Cholinergic coordination of presynaptic and postsynaptic activity induces timing-dependent hippocampal synaptic plasticity

Correlated presynaptic and postsynaptic activity is the key factor in inducing Hebbian plasticity and memory. However, little is known about the physiological events that could mediate such coordination. Correlated cholinergic input induces spike timing-dependent plasticity-like hippocampal synaptic plasticity. Cholinergic receptors are localized to both presynaptic and postsynaptic glutamatergic sites and thus have the potential to coordinate presynaptic and postsynaptic activity to induce plasticity. By directly monitoring presynaptic and postsynaptic activities with genetically encoded calcium indicators in mouse septohippocampal cocultures, we found interactive but independent presynaptic and postsynaptic modulations in the cholinergic-dependent synaptic plasticity. Neither presynaptic nor postsynaptic modulation alone is sufficient, but instead a coordinated modulation at both sites is required to induce the plasticity. Therefore, we propose that correlated cholinergic input can coordinate presynaptic and postsynaptic activities to induce timing-dependent synaptic plasticity, providing a novel mechanism by which neuromodulators precisely modulate network activity and plasticity with high efficiency and temporal precision.     

Piracetam reverses hippocampal membrane alterations in Alzheimer's disease

Summary. The in vitro effects of piracetam treatment on the fluidity of membranes from the hippocampus of Alzheimer's Disease patients (AD) and non-demented controls were studied. Hippocampal membranes of AD patients showed a significant lower hydrocarbon core fluidity compared with membranes from elderly non-demented controls. Preincubation with piracetam enhanced the hydrocarbon core fluidity of hippocampal membranes from AD-patients as well as elderly controls in a concentration depending fashion, although the effect was more pronounced for the AD membranes. In the presence of piracetam, the difference of the membrane fluidity between AD and control membranes was not longer apparent. Received January 18, 1999; accepted April 13, 1999     

Triggers and substrates of hippocampal synaptic plasticity

It is widely assumed that behavioral learning reflects adaptive properties of the neuronal networks underlying behavior. Adaptive properties of networks in turn arise from the existence of biochemical mechanisms that regulate the efficacy of synaptic transmission. Considerable progress has been made in the elucidation of the mechanisms involved in synaptic plasticity at central synapses and especially those responsible for the phenomenon of long-term potentiation (LTP) of synaptic transmission in hippocampus. While the nature and the timing requirements of the triggering steps are reasonably well known, there is still a lot of uncertainty concerning the mechanisms responsible for the long-term changes. Several biochemical processes have been proposed to play critical roles in promoting long-lasting modifications of synaptic efficacy. This review examines first the triggers that are necessary to produce LTP in the hippocampus and then the different biochemical processes that have been considered to participate in the maintenance of LTP. Finally, we examine the relationships between LTP and behavioral learning.     

Adult hippocampal glucocorticoid receptor expression and dentate synaptic plasticity correlate with maternal care received by individuals early in life

Maternal care in mammals is the prevailing environmental influence during perinatal development. The adult rat offspring of mothers exhibiting increased levels of pup licking/grooming (LG; High LG mothers), compared to those reared by Low LG dams, show increased hippocampal glucocorticoid receptor expression, complex dendritic tree structure, and an enhanced capacity for synaptic potentiation. However, these data were derived from studies using the total amount of maternal care directed toward the entire litter, thus ignoring possible within-litter variation. We show that the amount of LG received by individual pups within a litter varies considerably. Therefore, we questioned if the amount of LG received by individual pups correlates with and thus putatively predicts later hippocampal structure and function. To this end, LG-scores were determined during the first postnatal week for all pups in 32 litters and correlated with neuroendocrine and hippocampal parameters in young-adulthood. Pup LG-score positively correlated with the glucocorticoid receptor mRNA expression in the adult hippocampus. Moreover, the ability to induce synaptic potentiation in the dentate gyrus in vitro was enhanced in animals with high LG-scores. Structural plasticity correlated less reliably with LG-scores early in life and differed between sexes. Male offspring with high LG-scores displayed fewer newborn neurons, higher brain derived neurotrophic factor expression and tended to have more complex granule cell dendritic trees. We conclude that even moderate variations in early life environment have a major impact on adult hippocampal function. This principle could provide a mechanistic basis for individual differences in susceptibility to psychopathology.     

