Cellular Mechanisms Of Learning Research Articles

Differential Roles of GluN2B in Two Types of Chemical-induced Long Term Potentiation-mediated Phosphorylation Regulation of GluA1 at Serine 845 in Hippocampal Slices

Synaptic plasticity, such as long term potentiation (LTP) and long term depression (LTD), underlies the cellular mechanism of learning and memory. Chemical-induced LTP (cLTP), which facilitates biochemical analysis of molecular changes in brain slices or neuronal cultures, has been accepted as an in vitro model to explore synaptic plasticity. cLTP, by either forskolin and rolipram (F&R) or glycine, is thought to be dependent on NMDA receptor. However, subunit-specific dependence and regulation of the NMDA receptor in cLTP remain poorly understood. In the present study, we found that phosphorylation level of GluN2B at tyrosine 1472 was modulated by F&R-induced LTP but not by glycine-induced LTP in hippocampal slices. Furthermore, an increased phosphorylation level of GluA1 at serine 845 by F&R-induced LTP rather than glycine-induced LTP was dependent on the activation of GluN2B, which is supported by the results from GluN2B antagonists, small interfering peptide and CRISPR-Cas9-mediated knock out of GluN2B. Taken together, we reveal the significant role of GluN2B in F&R-induced LTP, uncovering the role of GluN2B subunit of NMDA receptor in a specified cLTP.

Acute application of Centella asiatica extract enhanced AMPAR-mediated postsynaptic currents in rat entorhinal cortex.

Centella asiatica is notable for its wide range of biological activities beneficial to human health, particularly its cognitive enhancement and neuroprotective effects. The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors are ionotropic glutamate receptors mediating fast excitatory neurotransmission essential in long-term potentiation widely thought to be the cellular mechanism of learning and memory. The method of whole-cell patch-clamp was used to study the effect of the acute application of Centella asiatica extract on the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated spontaneous excitatory postsynaptic currents in the entorhinal cortex of rat brain slices. The respective low dose of test compounds significantly increased the amplitude of spontaneous excitatory postsynaptic currents while having no significant effects on the frequency. The findings suggested that Centella asiatica extract increased the response of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors at the postsynaptic level, revealing the potential role of Centella asiatica in modulating the glutamatergic responses in the entorhinal cortex of rat brain slices to produce cognitive enhancement effects.

Synaptic Plasticity and its Modulation byAlcohol.

Alcohol is one of the oldest pharmacological agents used for its sedative/hypnotic effects, and alcohol abuse and alcohol use disorder (AUD) continues to be major public health issue. AUD is strongly indicated to be a brain disorder, and the molecular and cellular mechanism/s by which alcohol produces its effects in the brain are only now beginning to be understood. In the brain, synaptic plasticity or strengthening or weakening of synapses, can be enhanced or reduced by a variety of stimulation paradigms. Synaptic plasticity is thought to be responsible for important processes involved in the cellular mechanisms of learning and memory. Long-term potentiation (LTP) is a form of synaptic plasticity, and occurs via N-methyl-D-aspartate type glutamate receptor (NMDAR or GluN) dependent and independent mechanisms. In particular, NMDARs are a major target of alcohol, and are implicated in different types of learning and memory. Therefore, understanding the effect of alcohol on synaptic plasticity and transmission mediated by glutamatergic signaling is becoming important, and this will help us understand the significant contribution of the glutamatergic system in AUD. In the first part of this review, we will briefly discuss the mechanisms underlying long term synaptic plasticity in the dorsal striatum, neocortex and the hippocampus. In the second part we will discuss how alcohol (ethanol, EtOH) can modulate long term synaptic plasticity in these three brain regions, mainly from neurophysiological and electrophysiological studies. Taken together, understanding the mechanism(s) underlying alcohol induced changes in brain function may lead to the development of more effective therapeutic agents to reduce AUDs.

Oestradiol, threat conditioning and extinction, post-traumatic stress disorder, and prolonged exposure therapy: A common link.

