Stimulus-selective response plasticity in the visual cortex: an assay for the assessment of pathophysiology and treatment of cognitive impairment associated with psychiatric disorders

Long-term potentiation (LTP) is a form of experimentally induced enhancement of chemical synaptic transmission that has long been proposed as a model of the endogenous processes of synaptic plasticity that mediate memory. There is a large body of evidence that the molecular mechanisms underlying experimentally induced LTP also subserve various forms of naturally occurring, experience-dependent synaptic plasticity in animals and humans. Here we describe a phenomenon called stimulus-specific response potentiation (SRP), which occurs in the primary visual cortex of mice as a result of repeated exposure to visual stimuli and is believed to reveal the mechanisms that underlie perceptual learning. We first describe evidence that SRP represents naturally occurring LTP of thalamo-cortical synaptic transmission. We then discuss the potential value of SRP as a preclinical assay for the assessment of putative drug treatments on synaptic plasticity. Stimulus-specific response potentiation is not only easy to assay and robust but captures features of feed-forward glutamatergic function and visual learning that are deficient in human psychiatric disorders, notably including schizophrenia. We suggest that phenomena analogous to SRP in humans are likely to be useful biomarkers of altered cortical LTP and of treatment response in diseases associated with impaired cognition.     

Regulation and Interaction of Multiple Types of Synaptic Plasticity in a Purkinje Neuron and Their Contribution to Motor Learning

There are multiple types of plasticity at both excitatory glutamatergic and inhibitory GABAergic synapses onto a cerebellar Purkinje neuron (PN). At parallel fiber to PN synapses, long-term depression (LTD) and long-term potentiation (LTP) occur, while at molecular layer interneuron to PN synapses, a type of LTP called rebound potentiation (RP) takes place. LTD, LTP, and RP seem to contribute to motor learning. However, each type of synaptic plasticity might play a different role in various motor learning paradigms. In addition, defects in one type of synaptic plasticity could be compensated by other forms of synaptic plasticity, which might conceal the contribution of a particular type of synaptic plasticity to motor learning. The threshold stimulation for inducing each type of synaptic plasticity and the induction conditions are different for different plasticity mechanisms, and they change depending on the state of an animal. Facilitation and/or saturation of synaptic plasticity occur after certain behavioral experiences or in some transgenic mice. Thus, the regulation and roles of synaptic plasticity are complicated. Toward a comprehensive understanding of the respective roles of each type of synaptic plasticity and their possible interactions during motor learning processes, I summarize induction conditions, modulations, interactions, and saturation of synaptic plasticity and discuss how multiple types of synaptic plasticity in a PN might work together in motor learning processes.     

Genetic studies in Drosophila: vesicle pools and cytoskeleton-based regulation of synaptic transmission

Presynaptic plasticity mechanisms rely on modulation of the synaptic vesicle fusion machinery and the regulated mobilization of synaptic vesicles at the active zone. This review discusses recent evidence suggesting that the relative proportions of synaptic vesicles in the reserve and ready releasable pools is the primary determinant of synaptic transmission strength, and that transport of vesicles between these pools is mediated by cytoskeletal mechanisms. Recent efforts to identify the molecules required for regulation of the presynaptic cytoskeleton suggest that common mechanisms may exist to regulate synaptic vesicle pools in widely divergent neuronal types, ranging from synaptic modulation at the Drosophila neuromuscular junction to the synaptic plasticity required for learning and memory in the mammalian brain.     

Synaptic learning rules, cortical circuits, and visual function.

Sensory experience is essential for the refinement of neuronal circuits during development and for learning and memory in the adult brain. Such experience-dependent plasticity is largely mediated by activity-dependent synaptic modification. In this review, we focus on a spike timing-dependent synaptic learning rule, in which the direction and magnitude of synaptic modification depend on the relative spike timing of presynaptic and postsynaptic neurons. We discuss a series of recent studies exploring the functional implications of this learning rule in the visual system. These studies show that temporally patterned visual stimuli can cause rapid changes in visual circuits, neuronal receptive fields, and visual perception, with a temporal specificity of tens of milliseconds. Particularly, motion stimuli that are common in natural scenes may interact strongly with the spike timing-dependent learning rule, leaving distinct marks in the perceptual function of the mature brain.     

