The proteolysis of the extracellular matrix plays a key role in the synaptic neuroplasticity of the central nervous system (CNS), which results in learning and memory. Proteases from the serine family and metalloproteinases of the extracellular matrix are localized within the synapses and are released into the extracellular space in proportion to the degree of neuronal excitation. These enzymes cause changes in the morphology, shape and size, and the overall number of synapses and synthesize new synaptic connections. The proteinase also changes the function of receptors, and consequently, the secretion of neu- rotransmitter/neuromodulator from the presynaptic glutamatergic and/or pu- rinergic elements are either strengthened or weakened. Neuroglia involved in homeostasis, melanin synthesis and defense of the brain contain different combinations of purinergic receptors, which contributes to many neurotrans- mitters. This review summarizes a concept of brainplasticity, the role of ATP and P2 receptors interaction with glutamatergic system during plasticity of the brain in the one hand and after physical exercise in the other, which may be triggering phenomena facilitative synaptic plasticity as well as potentiates an personal efficiency to react to biobehavioral adaptation and disorders.
Beneficial effects of the same agonist, chronically administered, were also observed in adult mouse models of RTT. This syndrome is a severe X-linked neurological disorder characterized by deficits in autonomic, cognitive, motor functions and autistic features. In vivo systemic repeated stimulation of 5-HT7R with a selective brain-permeant agonist was able to improve cognitive and motor coordination deficits, as well as spatial memory and synaptic plasticity in RTT mice. 5-HT7R stimulation also restored the normal level of key molecules regulating actin cytoskeleton dynamics, such as Rho GTPases and mTOR signaling pathways that showed altered expression levels in the hippocampus of RTT mice [96,97]. The 5-HT7R-mediated neurobehavioral and molecular changes were still present 2 months after the last injection, suggesting long-lasting beneficial effects on RTT- related impairments. Subsequent studies uncovered functional alterations of brain mitochondria in RTT mouse models, that were rescued by chronic pharmacological stimulation of the 5-HT7R [98,99]. Similar promising preclinical results have been recently obtained in a mouse model of CDD, a rare neurodevelopmental syndrome characterized by severe neurobehavioral and motor deficits and stereotyped movements .
of a natural phenomenon heavily dependent on the environment. The same is the case for most elements, their structure and functions. Carbon is coal with one molecular structure when established in one environment and diamond with a totally different structure if established under other environmental circumstances and in another inter-functionality. The same element acquires a unique structure and function owing to the impact of other elements and the environment. It also changes structure and function through time. The human brain are no exceptions in this respect, it also adjusts to the environment, the social situation and to our psychological reactions. The brain develops new capacity as a result of our experience, our physi- cal and mental activity and how we cope with the situation. It stores what happens and creates new ways of thinking, feeling and behaving. This quality of the brain is due to its “plasticity”, or ability to develop and change. Physical and mental activity produces structural changes in the brain due to the brain plas- ticity in humans (Kolb & Whishaw, 1998). Two decades ago the brain was looked upon as anatomically hard-wired at birth. In the past two decades, however, an enormous amount of re- search has revealed that the brain never stops changing and adjusting. So it is not really legitimate any longer to regard the brain as a fixed collection of wired-up neurons like the hard- ware in a PC. The interconnections between neurons are chang- ing all the time and brain structure is more like the software. This model explains the importance of social and cultural in- fluences since experiences are internalized and stored both in mind and brain. Norman Doidge stated that neuroplasticity is “one of the most extraordinary discoveries of the twentieth century” (Doidge, 2007).