The accumulating evidence regarding the impact of estradiol on learning and memory synergized studies to examine its influence on enhancing animal's ability to quell fear and anxiety. In this review, we first provide a foundational platform regarding the impact of oestradiol on cellular mechanisms of learning and memory and we review recent advances from rodent and human data showing that oestrogen enhances extinction learning across species. We then propose clinical application to these data. We discuss the potential role of oestradiol variance on the aetiology, maintenance and treatment for post-traumatic stress disorder. Specifically, we argue that the use of oestradiol as an adjunct to prolonged exposure (PE) therapy for PTSD may provide a new treatment approach for enhancing the efficacy of PE in women with PTSD. This could advance our understanding of the mechanisms of PTSD and help tailor sex-specific treatments for this disorder.

Transient Hypoxemia Disrupts Anatomical and Functional Maturation of Preterm Fetal Ovine CA1 Pyramidal Neurons.

Children who survive premature birth often exhibit reductions in hippocampal volumes and deficits in working memory. However, it is unclear whether synaptic plasticity and cellular mechanisms of learning and memory can be elicited or disrupted in the preterm fetal hippocampus. CA1 hippocampal neurons were exposed to two common insults to preterm brain: transient hypoxia-ischemia (HI) and hypoxia (Hx). We used a preterm fetal sheep model using both sexes in twin 0.65 gestation fetuses that reproduces the spectrum of injury and abnormal growth in preterm infants. Using Cavalieri measurements, hippocampal volumes were reduced in both Hx and HI fetuses compared with controls. This volume loss was not the result of neuronal cell death. Instead, morphometrics revealed alterations in both basal and apical dendritic arborization that were significantly associated with the level of systemic hypoxemia and metabolic stress regardless of etiology. Anatomical alterations of CA1 neurons were accompanied by reductions in probability of presynaptic glutamate release, long-term synaptic plasticity and intrinsic excitability. The reduction in intrinsic excitability was in part due to increased activity of the channels underlying the fast and slow component of the afterhyperpolarization in Hx and HI. Our studies suggest that even a single brief episode of hypoxemia can markedly disrupt hippocampal maturation. Hypoxemia may contribute to long-term working memory disturbances in preterm survivors by disrupting neuronal maturation with resultant functional disturbances in hippocampal action potential throughput. Strategies directed at limiting the duration or severity of hypoxemia during brain development may mitigate disturbances in hippocampal maturation.SIGNIFICANCE STATEMENT Premature infants commonly sustain hypoxia-ischemia, which results in reduced hippocampal growth and life-long disturbances in learning and memory. We demonstrate that the circuitry related to synaptic plasticity and cellular mechanisms of learning and memory (LTP) are already functional in the fetal hippocampus. Unlike adults, the fetal hippocampus is surprisingly resistant to cell death from hypoxia-ischemia. However, the hippocampus sustains robust structural and functional disturbances in the dendritic maturation of CA1 neurons that are significantly associated with the magnitude of a brief hypoxic stress. Since transient hypoxic episodes occur commonly in preterm survivors, our findings suggest that the learning problems that ensue may be related to the unique susceptibility of the hippocampus to brief episodes of hypoxemia.

Potential role of arteether on N-methyl-D-aspartate (NMDA) receptor expression in experimental cerebral malaria mice and extension of their survival.

Cerebral malaria (CM) is the severe neurological complication causing acute non-traumatic encephalopathy in tropical countries. The mechanisms underlying the fatal cerebral complications are still not fully understood. Glutamate, a major excitatory neurotransmitter in the central nervous system of the mammalian brain, plays a key role in the development of neuronal cells, motor function, synaptic plasticity, learning and memory processes under normal physiological conditions. The subtypes of ionotropic glutamate receptor are N-methyl-D-aspartate receptors (NMDARs) which are involved in cellular mechanisms of learning and memory, synaptic plasticity and also mediate excitotoxic neuronal injury. In the present study, we found that glutamate level in synaptosomes, as well as expression of NMDAR, was elevated during the extreme condition of CM in C57BL6 mice. Arteether at 50 mg kg-1 × 1, 25 mg kg-1 × 2, days decreased the NMDAR expression and increased the overall survival of the experimental CM mice.

Monoamines, Insulin and the Roles They Play in Associative Learning in Pond Snails.