Alzheimer's disease Abeta assemblies mediating rapid disruption of synaptic plasticity and memory

ABSTRACT: Alzheimer's disease (AD) is characterized by episodic memory impairment that often precedes clinical diagnosis by many years. Probing the mechanisms of such impairment may provide much needed means of diagnosis and therapeutic intervention at an early, predementia, stage. Prior to the onset of significant neurodegeneration, the structural and functional integrity of synapses in mnemonic circuitry is severely compromised in the presence of amyloidosis. This review examines recent evidence evaluating the role of amyloid-beta protein (Abeta) in causing rapid disruption of synaptic plasticity and memory impairment. We evaluate the relative importance of different sizes and conformations of Abeta, including monomer, oligomer, protofibril and fibril. We pay particular attention to recent controversies over the relevance to the pathophysiology of AD of different water soluble Abeta aggregates and the importance of cellular prion protein in mediating their effects. Current data are consistent with the view that both low-n oligomers and larger soluble assemblies present in AD brain, some of them via a direct interaction with cellular prion protein, cause synaptic memory failure. At the two extremes of aggregation, monomers and fibrils appear to act in vivo both as sources and sinks of certain metastable conformations of soluble aggregates that powerfully disrupt synaptic plasticity. The same principle appears to apply to other synaptotoxicamyloidogenic proteins including tau, alpha-synuclein and prion protein.     

Basement membrane protein nidogen‐1 shapes hippocampal synaptic plasticity and excitability

The basement membrane (BM) is a specialized form of extracellular matrix (ECM) underlying epithelia and endothelia and surrounding many types of mesenchymal cells. Nidogen, along with collagen IV and laminin, is a major component of BMs. Although certain ECM proteins such as laminin or reelin influence neuronal function via interactions with cell‐surface receptors such as integrins, behavioral neurological impairments due to deficits of BM components have been recognized only recently. Here, alterations in neuronal network function underlying these behavioral changes are revealed. Using nidogen‐1 knockout mice, with or without additional heterozygous nidogen‐2 knockout (NID1^−/−/NID2^+/+ or NID1^−/−/NID2^±), we demonstrate that nidogen is essential for normal neuronal network excitability and plasticity. In nidogen‐1 knockouts, seizurelike behavior occurs, and epileptiform spiking was seen in hippocampal in vivo EEG recordings. In vitro, hippocampal field potential recordings revealed that lack of nidogen‐1, while not causing conspicuous morphological changes, led to the appearance of spontaneous and evoked epileptiform activity, significant increase of the input/output ratio of synaptically evoked responses in CA1 and dentate gyrus, as well as of paired pulse accentuation, and loss of perforant‐path long‐term synaptic potentiation. Nidogen‐1 is thus essential for normal network excitability and plasticity. © 2009 Wiley‐Liss, Inc.     

Cholinergic regulation of synaptic plasticity as a therapeutic target in Alzheimer's disease

There is increasing evidence for disturbances in nicotinic acetylcholine receptor (nAChR) function in Alzheimer's disease (AD). nAChRs are involved in the regulation of many processes, including synaptic plasticity and memory. Levels of nAChRs are altered in the Alzheimer brain and there is evidence that the amyloid betaprotein (Abeta) can directly bind to nAChRs. Nicotinic agonists may also protect cells from Abeta toxicity. Drugs which interact with the nAChR or which inhibit Abeta binding to nAChRs may be of value for the treatment of AD.     

Multideterminant role of calcium in hippocampal synaptic plasticity

Hippocampal CA1 cells possess several varieties of long-lasting synaptic plasticity: two different forms of long-term potentiation (LTP) and at least one form of long-term depression (LTD). All forms of synaptic plasticity are induced by afferent activation, all involve Ca²⁺ influx, all can be blocked by Ca²⁺ chelators, and all activate Ca²⁺-dependent mechanisms. The question arises as how different physiological responses can be initiated by activation of the same second messenger. We consider two hypotheses which could account for these phenomena: voltage-dependent differences in cytosolic Ca²⁺ concentration acting upon Ca²⁺ substrates of differing Ca²⁺ affinities and compartmentalization of the Ca²⁺ and its substrates. © 1994 Wiley-Liss, Inc.     