Bioelectronic medicine encompasses a set of tech- nologies that harness the electrical nerve impulses of the body to treat disease. The current approaches have mainly focused on electrical stimulation of the peripheral nervous system, but there is also potential of employing the principles of synaptic function, syn- aptic plasticity, and brain biochemistry for the imple- mentation of bioelectronic approaches in the CNS. Glutamate is the principal excitatory neurotransmitter in the brain. It is released from the presynaptic termi- nals of pyramidal neurons and it binds to glutamate receptors that are located in the postsynaptic neurons. There are three classes of ionotropic glutamate recep- tors, namely NMDARs, AMPARs and kainate recep- tors, which have a role not just in excitatory synaptic transmission but also in synaptic plasticity and higher cognitive functions. Importantly, abnormal elevations of glutamate can induce neurotoxicity, and because of this, glutamate has been implicated as a potential contributor to the pathogenesis of several neurode- generative disorders. In this study, we aimed to investigate whether uridine is capable of altering glu- tamatergic synaptic transmission and synaptic plasti- city with the use of ex vivo hippocampal slices and electrophysiological recordings. The hippocampal slice is an ideal preparation because it maintains many of the functions that neurons perform in vivo and it preserves the local synaptic circuitry. Therefore, brain slices are a good system in which to evaluate the mo- lecular changes associated with drug treatment or by external neuromodulation, such as via direct current stimulation (e.g., transcranial direct current stimula- tion or deep brain stimulation). Moreover, hippocam- pal slices are able to sustain glutamatergic synaptic plasticity, which is usually tested with the paradigm of LTP. Extensive research has shown that LTP repre- sents a form of synaptic plasticity that is input- specific, associative, and widely accepted as a synaptic model of memory formation (Bliss and Lomo, 1973; Bliss and Collingridge, 1993). In addition, it has been shown that brain slices subjected to a brief OGD
and cortisol increased. Together, these data suggest that exposure to Al toxicity in acidified water has a negative impact on both the brain and learning behavior in salmon. Such an effect is likely to have a negative influence on the ability of the fish to cope with the transition from freshwater to the marine environment, a time when the fish need to perform critical behaviors such as predator avoidance, social interactions and navigation (McCormick et al., 1998; Ebbesson and Braithwaite, 2012). Furthermore, it is possible that the reduced forebrain neural plasticity and cognitive deficit at the critical smolt stage also affect imprinting, by altering the olfactory-telencephalic plasticity associated with smoltification (Ebbesson et al., 1996a; Ebbesson et al., 2003; Folgueira et al., 2004). Memories of the natal stream formed during imprinting are later used to return as adults (Hasler and Scholz, 1983; Yamamoto et al., 2010), and thus impaired imprinting could have a profound impact on return success. Such behavioral processes are likely to involve the area of the brain involved in spatial learning and memory, namely the dorsolateral area of the telencephalon (Ebbesson and Braithwaite, 2012).
Chronic progressive diseases are a challenge for NBS. The evolution of these diseases occurs over the longer-term and is constantly changing, whereas NBS is difficult to administer chronically and probably does not have the flexibility to manage a constantly changing baseline. Par- kinson's disease (PD) is a progressively developing move- ment disorder arising from loss of dopaminergic neurons in the substantia nigra and depletion of dopamine in the basal ganglia. Although the pathology is subcortical, sec- ondary abnormalities manifest in cortical structures, including changes in cortical inhibition and shifts in the cortical representation of hand muscles which can occur in both early and late stages of the disease [24,25]. Map shifts correlate with the severity of clinical symptoms (UPDRS) and suggest an ongoing process of cortical reor- ganization with functional consequences . Dopamine has been implicated in the modulation of neuroplasticity , and the loss of dopaminergic neurons in PD may have secondary effects on cortical organization or limit the natural ability of plasticity mechanisms to compen- sate for disease-related processes, and there is some indi- cation that NBS may be more effective when applied during levodopa therapy, when plasticity mechanisms may be more functional [26,27]. As well, cortical rTMS interventions can lead to release of dopamine in the basal ganglia and raise serum dopamine levels . As to whether NBS can have a lasting benefit in a progressive disease such as PD, in which the primary pathology is sub- cortical, and which manifests as a generalized disorder, is uncertain. However a number of NBS interventions have been trialed in PD and have yielded some modest if tran- sient functional improvement, and meta-analysis of rand- omized controlled trials in PD indicate NBS can be beneficial over and above placebo effects . Plasticity in PD may be functional in the earlier stages of the dis- ease, as the brain adapts to the initial loss of dopaminergic neurons, but is probably dysfunctional later in the pro- gression of the disease as plasticity mechanisms become gradually impaired as a result of dopamine depletion. Dystonia