Repetitive induction of late-phase LTP produces long-lasting synaptic enhancement accompanied by synaptogenesis in cultured hippocampal slices

Long-term plasticity of synaptic transmission is assumed to underlie the formation of long-term memory. Although the cellular mechanisms underlying short-term plasticity have been analyzed in detail, the mechanisms underlying the transformation from short-term to long-term plasticity remain largely unrevealed. We propose the novel long-lasting phenomenon as a model system for the analysis of long-term plasticity. We previously reported that the repetitive activation of cAMP-dependent protein kinase (PKA) by forskolin application led to an enhancement in synaptic strength coupled with synaptogenesis that lasted more than 3 weeks in cultured rat hippocampal slices. To elucidate whether this long-lasting synaptic enhancement depended on the induction of long-term potentiation (LTP) or on the pharmacological effect of forskolin, we applied glutamate (Glu) and correlated its dose with the production of the long-lasting synaptic enhancement. When the dose of Glu was low (10, 30 muM), only transient excitation or early-phase LTP (E-LTP) was induced by a single application and no long-lasting synaptic enhancement was produced by three applications. When the dose was raised to 100 or 300 muM, late-phase LTP (L-LTP) was induced by a single application and long-lasting synaptic enhancement was produced by three applications. The Glu-produced enhancement was accompanied by an increase in the frequency (but not the amplitude) of miniature EPSC and the number of synaptic structures. The enhancement depended on the interval of repetition and protein synthesis immediately after the Glu applications. These results indicate that the repetitive induction of L-LTP, but not E-LTP or transient excitation, triggers cellular processes leading to the long-lasting synaptic enhancement and the formation of new synapses.     

Role of the hippocampus on learning and memory functioning and pain modulation★

Abstract The hippocampus, an important part of the limbic system, is considered to be an important region of the brain for learning and memory functioning. Recent studies have demonstrated that synaptic plasticity is thought to be the basis of learning and memory functioning. A series of studies report that similar synaptic plasticity also exists in the spinal cord in the conduction pathway of pain sensation, which may contribute to hyperalgesia, abnormal pain, and analgesia. The synaptic plasticity of learning and memory functioning and that of the pain conduction pathway have similar mechanisms, which are related to the N-methyl-D-aspartic acid receptor. The hippocampus also has a role in pain modulation. As pain signals can reach the hippocampus, the precise correlation between synaptic plasticity of the pain pathway and that of learning and memory functioning deserves further investigation. The role of the hippocampus in processing pain information requires to be identified. Key Words: hippocampus; learning; memory; neuronal plasticity; pain     

Synaptic plasticity and dysconnection in schizophrenia.

Current pathophysiological theories of schizophrenia highlight the role of altered brain connectivity. This dysconnectivity could manifest 1) anatomically, through structural changes of association fibers at the cellular level, and/or 2) functionally, through aberrant control of synaptic plasticity at the synaptic level. In this article, we review the evidence for these theories, focusing on the modulation of synaptic plasticity. In particular, we discuss how dysconnectivity, observed between brain regions in schizophrenic patients, could result from abnormal modulation of N-methyl-D-aspartate (NMDA)-dependent plasticity by other neurotransmitter systems. We focus on the implication of the dysconnection hypothesis for functional imaging at the systems level. In particular, we review recent advances in measuring plasticity in the human brain using functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) that can be used to address dysconnectivity in schizophrenia. Promising experimental paradigms include perceptual and reinforcement learning. We describe how theoretical and causal models of brain responses might contribute to a mechanistic understanding of synaptic plasticity in schizophrenia.     