Molluscan gastropods have long been used for studying the cellular and molecular mechanisms underlying learning and memory. One such gastropod, the pond snail Lymnaea stagnalis, exhibits long-term memory (LTM) following both classical and operant conditioning. Using Lymnaea, we have successfully elucidated cellular mechanisms of learning and memory utilizing an aversive classical conditioning procedure, conditioned taste aversion (CTA). Here, we present the behavioral changes following CTA training and show that the memory score depends on the duration of food deprivation. Then, we describe the relationship between the memory scores and the monoamine contents of the central nervous system (CNS). A comparison of learning capability in two different strains of Lymnaea, as well as the filial 1 (F1) cross from the two strains, presents how the memory scores are correlated in these populations with monoamine contents. Overall, when the memory scores are better, the monoamine contents of the CNS are lower. We also found that as the insulin content of the CNS decreases so does the monoamine contents which are correlated with higher memory scores. The present review deepens the relationship between monoamine and insulin contents with the memory score.

Опыт применения оптогенетических подходов к исследованию функций мозга и протезированию дегенеративной сетчатки

Optogenetics, which allows control the activity of neurons by means of light after expression of light-activated proteins in them, is a powerful tool in neuroscience that determined significant progress in the study of brain functions in the last decade. The progress of optogenetics crucially depends on the development of new molecular tools - light-activated proteins. In 2015, the natural light-activated chlorine channel GtACR2 was identified. This channel is capable of suppressing neuron activity with high efficiency in optogenetic experiments. We discovered the unique properties of this channel, showing that in GtACR2-expressing neurons, the light stimulus, in addition to strong inhibition, can also induce the generation of action potentials, which occurs, apparently, in axon terminals of the neuron due to the altered chlorine reversal potential in these cell compartments . In our work, we use optogenetic methods to study the cellular mechanisms of learning and memory. Using the expression of channelrhodopsin2 in the network of presynaptic neurons, we used light stimulation to study the properties of synaptic connections and their plasticity in a whole population of neurons in a single experiment. One of the promising areas of clinical application of optogenetics is its use for prosthetic of degenerative retina. A variant of this approach is to recreate the ON / OFF receptive field of ganglion neurons by targeted expression of the excitatory light-activated protein in the central part of the ganglion cell, and the inhibitory opsins in the peripheral. In the framework of this approach, we created a bicistronic construct that carries the genes of the excitatory and inhibitory opsins, the expression of which was able to lead to the restoration of ON / OFF interactions typical for ganglion cells.

Differential expression of entorhinal cortex and hippocampal subfields α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors enhanced learning and memory of rats following administration of Centella asiatica

Centella asiatica (CA) is a widely used traditional herb, notably for its cognitive enhancing effect and potential to increase synaptogenesis. The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and N-methyl-D-aspartate receptors (NMDARs) mediate fast excitatory neurotransmission with key roles in long-term potentiation which is believed to be the cellular mechanism of learning and memory. Improved learning and memory can be an indication to the surface expression level of these receptors. Our previous study demonstrated that administration of CA extract improved learning and memory and enhanced expression of AMPAR GluA1 subunit while exerting no significant effects on GABAA receptors of the hippocampus in rats. Hence, to further elucidate the effects of CA, this study investigated the effects of CA extract in recognition memory and spatial memory, and its effects on AMPAR GluA1 and GluA2 subunit and NMDAR GluN2 A and GluN2B subunit expression in the entorhinal cortex (EC) and hippocampal subfields CA1 and CA3. The animals were administered with saline, 100 mg/kg, 300 mg/kg, and 600 mg/kg of CA extract through oral gavage for 14 days, followed by behavioural analysis through Open Field Test (OFT), Novel Object Recognition Task (NORT), and Morris Water Maze (MWM) and lastly morphological and immunohistochemical analysis of the surface expression of AMPAR and NMDAR subunits were performed. The results showed that 14 days of administration of 600 mg/kg of CA extract significantly improved memory assessed through NORT while 300 mg/kg of CA extract significantly improved memory of the animals assessed through MWM. Immunohistochemical analysis revealed differential modulation effects on the expressions of receptor subunits across CA1, CA3 and EC. The CA extract at the highest dose (600 mg/kg) significantly enhanced the expression of AMPAR subunit GluA1 and GluA2 in CA1, CA3 and EC, and NMDAR subunit GluN2B in CA1 and CA3 compared to control. At 300 mg/kg, CA significantly increased expression of AMPAR GluA1 in CA1 and EC, and GluA2 in CA1, CA3 and EC while 100 mg/kg of CA significantly increased expression of only AMPAR subunit GluA2 in CA3 and EC. Expression of NMDAR subunit GluN2 A was significantly reduced in the CA3 (at 100, 300, and 600 mg/kg) while no significant changes of subunit expression was observed in CA1 and EC compared to control. The results suggest that the enhanced learning and memory observed in animals administered with CA was mainly mediated through increased expression of AMPAR GluA1 and GluA2 subunits and differential expression of NMDAR GluN2 A and GluN2B subunits in the hippocampal subfields and EC. With these findings, the study revealed a new aspect of cognitive enhancing effect of CA and its therapeutic potentials through modulating receptor subunit expression.