In contrast to the mammalian brain, cellular and network mechanisms of neural plasticity in central neurons of the insect brain have not yet been studied with electrophysiological methods in any great detail. The modulatory effect of biogenic amines, in particular octopamine and serotonin, on the excitability and spiking pattern of neurons in the thoracic ganglia were examined with the aim of understanding the release and performance of motor patterns (chapter 6 in Burrows, 1996; Pflüger, 1999). These modulatory effects are usually brief and are not related to learning. Visual interneurons in the bee brain were found to be antagonistically modulated by octopamine (upregulation) and serotonin (downregulation; Kloppenburg and Erber, 1995), but the mechanisms are unknown. Several classes of olfactory interneurons change their response properties when honeybees are trained to an odour (projection neurons: Abel, 1997; PCT neurons, the recurrent neurons from the alpha lobe to the calyx: Grünewald, 1999; the PE1 neuron: Mauelshagen, 1993), but the cellular mechanisms and the synapses involved are unknown. Long-term potentiation was observed in field potentials recorded in the MB of the honeybee, but the underlying mechanisms are unknown (Oleskevich et al., 1997). In particular, it is unknown whether central insect neurons show Hebbian plasticity in the sense that coincidence of pre-post-synaptic activity leads to lasting changes of synaptic transmission and/or neural excitation. This form of plasticity was studied in great detail in hippocampal and cortical neurons of the mammalian brain (Bear et al., 1987; Bear and Malenka, 1994; Fregnac et al., 1994; Markram et al., 1997). It was found that the precise timing of pre- and postsynaptic spikes leaves traces of lasting synaptic plasticity: either long-term potentiation (LTP) or long-term depression (LTD), depending on the timing of pre- and postsynaptic activity, and
Compensatory plasticity in MS can involve regional re- dedication (for example, the hyper-activation of alternative regions during the active phases of MS) or microstructural modification (for example, modifications of synaptic strength in intact regions). MS patients with a lateralized motor deficit display high ipsilateral and contra-lateral ac- tivity in cortical motor areas, which are less activated or not activated at all in control individuals. The enhance- ment of activity in cortical motor regions is correlated with brain damage [211,212] and can be seen from the amplitude of low frequency resting state activity . This pattern is partially reversible during the remission phase. Strong LTP in MS patients demonstrates the plastic adaptation of intact neurons. In patients undergoing re- mission, platelet-derived growth factor (PDGF) is associ- ated with strong LTP and high regional compensation. By contrast, in MS patients not undergoing remission or in those with progressive MS, strong LTP is not detected in intact regions [214,215]. A protective effect of physio- logical T may be responsible, at least in part, for the low susceptibility of men to MS . However, animal models enabling the effects of sex hormones and chromo- somes to be studied separately indicate that genetic sex plays a major role. For instance, genes on the Y chromo- some have a protective effect in EAE, an animal model of MS .
ulation (TMS) is delivered to the brain by passing a strong brief electrical current through an insulated wire coil placed on the skull. Current generates a transient mag- netic field, which in turn, if the coil is held over the sub- jects head, induces a secondary current in the brain that is capable of depolarising neurons. Depending on the fre- quency, duration of the stimulation, the shape of the coil and the strength of the magnetic field, TMS can activate or suppress activity in cortical regions . Another method of non-invasive brain stimulation is transcranial Direct Current Stimulation (tDCS) which delivers weak polariz- ing direct currents to the cortex via two electrodes placed on the scalp: an active electrode is placed on the site over- lying the cortical target, and a reference electrode is usu- ally placed over the contralateral supraorbital area or in a non-cephalic region. tDCS acts by inducing sustained changes in neural cell membrane potential: cathodal tDCS leads to brain hyperpolarization (inhibition), whereas anodal results in brain depolarization (excita- tion) [28,29]. Differences between tDCS and TMS include presumed mechanisms of action, with TMS acting as neuro-stimulator and tDCS as neuro-modulator. Moreo- ver, TMS has better spatial and temporal resolution, TMS protocols are better established, but tDCS has the advan- tage to be easier to use in double-blind or sham-control- led studies  and easier to apply concurrently with behavioural tasks (for discussion of these methods, simi- larities and differences, see the review by Wagner et al. ). Despite their differences, both TMS and tDCS can induce long-term after-effects on cortical excitability that may translate into behavioural impacts that can last for months [32-35]. These long-term after-effects are believed to engage mechanisms of neural plasticity, rendering these techniques ideally suited to promote motor recovery particularly when combined with suitable behavioural interventions (for review, see [26,36,37]).