Random noise stimulation improves neuroplasticity in perceptual learning

Perceptual learning is considered a manifestation of neural plasticity in the human brain. We investigated brain plasticity mechanisms in a learning task using noninvasive transcranial electrical stimulation (tES). We hypothesized that different types of tES would have varying actions on the nervous system, which would result in different efficacies of neural plasticity modulation. Thus, the principal goal of the present study was to verify the possibility of inducing differential plasticity effects using two tES approaches [i.e., direct current stimulation (tDCS) and random noise stimulation (tRNS)] during the execution of a visual perceptual learning task.     

Role of the hippocampus on learning and memory functioning and pain modulation★

The hippocampus, an important part of the limbic system, is considered to be an important region of the brain for learning and memory functioning. Recent studies have demonstrated that synaptic plasticity is thought to be the basis of learning and memory functioning. A series of studies report that similar synaptic plasticity also exists in the spinal cord in the conduction pathway of pain sensation, which may contribute to hyperalgesia, abnormal pain, and analgesia. The synaptic plasticity of learning and memory functioning and that of the pain conduction pathway have similar mechanisms, which are related to the N-methyl-D-aspartic acid receptor. The hippocampus also has a role in pain modulation. As pain signals can reach the hippocampus, the precise correlation between synaptic plasticity of the pain pathway and that of learning and memory functioning deserves further investigation. The role of the hippocampus in processing pain information requires to be identified.     

Brain plasticity mechanisms and memory: a party of four.

A defining characteristic of the brain is its remarkable capacity to undergo activity-dependent functional and morphological remodeling via mechanisms of plasticity that form the basis of our capacity to encode and retain memories. Today, it is generally accepted that the neurobiological substrate of memories resides in activity-driven modifications of synaptic strength and structural remodeling of neural networks activated during learning. Since the discovery of long-term potentiation, the role of synaptic strengthening in learning and memory has been the subject of considerable investigation, and numerous studies have provided new insights into how this form of plasticity can subserve memory function. At the same time, other studies have explored the contribution of synaptic elimination or weakening; synaptogenesis, the growth of new synaptic connections and synapse remodeling; and more recently, neurogenesis, the birth and growth of new neurons in the adult brain. In this review, based on work in the hippocampus, the authors briefly outline recent advances in their understanding of the mechanisms and functional role of these four types of brain plasticity in the context of learning and memory. While they have long been considered as alternative mechanisms of plasticity underlying the storage of long-term memories, recent evidence suggests that they are functionally linked, suggesting the mechanisms underlying plasticity in the brain required for the formation and retention of memories are multifaceted.     

Fyn, a potential target for Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia characterized by the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles. The mechanisms leading to AD are not completely understood; however, recent evidence suggests that alterations in Fyn, a Src family kinase, might contribute to AD pathogenesis. A number of studies have demonstrated that Fyn is involved in synaptic plasticity, a cellular mechanism for learning and memory. In addition, Fyn plays a role in the regulation of Aβ production and mediates Aβ-induced synaptic deficits and neurotoxicity. Fyn also induces tyrosine phosphorylation of tau. Although many studies have implicated a role for Fyn in AD, the precise cellular and molecular mechanisms require further investigation. Novel insights into the role of Fyn in AD may help identify alternative pharmacological approaches for the treatment of AD.     

Stress, corticosteroid hormones and hippocampal synaptic function

Exposure to stressful events has profound impact on hippocampus-dependent learning and memory processes. Traumatic and stressful experiences are remembered well in general, but have also been reported to suppress learning and memory processes. These bi-directional effects are, at least in part, modulated by corticosteroid hormones that are released during exposure to stressful experiences. An important question that remains to be addressed is how exactly exposure to stressful situations and elevated corticosteroid hormone levels affect learning and memory processes. Evidence is accumulating that exposure to stressful situations and elevated corticosteroid hormone levels modulates fast excitatory amino acid mediated synaptic transmission and synaptic plasticity, which are considered to underlie learning and memory processes in the hippocampus. In particular, exposure to stressful events has been reported to facilitate synaptic plasticity when delivered shortly before or after high frequency stimulation. By contrast, stressful events and elevated corticosteroid hormones suppress synaptic potentiation when stress precedes high frequency stimulation. From the mechanistic point of view, it is potentially important that exposure to stressful events and elevated corticosteroid hormone levels target key mechanisms that are involved in synaptic plasticity, i.e. AMPA receptors and NMDA receptors.     