Chronic 2P-STED imaging reveals high turnover of dendritic spines in the hippocampus in vivo.

Rewiring neural circuits by the formation and elimination of synapses is thought to be a key cellular mechanism of learning and memory in the mammalian brain. Dendritic spines are the postsynaptic structural component of excitatory synapses, and their experience-dependent plasticity has been extensively studied in mouse superficial cortex using two-photon microscopy in vivo. By contrast, very little is known about spine plasticity in the hippocampus, which is the archetypical memory center of the brain, mostly because it is difficult to visualize dendritic spines in this deeply embedded structure with sufficient spatial resolution. We developed chronic 2P-STED microscopy in mouse hippocampus, using a 'hippocampal window' based on resection of cortical tissue and a long working distance objective for optical access. We observed a two-fold higher spine density than previous studies and measured a spine turnover of ~40% within 4 days, which depended on spine size. We thus provide direct evidence for a high level of structural rewiring of synaptic circuits and new insights into the structure-dynamics relationship of hippocampal spines. Having established chronic super-resolution microscopy in the hippocampus in vivo, our study enables longitudinal and correlative analyses of nanoscale neuroanatomical structures with genetic, molecular and behavioral experiments.

A Time of Forgetting: Menopause May Hold a Key to Understanding the Development of Alzheimer?s Disease.

One day in the mid-1980s, at New York City's Rockefeller Hospital, two scientists met at opposite poles of their careers. Roberta Diaz Brinton (Figure 1) was a newly minted Ph.D. and a postdoctoral researcher at the hospital, where she was studying the molecular and cellular mechanisms of learning and memory. Dr. Rowena Ansbacher was a patient who'd spent her working life at the University of Vermont as a passionate scholar of Adlerian psychology. The pair clicked immediately, playfully bantering at times or expounding on Alfred Adler's ideas, which shaped much of the field of psychology in the 20th century. Afterward, Brinton walked Ansbacher back to her room and bid her goodnight. Half a minute later, she knocked on the door and entered her room.

Long Term Depression in Rat Hippocampus and the Effect of Ethanol during Fetal Life

Alcohol (ethanol) disturbs cognitive functions including learning and memory in humans, non-human primates, and laboratory animals such as rodents. As studied in animals, cellular mechanisms for learning and memory include bidirectional synaptic plasticity, long-term potentiation (LTP), and long-term depression (LTD), primarily in the hippocampus. Most of the research in the field of alcohol has analyzed the effects of ethanol on LTP; however, with recent advances in the understanding of the physiological role of LTD in learning and memory, some authors have examined the effects of ethanol exposure on this particular signal. In the present review, I will focus on hippocampal LTD recorded in rodents and the effects of fetal alcohol exposure on this signal. A synthesis of the findings indicates that prenatal ethanol exposure disturbs LTD concurrently with LTP in offspring and that both glutamatergic and γ-aminobutyric acid (GABA) neurotransmissions are altered and contribute to LTD disturbances. Although the ultimate mode of action of ethanol on these two transmitter systems is not yet clear, novel suggestions have recently appeared in the literature.