Honey bees begin adult life working inside the hive, but typically when more than 14 days old as adults they transition into a foraging role . The onset of foraging exposes bees to new environments and places demands on bee cognition for spatial navigation, and identifying profitable sources of nectar or pollen, in an ever-changing environment [22,23]. The onset of foraging is preceded by a series of orientation flights in which bees learn the hive location [21,24]. These behavioural changes are accompanied by changes in the mushroom bodies (MBs) [5,18–20,25], which are regions of the bee brain needed for certain learning tasks [26,27]. Foragers have larger MBs than nurse bees that work inside the hive [5,18], and the MBs continue to increase in size with additional foraging experience [18,19]. The experience- dependent growth of the MBs is caused by dendritic arborisation [18,20,25] in their input sub- regions; the lips and collars of the MB calyx which receive olfactory and visual inputs respec- tively . In both subregions axon terminals of input neurons connect to the dendrites of intrinsic MB neurons, thus forming synaptic boutons (also called microglomeruli). Despite the growth in volume and dendritic arbours, foragers have fewer synaptic boutons in the lip and collar regions than younger bees working in the hive , suggesting a synaptic pruning at either the onset of foraging or during the orientation flights that immediately precede foraging. Such synaptic pruning in the collar has been suggested to be induced by light exposure in Cat- aglyphis ants and honey bees [29,30]. The functional consequences of this experience related structural plasticity of the MBs has been much speculated on [5,18,31], but remains unclear. Here we examined how the experience-dependent changes in honey bee MB microstruc- ture correlated with performance in a cognitive task which is dependent on MB function: reversal learning . In reversal learning, bees learn first to respond to a rewarded odour A and not to a non-rewarded odour B (A+B-). In a second phase, they learn the reverse contin- gencies (A-B+). The resolution of this task requires flexibility in learned behaviour [26,32]. This task is expected to be particularly meaningful for foraging bees, as they need to update the value of floral cues (e.g. odorants) as indicators of food, because nectar production varies in time [26,32]. Our results reveal a clear relationship between experience-dependent changes in MB synaptic bouton number and both an increased reversal learning performance at the onset of foraging, and a drop in reversal learning performance in more experienced foragers.
reliably observed in animal models. To date, numerous studies have associated regular cardiovascular exercise to changes in brainplasticity. In particular, aerobic exercise has been shown to have a direct effect on the hippocampus, which plays an important role in learning and memory (Firth et al., 2018). Scientific studies in rodents have revealed increased adult hippocampal neurogenesis (AHN), or the birth of new neurons, in the dentate gyrus (DG) subfield of the hippocampus as a response to increased voluntary aerobic exercise performed by rodents on a running wheel (van Praag, Kempermann, & Gage, 1999).
The findings presented here are derived from whole-brain transcriptomes, so they represent an aggregate of the individual states of each neuronal and glial cell in the brain. Brains are highly compartmentalized and consist of numerous specialized regions and neuronal subtypes. Only a subset of these neurons is likely to be activated in a given social context, and recently it was shown that even neurons of the same subtype and lineage can exhibit strikingly different transcriptomic profiles (Poulin et al., 2016). However, transcriptome-wide differences in brain expression associated with naturally occurring behavior have been reported for a variety of species (Hughes et al., 2012; Oliveira et al., 2016) ever since they were first discovered in honey bees (Whitfield et al., 2003). Given that many behaviors are known to be orchestrated in specific regions of invertebrate and vertebrate brains, why should there be such robust patterns of behaviorally related gene expression at the whole-brain level in honey bees and other organisms? A technical explanation is that the whole-brain transcriptomic profile largely reflects the profiles of the larger brain regions; in honey bees, this would include the mushroom bodies and optic lobes, which together account for ∼ 2/3 of the neurons in the adult bee brain. A biological explanation is that the whole-brain transcriptomic profile arises because there are similarities in gene expression in different brain regions. For instance, numerous neuromodulators and hormones are known to directly contribute to long-term changes in honey bee behavior (Hamilton et al., 2017), and many are known to have receptors in multiple regions of the adult insect brain (Baumann et al., 2017; Perry and Barron, 2013). This makes it likely that at least some neuromodulators and hormones are capable of coordinating gene expression across brain regions. Determining the role that either or both of these explanations play in contributing to the dynamics of brain transcriptional regulatory plasticity, and neural and behavioral plasticity in general, will require integrating information at the cellular level. Recent advances in single-cell RNA sequencing make this feasible for the first time, and future studies should use these exciting new developments to examine transcriptional regulatory plasticity at the level of individual neurons.
