .008. Remarkably, the interaction of stimulation x measurement was significant F(11, 330) = 2.249, p = .0128 [ Fig. 2 ]. GABA concentration decreased significantly in the anodal stimulation group at first (20th minute) post-stimulation measurement, and then stayed the same at measurements eighth, ninth and tenth ts (3) Discussion and conclusion Our results revealed a significant early drop of GABA concentration within 20 min following anodal stimulation and late drop of GABA after 66th minutes until the last post stimulation measurement (86th min). Early and late decrease in GABA could be due to a decrease of activity of glutamic acid decarboxylase (GAD) 67 and long term depression like plasticity, respectively. This technique may open a new field of application for long-lasting neuroplastic induction, especially in the rehabilitation of stroke patients.

Mice lacking the transcriptional regulator Bhlhe40 have enhanced neuronal excitability and impaired synaptic plasticity in the hippocampus.

Bhlhe40 is a transcription factor that is highly expressed in the hippocampus; however, its role in neuronal function is not well understood. Here, we used Bhlhe40 null mice on a congenic C57Bl6/J background (Bhlhe40 KO) to investigate the impact of Bhlhe40 on neuronal excitability and synaptic plasticity in the hippocampus. Bhlhe40 KO CA1 neurons had increased miniature excitatory post-synaptic current amplitude and decreased inhibitory post-synaptic current amplitude, indicating CA1 neuronal hyperexcitability. Increased CA1 neuronal excitability was not associated with increased seizure severity as Bhlhe40 KO relative to +/+ (WT) control mice injected with the convulsant kainic acid. However, significant reductions in long term potentiation and long term depression at CA1 synapses were observed in Bhlhe40 KO mice, indicating impaired hippocampal synaptic plasticity. Behavioral testing for spatial learning and memory on the Morris Water Maze (MWM) revealed that while Bhlhe40 KO mice performed similarly to WT controls initially, when the hidden platform was moved to the opposite quadrant Bhlhe40 KO mice showed impairments in relearning, consistent with decreased hippocampal synaptic plasticity. To investigate possible mechanisms for increased neuronal excitability and decreased synaptic plasticity, a whole genome mRNA expression profile of Bhlhe40 KO hippocampus was performed followed by a chromatin immunoprecipitation sequencing (ChIP-Seq) screen of the validated candidate genes for Bhlhe40 protein-DNA interactions consistent with transcriptional regulation. Of the validated genes identified from mRNA expression analysis, insulin degrading enzyme (Ide) had the most significantly altered expression in hippocampus and was significantly downregulated on the RNA and protein levels; although Bhlhe40 did not occupy the Ide gene by ChIP-Seq. Together, these findings support a role for Bhlhe40 in regulating neuronal excitability and synaptic plasticity in the hippocampus and that indirect regulation of Ide transcription may be involved in these phenotypes.

S181. Optimizing the neuroplastic effects of cathodal transcranial direct current stimulation (tDCS) over the primary motor cortex

Introduction Transcranial direct current stimulation (tDCS) can non-invasively induce polarity-dependent excitability alterations in the human motor cortex lasting more than an hour after stimulation. Clinical application with encouraging results have been reported in several pilot studies, but the optimal stimulation protocols remain to be determined. Methods We systemically explored the association between tDCS parameters (intensity, duration) and induced after-effects on motor cortex excitability. Cathodal tDCS was applied in three different intensities (1, 2 and 3 mA) and durations (15, 20 and 30mins) on 16 young healthy subjects and the after-effects were monitored with TMS-induced motor evoked potentials (MEP) until the next day evening after stimulation. The results revealed nonlinear after-effects, which might be caused by calcium dynamics relevant for long term depression and potentiation induction. Results The results revealed that 1 mA −15 min, 1 mA −30 min and 3 mA −20 min induced LTD-like plasticity, while LTP-like plasticity was observed after 2 mA stimulation for 20 min. It was shown that there is a nonlinear modulatory effect of stimulation intensity/duration on neuroplasticity, which might be caused by calcium dynamics relevant for long-term depression and potentiation induction. Conclusion Our study thus provides further insights on the dependency of tDCS-induced neuroplasticity on the stimulation parameters, and therefore delivers crucial information for future clinical applications.

A Multiple-Plasticity Spiking Neural Network Embedded in a Closed-Loop Control System to Model Cerebellar Pathologies.