Oxotremorine-M potentiates NMDA receptors by muscarinic receptor dependent and independent mechanisms

Muscarinic acetylcholine M1 receptors play an important role in synaptic plasticity in the hippocampus and cortex. Potentiation of NMDA receptors as a consequence of muscarinic acetylcholine M1 receptor activation is a crucial event mediating the cholinergic modulation of synaptic plasticity, which is a cellular mechanism for learning and memory. In Alzheimer's disease, the cholinergic input to the hippocampus and cortex is severely degenerated, and agonists or positive allosteric modulators of M1 receptors are therefore thought to be of potential use to treat the deficits in cognitive functions in Alzheimer's disease. In this study we developed a simple system in which muscarinic modulation of NMDA receptors can be studied in vitro. Human M1 receptors and NR1/2B NMDA receptors were co-expressed in Xenopus oocytes and various muscarinic agonists were assessed for their modulatory effects on NMDA receptor-mediated responses. As expected, NMDA receptor-mediated responses were potentiated by oxotremorine-M, oxotremorine or xanomeline when the drugs were applied between subsequent NMDA responses, an effect which was fully blocked by the muscarinic receptor antagonist atropine. However, in oocytes expressing NR1/2B NMDA receptors but not muscarinic M1 receptors, oxotremorine-M co-applied with NMDA also resulted in a potentiation of NMDA currents and this effect was not blocked by atropine, demonstrating that oxotremorine-M is able to directly potentiate NMDA receptors. Oxotremorine, which is a close analogue of oxotremorine-M, and xanomeline, a chemically distinct muscarinic agonist, did not potentiate NMDA receptors by this direct mechanism. Comparing the chemical structures of the three different muscarinic agonists used in this study suggests that the tri-methyl ammonium moiety present in oxotremorine-M is important for the compound's interaction with NMDA receptors.

Detection and characterization of individual endocytosis of AMPA-type glutamate receptor around postsynaptic membrane.

Synaptic plasticity such as long-term depression (LTD) has been regarded as a cellular mechanism of learning and memory. LTD is expressed by the decrease in number of postsynaptic AMPA-type receptor (AMPAR) at glutamatergic synapses. Although endocytosis is known to play an essential role in the decrease in AMPAR on postsynaptic membrane, the difficulty to detect individual endocytic events hampered clarification of AMPAR dynamics around synapses. Previously, we developed a method to induce formation of postsynaptic-like membrane (PSLM) on the glass surface and observed pHluorin-tagged AMPAR around PSLM with total internal reflection fluorescence microscopy. By this method, individual exocytosis of AMPAR-pHluorin was recorded in both PSLM and non-PSLM. In other studies, endocytic vesicles containing pHluorin-tagged receptors were visualized by changing extracellular pH. Here, we have combined PSLM formation method and rapid pH change method, and detected individual endocytic events of AMPAR around PSLM with high spatial and temporal resolutions. Endocytic events of AMPAR were characterized by comparison with those of transferrin receptor. Constitutive endocytosis of AMPAR was not dependent on clathrin and dynamin in contrast to that of transferrin receptor. However, AMPAR endocytosis triggered by LTD-inducing stimulation was clathrin- and dynamin-dependent.

Influence of N-acetyl cysteine on beta-amyloid-induced Alzheimer's disease in a rat model: A behavioral and electrophysiological study.

Alzheimer's disease is an age-related neurodegenerative disorder characterized by a progressive decline in cognitive function due to the extracellular accumulation and deposition of beta-amyloid peptide (Aβ). The purpose of this study was to evaluate the protective effect of N-acetyl cysteine (NAC) on learning and memory in an Aβ-induced Alzheimer's disease model in adult male rats, using behavioral and electrophysiological methods Thirty-five rats were divided into five groups: control, sham-operated, Aβ, Aβ+NAC (1-14days), and Aβ+NAC (14-28days). Learning and memory were evaluated behaviorally using the passive avoidance test and electrophysiologically by assessing hippocampal long-term potentiation, a cellular mechanism of learning and memory. Intrahippocampal Aβ injections reduced step-through latency in the passive avoidance test, and decreased both the amplitude of hippocampal neuron population spikes and the slope of excitatory postsynaptic potentials, compared to the sham and control groups. Administration of NAC in rats receiving Aβ alleviated the Aβ-induced deficits in comparison to the Aβ-only group. The results of this study suggest that NAC shows potential for treatment of Alzheimer's disease.