Pre- and postsynaptic contributions to age-related alterations in corticostriatal synaptic plasticity

Aging creates deficits in motor performance related to changes in striatal processing of cortical information. This study describes age-related changes in corticostriatal snaptic plasticity and associated mechanisms, which may contribute to declines in motor behavior. Intracellular recordings revealed an age-related decrease in the expression of paired-pulse, posttetanic, and long-term potentiation (LTP). The age-related difference in LTP was associated with reduced sensitivity to block of N-methyl-D-aspartate (NMDA) receptors in the aged population. These age-related changes could not be explained by increased L-type Ca(2+)channel activity, since block of L-type Ca(2+) channels with nifedipine increased rather than decreased the age-related difference in long-term plasticity. Age-related increases in reactive oxygen species (ROS) modulation were also ruled out, since application of H(2)O(2) produced changes in synaptic function that were opposite to trends seen in aging, and addition of the antioxidant Trolox-C had a larger effect on long-term plasticity in young rats than in older rats. A robust age-related difference in long-term synaptic plasticity was found by studying synaptic plasticity following the blocking of D2 receptors with l-sulpiride, which may involve age-difference in NMDA receptor function. l-sulpiride consistently enabled a slow development of LTP at young (but not aged) corticostriatal synapses. However, No age differences were found in the sensitivity to the addition of the D2 receptor agonist quinpirole. These findings provide evidence for age-induced changes in the release properties of cortical terminals and in the functioning of postsynaptic striatal NMDA receptors, which may contribute to age-related deficits in striatum control of movement.     

Presenilins and APP in neuritic and synaptic plasticity: implications for the pathogenesis of Alzheimer's disease

A key neuropathological hallmark of Alzheimer’s disease (AD) is the loss of neocortical and hippocampal synapses, which is closely correlated with the degree of memory impairment. Mutations in the genes encoding the amyloid precursor protein (APP) and presenilins are responsible from some cases of early-onset autosomal-dominant AD. This article reviews the current understanding of how alterations in the cellular functions of APP and presenilins may result in the dysfunction and degeneration of synapses in AD. APP mutations result in increased production/aggregation of amyloid β-peptide (Aβ), which induces oxidative stress, resulting in the impairment of synaptic membrane ion, glutamate, and glucose transporters. APP mutations may also compromise the production and/or function of secreted forms of APP that are believed to play important roles in learning and memory processes. Presenilin (PS1) mutations result in a major defect in endoplasmic reticulum (ER) calcium regulation, which may perturb synaptic function in ways that lead to impaired synaptic plasticity and neuronal degeneration. Studies in transgenic mice that express APP and PS1 mutations have provided evidence that the mutations result in altered cellular calcium homeostasis and synaptic plasticity, and impaired learning and memory. This article provides a brief review of the pathophysiological interactions of APP and presenilins with synaptic proteins, and discusses how AD-linked mutations in APP and PS1 may disrupt synaptic processes that contribute to memory formation.     

Visuomotor integration is impaired in early stage Alzheimer's disease

When the sensory information guiding a reach movement is dissociated from the required motor output, humans must integrate rule-based information in order to reach accurately. Here, we examine the accuracy of movements requiring a visuomotor transformation in neurologically healthy elderly subjects and patients diagnosed with probable Alzheimer's disease. Participants made sliding finger movements over a clear touch-sensitive screen positioned in three spatial planes to displace a cursor from a central target to one of four peripheral targets viewed on a monitor. These spatial plane conditions were repeated under conditions where the direction of cursor motion was rotated 180 degrees relative to the direction of hand motion. Significant main effects were observed between patient and control groups on reaction time and movement time measures. Also, significant increases in task completion errors were observed in the patient population. Further, performance was affected more by the visual feedback changes relative to the plane location changes. Notably, there were substantial performance deficits observed in the patient population, even those with minimal cognitive deficits. We suggest that the integration of eye and hand information may be impaired in these patients.     