Intra-spaced stimulation and protein phosphatase 1 dictate the direction of synaptic plasticity

Changes in the strength of synapses in the hippocampus that occur with long-term potentiation (LTP) or long-term depression (LTD) are thought to underlie the cellular basis of learning and memory. Memory formation is known to be regulated by spacing intervals between training episodes. Using paired whole-cell recordings to record from synapses connecting two CA3 pyramidal neurons, we now show that stimulation frequency and spacing between LTP and LTD induction protocols alter the expression of synaptic plasticity. These effects were found to be dependent on protein phosphatase 1 (PP1), an essential protein serine/threonine phosphatase involved in synaptic plasticity, learning and memory. We also show for the first time that PP1 not only regulates the expression of synaptic plasticity, but also has the ability to depress synaptic transmission at basal activity levels. Moreover, PP1 can sort two consecutive messages received by the postsynaptic neuron and control the direction of change in synaptic strength. This study highlights new roles of PP1 in regulating timing-dependent constraints on the expression of synaptic plasticity that may correlate with memory processes, and together PP1 and the spacing of stimulation protocols provide mechanisms to regulate the expression of synaptic plasticity at CNS synapses.     

Embryonic striatal grafts restore bi‐directional synaptic plasticity in a rodent model of Huntington’s disease

Embryonic striatal grafts integrate with the host striatal circuitry, forming anatomically appropriate connections capable of influencing host behaviour. In addition, striatal grafts can influence host behaviour via a variety of non‐specific, trophic and pharmacological mechanisms; however, direct evidence that recovery is dependent on circuit reconstruction is lacking. Recent studies suggest that striatal grafts alleviate simple motor deficits, and also that learning of complex motor skills and habits can also be restored. However, although the data suggest that such ‘re‐learning’ requires integration of the graft into the host striatal circuitry, little evidence exists to demonstrate that such integration includes functional synaptic connections. Here we demonstrate that embryonic striatal grafts form functional connections with the host striatal circuitry, capable of restoring stable synaptic transmission, within an excitotoxic lesion model of Huntington’s disease. Furthermore, such ‘functional integration’ of the striatal graft enables the expression of host–graft bi‐directional synaptic plasticity, similar to the normal cortico‐striatal circuit. These results indicate that striatal grafts express synaptic correlates of learning, and thereby provide direct evidence of functional neuronal circuit repair, an essential component of ‘functional integration’.     

Different chronic cocaine administration protocols induce changes on dentate gyrus plasticity and hippocampal dependent behavior

Hippocampus is a limbic structure that participates in learning and memory formation. Specifically the dentate gyrus has been described as a hippocampal subregion with high rates of plasticity and it is targeted by different psychoactive drugs modulating synaptic plasticity. Repeated cocaine administration induces sensitization to the locomotor effects and it is believed that sensitization involves the same mechanisms of drug seeking and relapse. Although, the mechanisms underlying sensitization is not fully understood. In this work we investigated the impact of repeated intraperitoneal administration of cocaine (15 or 20 mg/kg/day along 5 or 15 days respectively; and 15 mg/kg/day along 5 day followed by a challenge dose after three days of withdrawal) on the dentate gyrus synaptic plasticity, differentiating between sensitized and nonsensitized rats. Furthermore, we correlated changes on the hippocampal synaptic plasticity to memory retention. Our results revealed that the prevalence of cocaine sensitization (around 50%) was identical in all protocols used. The results found in the threshold to generate LTP were similar for all protocols used, being the threshold values cocaine‐treated groups (sensitized and nonsensitized) significantly reduced compared to controls, observing the highest reduction in the sensitized group. Moreover, we observed a facilitated retention of recent memory formation only in sensitized animals the nonsensitized subjects remained at the control levels. In conclusion, sensitization to cocaine generates a high efficiency of hippocampal synaptic plasticity that may underlie the aberrant engagement of learning processes occurred during drug addiction. Synapse 64:742–753, 2010. © 2010 Wiley‐Liss, Inc.     