Huang et al. (2005), making direct comparison with the original protocol problematic (52). McAllister et al. investigated the modulation of cortical oscillatory activity by cTBS of 600 pulses after a visuomotor training task using both MEP and EEG measurements (53). The authors only found significant alpha power that was positively correlated with MEP after the visuomotor training. They concluded that EEG was not useful as an index of cortical output to plasticity-inducing paradigms such as cTBS. However, in that study, the EEG was recorded using a single electrode of C3 over the motor cortex, and was therefore unable to ascertain the possible cTBS effects on cortico-cortical coupling (53). An investigation using multi-channel EEG will provide a more thorough outlook on the effects of cTBS on the motor network excitability. In a subsequent experiment, Noh et al. addressed the lack of knowledge of cTBS effects on motor network oscillations and their correlation with behavioural measurements by applying the original cTBS protocol consisting of 100 bursts of three pulses (300 pulses) at 50Hz repeated every 200ms (5Hz) in 13 healthy subjects and measured the EEG oscillatory properties using high-density multi-channel EEG (37). Their results showed that cTBS could modulate the cortical brain rhythms, particularly beta oscillations, for at least 30 minutes compared to the 20 minutes MEP suppression. This finding suggests that EEG is probably a more sensitive index of cortical output after cTBS compared to MEP (37).
The signal transduction pathways downstream of NMDA receptor activation, which underlie LTP, include the PI3K [26– 28,95,96] and MAPK/ERK pathways [57,69,70]. Both the PI3K and MAPK/ERK pathways are further implicated in the insulin/ IGF-1-mediated modulation of synaptic function in several neurons [54,55,97,98], and are prominent targets of IRS proteins [20,21,23,71]. Furthermore, in knockout mice expressing a brain- restricted insulin receptor deficiency (NIRKO) brain insulin resistance impairs insulin-mediated activation of either the PI3K/Akt/GSK-3b or MAPK/ERK pathways in cerebellar granule cells . In NesCreIrs2KO mice the basal activity of p42/44 MAPK is not affected, while phosphorylation of the downstream target of PI3K, Akt/protein kinase B, is substantially reduced, providing a further potential mechanism for the impaired LTP observed in the absence of neuronal IRS-2. However, we cannot exclude that p42/44 MAPK phosphorylation might be reduced in response to LTP-inducing stimuli, thus also partici- pating in the observed deficits in plasticity in IRS-2-deficient mice. This seems indeed to be the case in global IRS-2 KO mice, where activation of MAPK was not sustained 30 min after the induction of LTP .
non-invasive MR-imaging, it has become possible to identify short-term and long-term brainplasticity, usually associated with different types of learning in human subjects. For example, task-based fMRI has been applied successfully to show brainplasticity effects for motor and other types of tasks (Karni et al. 1995; Poldrack et al. 1998; Fletcher et al. 1999; Pleger et al. 2003; Limanowski et al. 2017). Since task-based fMRI tends to be confounded by changes in task performance, several studies have successfully used task-free ‘resting-state functional connectivity fMRI’ to identify neural connectivity changes (Taubert et al. 2011; Zhang et al. 2014; Ge et al. 2015; Amad et al. 2017; Mawase et al. 2017). Noteably, ‘structural’ MRI measures (T1-weighted and diffusion-MRI) have also been shown to identify signs of brainplasticity. After the seminal work of Draganski and colleagues, who showed changes in grey matter density (GMD) after 3 months of juggling training, several other studies have also demonstrated changes in GMD after different types of learning within several days or weeks (Draganski et al. 2004; Taubert et al. 2010; Zatorre et al. 2012). Recently, several MRI studies successfully used ‘structural MRI measures’ to detect cerebral modifications after only a few hours of training or stimulation (Sagi et al. 2012; Hofstetter et al. 2013; Taubert et al. 2016; Schmidt-Wilcke et al. 2018), consistent with animal studies that showed signs of brainplasticity already within a few minutes of training (Xu et al. 2009; Moczulska et al. 2013; Kuhlman et al. 2014).
However, these structural changes and an enhancement in synaptic plasticity were observed only in rats subjected to 56 days of long-term wheel-running, as opposed to 14 days of short-term wheel-running, which emphasizes the need for long-term periods of physical exercise to facilitate its structural and functional benefits on the brain. Also, a study examining the effect of intensity of physical activity required to normalize corticomotor excitability and increase gait speed, stride length and step length in patients with early Parkinsons disease has demonstrated greater benefits using high-intensity exercise than low- and zero-intensity exercise. Furthermore, a study conducted on older adults by Kramer et. al has found that a six month intervention of moderate aerobic exercise in the form of walking as opposed to stretching and toning exercises, can dramatically enhance executive functions in the brain, thereby re-enforcing the view that plasticity or the potential for positive change is maintained even during adulthood.