Involvement of hippocampal synaptic plasticity in age-related memory decline

This article examines the functional significance of Ca²⁺-dependent synaptic plasticity in relation to compromised memory function during aging. Research characterizing an age-related decline in memory for tasks that require proper hippocampal function is summarized. It is concluded that aged animals possess the mechanisms necessary for memory formation, and memory deficits, including rapid forgetting, result from more subtle changes in memory processes for memory storage or maintenance. A review of experimental studies concerning changes in hippocampal neural plasticity over the course of aging indicates that, during aging, there is a shift in mechanisms that regulate the thresholds for synaptic modification, including Ca²⁺ channel function and subsequent Ca²⁺-dependent processes. The results, combined with theoretical considerations concerning synaptic modification thresholds, provide the basis for a model of age-related changes in hippocampal synaptic function. The model is employed as a foundation for interpretation of studies examining therapeutic intervention in age-related memory decline. The possible role of altered synaptic plasticity thresholds in learning and memory deficits suggests that treatments that modify synaptic plasticity may prove fruitful for the development of early therapeutic interventions in age-related neurodegenerative diseases.     

Early presynaptic and postsynaptic calcium signaling abnormalities mask underlying synaptic depression in presymptomatic Alzheimer's disease mice

Alzheimer's disease (AD)-linked presenilin (PS) mutations result in pronounced endoplasmic reticulum calcium disruptions that occur before detectable histopathology and cognitive deficits. More subtly, these early AD-linked calcium alterations also reset neurophysiological homeostasis, such that calcium-dependent presynaptic and postsynaptic signaling appear functionally normal yet are actually operating under aberrant calcium signaling systems. In these 3xTg-AD mouse brains, upregulated ryanodine receptor (RyR) activity is associated with a shift toward synaptic depression, likely through a reduction in presynaptic vesicle stores and increased postsynaptic outward currents through small-conductance calcium-activated potassium SK2 channels. The deviant RyR-calcium involvement in the 3xTg-AD mice also compensates for an intrinsic predisposition for hippocampal long-term depression (LTD) and reduced long-term potentiation (LTP). In this study, we detail the impact of disrupted RyR-mediated calcium stores on synaptic transmission properties, LTD, and calcium-activated membrane channels of hippocampal CA1 pyramidal neurons in presymptomatic 3xTg-AD mice. Using electrophysiological recordings in young 3xTg-AD and nontransgenic (NonTg) hippocampal slices, we show that increased RyR-evoked calcium release in 3xTg-AD mice "normalizes" an altered synaptic transmission system operating under a shifted homeostatic state that is not present in NonTg mice. In the process, we uncover compensatory signaling mechanisms recruited early in the disease process that counterbalance the disrupted RyR-calcium dynamics, namely increases in presynaptic spontaneous vesicle release, altered probability of vesicle release, and upregulated postsynaptic SK channel activity. Because AD is increasingly recognized as a "synaptic disease," calcium-mediated signaling alterations may serve as a proximal trigger for the synaptic degradation driving the cognitive loss in AD.     

Glutamate transmission and toxicity in Alzheimer's disease

1. Despite intensive research, the cause of Alzheimer's disease is unknown. 2. Glutamate is the major excitatory transmitter of the cerebral cortex and hippocampus and it appears to have an important role in learning and memory. In addition to its transmitter function, glutamate is a neurotoxin which has been implicated in the pathogenesis of a variety of neurodegenerative disorders. 3. Glutamate toxicity may play a role in the pathogenesis of Alzheimer's disease. 4. Disruption of glutamatergic neurotransmission may account, in part, for the learning and memory deficits of Alzheimer's disease. 5. Labeling of the glutamate receptor complex may allow in vivo diagnosis by positron emission tomography. 6. Glutamate receptor ligands may provide a means of therapeutic intervention in Alzheimer's disease.     