T021 Synaptic plasticity mechanism explains the specificity of direct current stimulation

Abstract Long term effects of transcranial electric stimulation with direct currents (tDCS) have been often attributed to synaptic plasticity. A number of human and animal studies provide support for this hypothesis. However, the exact mechanisms by which direct current stimulation affects synaptic plasticity remain unclear. Here we will present data on long term potentiation (LTP) and long term depression (LTD) of synaptic efficacy – the presumed cellular mechanism of learning. The experiments leverage classic plasticity induction protocols in hippocampal rodent brain slices (high frequency pulses, low frequency pulses, and theta burst stimulation). The main finding is that direct current stimulation in isolation does not affect synaptic efficacy. Only when stimulation is paired with one of these induction protocols do we observe effects on synaptic efficacy. The effects vanish in the presence of NMDA receptor blockers. The polarity of the effect depends on the induction mechanism and the site of plasticity, suggesting that the local polarization of the cellular membrane is the mediating factor. Based on these data we propose that tDCS in human experiments is task specific, not because of the exact placement of electrodes, but because stimulation only affects those synapses that are already undergoing plasticity. We predict that the most specific and effective tDCS interventions will be those that pair stimulation with a concurrent adaptation or learning protocol.

Nicotine-induced neuroplasticity counteracts the effect of schizophrenia-linked neuregulin 1 signaling on NMDAR function in the rat hippocampus

A high rate of heavy tobacco smoking among people with schizophrenia has been suggested to reflect self-medication and amelioration of cognitive dysfunction, a core feature of schizophrenia. NMDAR hypofunction is hypothesized to be a mechanism of cognitive dysfunction, and excessive schizophrenia-linked neuregulin 1 (NRG1) signaling through its receptor ErbB4 can suppress NMDAR function by preventing Src-mediated enhancement of NMDAR responses. Here we investigated whether chronic nicotine exposure in rats by subcutaneous injection of nicotine (0.5–1 mg/kg, twice daily for 10–15 days) counteracts the suppressive effect of NRG1β on NMDAR-mediated responses recorded from CA1 pyramidal cells in acute hippocampal slices. We found that NRG1β, which prevents the enhancement of NMDAR responses by the Src-family-kinase-activating peptide pYEEI in naive rats, failed to block the effect of pYEEI in nicotine-exposed rats. In naive rats, NRG1β acts only on GluN2B-NMDARs by blocking their Src-mediated upregulation. Chronic nicotine exposure causes enhanced GluN2B-NMDAR responses via Src upregulation and recruits Fyn for the enhancement of GluN2A-NMDAR responses. NRG1β has no effect on both enhanced basal GluN2B-NMDAR responses and Fyn-mediated enhancement of GluN2A-NMDAR responses. Src-mediated enhancement of GluN2B-NMDAR responses and Fyn-mediated enhancement of GluN2A-NMDAR responses initiate long-term potentiation (LTP) of AMPAR synaptic responses in naive and nicotine-exposed CA1 pyramidal cells, respectively. These results suggest that NRG1β suppresses LTP by blocking Src-mediated enhancement of GluN2B-NMDAR responses, but has no effect on LTP in nicotine-exposed rats. These effects of chronic nicotine exposure may counteract the negative effect of increased NRG1-ErbB4 signaling on the cellular mechanisms of learning and memory in individuals with schizophrenia, and therefore may motivate heavy smoking.

Low-frequency stimulation induces a durable long-term depression in young adult hyperthyroid rats: the role of p38 mitogen-activated protein kinase and protein phosphatase 1.