pattern of practice-induced functional change is likely to occur in response to such interventions? Although the answer to this question is likely to depend principally on the extent and severity of the injury, there are a number of insights to be gained from the examination of normal practice-induced plas- ticity that may apply to rehabilitative situations. In the first part of this review, we provide a brief overview of the patterns of normal brainplasticity that occur in response to practice, with a particular emphasis on the potential for practice of cognitive functions. To demonstrate this potential, we provide some preliminary but promising behavioral data that show how prac- tice on higher cognitive tasks can benefit cognitive functioning more generally. In the second section of the review, we discuss the small number of studies that have used neuroimaging methods to examine the neural consequences of cognitive training in clinical populations. These studies provide an illus- tration of how the insights gained from the examination of neuroplasticity in normative populations, discussed in the first
One of the most interesting questions in neuroscience concerns the manner in which the nervous system can modify its organization and ultimately its function throughout an individual's lifetime based on sensory input, experience, learning and injury[12,13]. This phe- nomenon is often referred to as brainplasticity [14,15]. Plasticity changes can be divided into rapid and long term plasticity. Rapid changes are typically seen minutes after injury or intervention, and are often based on decreased inhibition. Decreased inhibition increases the receptive field size and enables more neurons to be activated by a specific stimulus. This is sometimes referred to as unmask- ing of synapses or neural structures. Long-term changes are typically seen weeks or months after an injury or inter- vention and are based on increase or decrease in synaptic transmission or axonal and dendritic sprouting. Synaptic transmission becomes facilitated in a pathway that is fre- quently used, while those that lay dormant atrophy. Sprouting can be seen in response to injury or to increased functional demand . Axons at the edges of a lesion send new axonal branches into the damaged area and re- innervate dendrites that have lost their synaptic input. Plasticity changes also include changes in nerve signal amplitude and activation of additional cortical areas [14,15].
While this previous work explores the idea of activity dependent glomerular volume changes, the ultrastructural implications of activity-dependent plasticity in the ALs of the bee brain remain unknown. To begin to explore the origins of this plasticity, a combination of light microscopy and transmission electron microscopy (TEM) has been used to determine the total synapse number in the T4- 2(1) glomerulus, of bees of different ages (0-day, 4- day, 10-day and forager-aged bees) and in bees performing different tasks (newly-emerged, cleaning/ nurse-bees and pollen foragers). We hypothesise that
or overexpression of a single gene can lead to compensatory changes in the expression of other genes, the presence or absence of which can vary according to the genetic backgrounds of the mouse strains used to generate a genetically modified line of mice (Crawley et al., 1997). Valid interpretation of the neurophysiological phenotypes that emerge from genetically modified mice therefore requires knowledge of the synaptic properties of relevant neurons in the parent strains used to produce genetically modified lines of mice. Hence, the characterization of synaptic phenotypes of neurons in relevant brain structures of inbred mice is an important step towards defining the genetic and molecular bases of synaptic plasticity. It can also lead to the compilation of physiological databases (mouse ‘physiomes’) needed to construct mouse models of synaptic and cognitive dysfunction. Long-term potentiation (LTP) and long-term depression (LTD) constitute activity-dependent enhancement and reduction, respectively, of excitatory synaptic strength (Lomo, 1966; Bliss and Lomo, 1973; Dudek and Bear, 1992). These two types of synaptic plasticity are believed to play important roles in mediating learning and memory (Martin et al., 2000; Lynch, 2004), perception (Klein et al., 2004), and the refinement of synaptic circuitry (Kirkwood et al., 1995). In humans and mice, area CA1 (cornu ammonis-1) of the hippocampus is vital for the formation of long-term memory (Zola-Morgan et al., 1986; Tsien et al., 1996). Genetic modifications of key signalling molecules within area CA1 of the mouse hippocampus can impair long-term memory and LTP (reviewed by Lynch, 2004). Some comparative data showing strain-associated variations of hippocampal memory and LTP in area CA1 of in vitro slices have been reported (Nguyen et al., 2000a; Nguyen et al., 2000b; Schimanski et al., 2002; Schimanski et al., 2005a; Schimanski et al., 2005b) [for in vivo data, see (Bampton et al., 1999; Jones et al., 2001)]. However, the mechanisms underlying strain-dependent variations in LTP are mostly undefined, and conjoint characterization of LTP and memory in inbred mouse strains is still nascent. Also, it should be emphasized that comparative analysis of inbred strains can shed light on which particular types of synaptic plasticity are critical for expression of specific forms of learning and memory. The question, ‘Does LTP=memory?’ can be effectively addressed by using inbred mice: they provide an experiment of nature to test this hypothesis in a less biased manner than experiments that use reverse genetic approaches.