Longitudinal EEG spectral analysis in early stage of Alzheimer's disease

Twenty-four patients with mild to moderate Alzheimer's disease (AD) were studied using quantitative spectral analysis of EEG at the time of the diagnosis and 1 year later. In 50% of the patients EEG spectra from the T6-O2 derivation were either normal or mildly abnormal at baseline and did not change at 1 year. In another half of the patients the mean quantitative EEG variables (the alpha and the delta power and the mean frequency) deteriorated significantly when baseline and 1 year values were compared. The patient groups with deteriorating and stable EEGs did not differ in age, sex, age at onset or duration of the disease or clinical severity at baseline or at 1 year. Dementia also progressed significantly in both subgroups of AD patients. We conclude that even if the mean values of quantitative EEG variables analysed from the T6-O2 derivation showed distinct slowing at the time of the AD diagnosis and further deterioration 1 year later, in 50% of these early AD cases there was no EEG alteration or worsening in 1 year follow-up, suggesting heterogeneity of the disease.     

Predictors of cognitive decline in the early stage of probable Alzheimer's disease

Several papers have attempted to find neurological and neuropsychological predictors of progression in Alzheimer's disease (AD) till now. Despite this quite large amount of works, different and not univocal conclusions have been reported in this field. Different study samples, different end-points and differences in statistical methods can explain much of the inconsistency in the results obtained. In our study, AD patients were examined in a very early stage of the disease to avoid any possible risk to examine subjects at different times of evolution. All the patients underwent an extensive neuropsychological test battery twice (baseline and follow-up) spaced out over about 1 year and were divided into two groups of fast decliners (FD) and slow decliners (SD) on the basis of their rate of decay at the MMSE score. Verbal memory tests, mental control abilities and attention-demanding tasks seem to play a pivotal role in distinguishing the two groups of subjects in the early stage of the disease. Moreover, FD patients show a worse performance than SD at the baseline in most of the cognitive domains explored. In conclusion, different subtypes of AD do exist and an important predictor of progression is represented by the severity of the cognitive impairment at the onset.     

Reaction time prolongation in the early stage of presenile onset Alzheimer's disease

Summary Simple reaction times (RT) to clicks, flashes and numerical signals were measured in four groups of subjects: 21 patients with mild presenile onset dementia of the Alzheimer type (PDAT, mean age 56 years), 14 patients with chronic cardiovascular disease and incipient cognitive deficit (mean age 55 years), 15 healthy older controls (mean age 53 years) and 16 younger controls (mean age 23 years). Both patient groups had significantly prolonged RTs, the PDAT group especially to the numerical signal (149%), compared with the age-matched controls.     

Hippocampal plasticity in Alzheimer's disease: changes in highly polysialylated NCAM immunoreactivity in the hippocampal formation

The highly polysialylated neural cell adhesion molecule (PSA-NCAM) is one of the most promising molecules that contributes to plasticity in the central nervous system. We evaluated PSA-NCAM immunoreactivity in the hippocampal formation of Alzheimer's disease (AD) patients. We found significant increases over control levels in the optical density ratios of PSA-NCAM immunoreactivity in the outer molecular layer/granule cell layer (ODoml/grl) and in the inner molecular layer/granule cell layer (ODiml/grl) in the dentate gyrus of AD patients. The optical density of the granule cell layer in the dentate gyrus did not differ significantly between AD patients and control subjects. However, the number of PSA-NCAM-immunopositive infragranule cells was higher in the AD group compared with control subjects. The major finding in the CA1, subiculum and entorhinal cortex of AD patients was the disorganization of PSA-NCAM-immunoreactive fibres. These results indicate that neuronal remodelling occurs, especially in the dentate gyrus of patients with AD.     

Nicotinic receptors and hippocampal synaptic plasticity ... it's all in the timing

As we learn more about the functional expression of nicotinic receptors in specific brain regions such as the hippocampus, intriguing interactions are being uncovered at the cellular and circuit levels. Recent work from John Dani's laboratory provides important insights into how nicotinic receptors can modify hippocampal synaptic plasticity in both positive and negative ways, and this could help explain the role of nicotinic receptors in learning and memory.