Long-term potentiation and long-term depression (LTD) are cellular mechanisms of learning and memory in the mammalian brain. We have previously shown that adult hyperthyroid rats showed a delay in the acquisition of a place learning task and attenuated long-term potentiation. However, changes in LTD in hyperthyroidism remain unclear. Rats were administered 0.2 mg/kg/day of L-thyroxine for 21 days starting at postnatal day 40 to induce hyperthyroidism. LTD was induced in the dentate gyrus using low-frequency stimulation (LFS) of the perforant pathway. The mRNA expressions of p38 mitogen-activated protein kinase (p38-MAPK) and protein phosphatase 1 (PP1) were evaluated using a quantitative reverse transcriptase PCR. In control rats, a standard LFS protocol induced a slight depression of the population spike (PS) amplitude during the induction phase of LTD (76±13% vs. baseline), but a small potentiation of the PS amplitude was observed in the early (107±18%) and late (111±20%) phases of LTD. Interestingly, in the hyperthyroid rats, the same LFS protocol induced a reliable LTD in the dentate gyrus of the hippocampus as evidenced by a marked depression in the PS amplitude during the induction (54±6% vs. baseline) and the early phases (56±8%) of LTD. Elevated mRNA levels of p38-MAPK and PP1 were observed in the hippocampus of the LFS-treated hyperthyroid rats compared with the hippocampus of the vehicle-treated hyperthyroid rats. No significant change in p38-MAPK or PP1 mRNA expression was observed in the euthyroid rats. The present study shows that a standard LFS protocol can induce a durable depression of synaptic strength and an upregulation of PP1 and p38-MAPK mRNA in hyperthyroid rats. We conclude that hyperthyroidism can induce molecular changes associated with degeneration of the hippocampus. The relationship between the levels of thyroid hormone and dementia requires further investigation.

Astrocytic face of Alzheimer’s disease

Ageing of the central nervous system (CNS) is the major risk factor for Alzheimer’s disease (AD), a type of neurodegeneration that is associated with deficits in cognition and memory and clinically manifested as severe senile dementia. Numerous mental processes underline cognition, including attention, producing and understanding language, learning, reasoning, problem solving, decision making and memory formation. In the past, neurones or their parts have been considered to be the exclusive cellular sites of memory and cognitive processes. However, it has become evident that astrocytes, the major homeostatic glial cell of the CNS, provide an essential contribution to memory formation, and astroglial failure may promote cognitive decline in AD. In response to the network reset mechanisms mediated by the noradrenergic projections of neurones located in the locus coeruleus, astrocytes get excited and participate in the morphological remodelling associated with synaptic plasticity, otherwise thought to represent a cellular mechanism of learning and memory. Astroglial morphological plasticity is an energy-demanding process requiring mobilisation of glycogen, which, in the CNS, is almost exclusively stored in astrocytes. Astroglia exhibit cytoplasmic excitability that engages ions (such as Ca2+ and Na+) and second messengers (such as cAMP). These ions/molecules contribute to the reception of extracellular signals and coordinate the secretion of glio-signalling molecules, including peptides such as apolipoporotein E, which participates in lipid transport between glia and neurones. In this setting, astrocytes are positioned as spatio-temporal integrators of neural network coordination, which disintegrates during progression of AD.

Endocannabinoid dynamics gate spike-timing dependent depression and potentiation.

Synaptic plasticity is a cardinal cellular mechanism for learning and memory. The endocannabinoid (eCB) system has emerged as a pivotal pathway for synaptic plasticity because of its widely characterized ability to depress synaptic transmission on short- and long-term scales. Recent reports indicate that eCBs also mediate potentiation of the synapse. However, it is not known how eCB signaling may support bidirectionality. Here, we combined electrophysiology experiments with mathematical modeling to question the mechanisms of eCB bidirectionality in spike-timing dependent plasticity (STDP) at corticostriatal synapses. We demonstrate that STDP outcome is controlled by eCB levels and dynamics: prolonged and moderate levels of eCB lead to eCB-mediated long-term depression (eCB-tLTD) while short and large eCB transients produce eCB-mediated long-term potentiation (eCB-tLTP). Moreover, we show that eCB-tLTD requires active calcineurin whereas eCB-tLTP necessitates the activity of presynaptic PKA. Therefore, just like glutamate or GABA, eCB form a bidirectional system to encode learning and memory.