The cerebellum plays a crucial role in sensorimotor control and cerebellar disorders compromise adaptation and learning of motor responses. However, the link between alterations at network level and cerebellar dysfunction is still unclear. In principle, this understanding would benefit of the development of an artificial system embedding the salient neuronal and plastic properties of the cerebellum and operating in closed-loop. To this aim, we have exploited a realistic spiking computational model of the cerebellum to analyze the network correlates of cerebellar impairment. The model was modified to reproduce three different damages of the cerebellar cortex: (i) a loss of the main output neurons (Purkinje Cells), (ii) a lesion to the main cerebellar afferents (Mossy Fibers), and (iii) a damage to a major mechanism of synaptic plasticity (Long Term Depression). The modified network models were challenged with an Eye-Blink Classical Conditioning test, a standard learning paradigm used to evaluate cerebellar impairment, in which the outcome was compared to reference results obtained in human or animal experiments. In all cases, the model reproduced the partial and delayed conditioning typical of the pathologies, indicating that an intact cerebellar cortex functionality is required to accelerate learning by transferring acquired information to the cerebellar nuclei. Interestingly, depending on the type of lesion, the redistribution of synaptic plasticity and response timing varied greatly generating specific adaptation patterns. Thus, not only the present work extends the generalization capabilities of the cerebellar spiking model to pathological cases, but also predicts how changes at the neuronal level are distributed across the network, making it usable to infer cerebellar circuit alterations occurring in cerebellar pathologies.

Honokiol and Pioglitazone Ameliorate Alzheimer's Disease Pathologies in vitro and ex vivo

Amyloid beta (AB) plaques are extracellular, neurotoxic protein aggregations. These plaques have historically been considered the hallmark of Alzheimer's disease due to their ability to reduce long term potentiation (LTP) and promote long term depression (LTD). Peroxisome proliferator‐activated receptor gamma (PPARg) agonists have been shown to be a novel and promising class of drugs capable of alleviating AD pathologies. In this study, we observed the neurotoxic effects of amyloid beta on hippocampal field potentials on the Schaffer collateral. In addition, we displayed honokiol, a novel SIRT3 and partial PPARg agonist, and pioglitazone, a full PPARg agonist, is capable of improving mitochondrial function, increasing LTP, and reducing AB aggregation. The hippocampal field potential along the Schaffer collateral was measured by the LTP theta burst protocol, while signaling mechanisms were evaluated using western blot, RT‐qPCR, mitochondrial assays, and imaging techniques. We hypothesize and provide evidence that these compounds regulate mitochondria‐endoplasmic reticulum communication in order to modify AD pathologies providing evidence for the MAM hypothesis. Both compounds performed comparably suggesting honokiol may be a promising compound for the treatment of AD as its blood brain barrier (BBB) permeability is much higher than pioglitazone.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Long-Term Depression Is Independent of GluN2 Subunit Composition.

NMDA receptors (NMDARs) mediate both long-term potentiation and long-term depression (LTD) and understanding how a single receptor can initiate both phenomena remains a major question in neuroscience. A prominent hypothesis implicates the NMDAR subunit composition, specifically GluN2A and GluN2B, in dictating the rules of synaptic plasticity. However, studies testing this hypothesis have yielded inconsistent and often contradictory results, especially for LTD. These inconsistent results may be due to challenges in the interpretation of subunit-selective pharmacology and in dissecting out the contributions of differential channel properties versus the interacting proteins unique to GluN2A or GluN2B. In this study, we address the pharmacological and biochemical challenges by using a single-neuron genetic approach to delete NMDAR subunits in conditional knock-out mice. In addition, the recently discovered non-ionotropic nature of NMDAR-dependent LTD allowed the rigorous assessment of unique subunit contributions to NMDAR-dependent LTD while eliminating the variable of differential charge transfer. Here we find that neither the GluN2A nor the GluN2B subunit is strictly necessary for either non-ionotropic or ionotropic LTD.SIGNIFICANCE STATEMENT NMDA receptors are key regulators of bidirectional synaptic plasticity. Understanding the mechanisms regulating bidirectional plasticity will guide development of therapeutic strategies to treat the dysfunctional synaptic plasticity in multiple neuropsychiatric disorders. Because of the unique properties of the NMDA receptor GluN2 subunits, they have been postulated to differentially affect synaptic plasticity. However, there has been significant controversy regarding the roles of the GluN2 subunits in synaptic long term depression (LTD). Using single-neuron knock-out of the GluN2 subunits, we show that LTD requires neither GluN2A nor GluN2B.

Purkinje cell BKchannel ablation induces abnormal rhythm in deep cerebellar nuclei and prevents LTD

Purkinje cells (PC) control deep cerebellar nuclei (DCN), which in turn inhibit inferior olive nucleus, closing a positive feedback loop via climbing fibers. PC highly express potassium BK channels but their contribution to the olivo-cerebellar loop is not clear. Using multiple-unit recordings in alert mice we found in that selective deletion of BK channels in PC induces a decrease in their simple spike firing with a beta-range bursting pattern and fast intraburst frequency (~200 Hz). To determine the impact of this abnormal rhythm on the olivo-cerebellar loop we analyzed simultaneous rhythmicity in different cerebellar structures. We found that this abnormal PC rhythmicity is transmitted to DCN neurons with no effect on their mean firing frequency. Long term depression at the parallel-PC synapses was altered and the intra-burst complex spike spikelets frequency was increased without modification of the mean complex spike frequency in BK-PC−/− mice. We argue that the ataxia present in these conditional knockout mice could be explained by rhythmic disruptions transmitted from mutant PC to DCN but not by rate code modification only. This suggests a neuronal mechanism for ataxia with possible implications for human disease.