An essential role for histone deacetylase 4 in synaptic plasticity and memory formation

Histone deacetylases (HDACs), a family of enzymes involved in epigenetic regulation, have been implicated in the control of synaptic plasticity, as well as learning and memory. Previous work has demonstrated administration of pharmacological HDAC inhibitors, primarily those targeted to class I HDACs, enhance learning and memory as well as long-term potentiation. However, a detailed understanding of the role of class II HDACs in these processes remains elusive. Here, we show that selective loss of Hdac4 in brain results in impairments in hippocampal-dependent learning and memory and long-term synaptic plasticity. In contrast, loss of Hdac5 does not impact learning and memory demonstrating unique roles in brain for individual class II HDACs. These findings suggest that HDAC4 is a crucial positive regulator of learning and memory, both behaviorally and at the cellular level, and that inhibition of Hdac4 activity may have unexpected detrimental effects to these processes.     

Passive perceptual learning modulates motor inhibitory control in superior frontal regions

Response inhibition is of vital importance in the context of controlling inappropriate responses. The role of perceptual processes during inhibitory control has attracted increased interest. Yet, we are far from an understanding of the mechanisms. One candidate mechanism by which perceptual processes may affect response inhibition refers to “gain control” that is closely linked to the signal‐to‐noise ratio of incoming information. A means to modulate the signal‐to‐noise ratio and gain control mechanisms is perceptual learning. In the current study, we examine the impact of perceptual learning (i.e., passive repetitive sensory stimulation) on response inhibition combining EEG signal decomposition with source localization analyses. A tactile GO/NOGO paradigm was conducted to measure action restraint as one subcomponent of response inhibition. We show that passive perceptual learning modulates response inhibition processes. In particular, perceptual learning attenuates the detrimental effect of response automation during inhibitory control. Temporally decomposed EEG data show that stimulus‐related and not response selection processes during conflict monitoring are linked to these effects. The superior and middle frontal gyrus (BA6), as well as the motor cortex (BA4), are associated with the effects of perceptual learning on response inhibition. Reliable neurophysiological effects were not evident on the basis of standard ERPs, which has important methodological implications for perceptual learning research. The results detail how lower level sensory plasticity protocols affect higher‐order cognitive control functions in frontal cortical structures.     

An epigenetic induction of a right-shift in hippocampal asymmetry: selectivity for short- and long-term potentiation but not post-tetanic potentiation

In humans, it is well established that major psychological functions are asymmetrically represented between the left and right cerebral cortices. The developmental origin of such functional lateralization remains unknown. Using the rat as a model system, we examined whether exposing neonates briefly to a novel environment can differentially affect synaptic plasticity in the left and right hippocampi during adulthood. During the first 3 weeks of life, one half of the pups from a litter spent 3 min daily away from their familiar home environment (Novel) while their littermates remained in that familiar environment (Home). At adulthood (7-months old), post-tetanic potentiation (PTP) of excitatory post-synaptic potentials (EPSPs), a very short-lasting form of plasticity, was greater among the Novel than the Home rats in both left and right hippocampi. In contrast, the novelty-induced increases in short- and long-term potentiation (STP, LTP), two relatively longer-lasting forms of plasticity, were found only in the right hippocampus. These findings demonstrate that a phase-selective asymmetry in hippocampal synaptic plasticity can be induced epigenetically by seemingly small systematic differences in early life environment. The selectivity of this asymmetry for the longer-lasting forms of synaptic plasticity suggests that the observed asymmetry in plasticity may contribute specifically to an asymmetric learning process which, in turn, may contribute to a functional asymmetry in the neocortex.