New genetic models that target the serotonin system show that transient alterations in serotonin homeostasis cause permanent changes to adult behaviour and modify the fine wiring of brain connections. These findings have revived a long-standing interest in the developmental role of serotonin. Molecular genetic approaches are now showing us that different serotonin receptors, acting at different developmental stages, modulate different developmental processes such as neurogenesis, apoptosis, axon branching and dendritogenesis. Our understanding of the specification of the serotonergic phenotype is improving. In addition, studies have revealed that serotonergic traits are dissociable, as there are populations of neurons that contain serotonin but do not synthesize it.
Signals through the Notch receptors are used throughout development to control cellular fate choices. Loss- and gain-of-function studies revealed both the pleiotropic action of the Notch signalling pathway in development and the potential of Notch signals as tools to influence the developmental path of undifferentiated cells. As we review here, Notch signalling affects the development of the nervous system at many different levels. Understanding the complex genetic circuitry that allows Notch signals to affect specific cell fates in a context-specific manner defines the next challenge, especially as such an understanding might have important implications for regenerative medicine.
The conversion of acetylcholine binding into ion conduction across the membrane is becoming more clearly understood in terms of the structure of the receptor and its transitions. A high-resolution structure of a protein that is homologous to the extracellular domain of the receptor has revealed the binding sites and subunit interfaces in great detail. Although the structures of the membrane and cytoplasmic domains are less well determined, the channel lining and the determinants of selectivity have been mapped. The location and structure of the gates, and the coupling between binding sites and gates, remain to be established.
In multiple sclerosis — the archetypal inflammatory response in the central nervous system — T cells and macrophages invade the brain and damage the myelin and neurons. In other chronic neurodegenerative diseases, there is an atypical inflammatory response that is characterized by large numbers of activated microglia. These macrophages are primed by components of the neuropathology but might be further activated by systemic infection, which in turn has pronounced effects on inflammation in the brain and perhaps on neurological function. There is emerging evidence to support the idea that nonspecific systemic infection or inflammation in people with existing inflammation in the brain contributes to the rate of disease progression through further activation of these already primed macrophages.
Activity has an important role in refining synaptic connectivity during development, in part through 'Hebbian' mechanisms such as long-term potentiation and long-term depression. However, Hebbian plasticity is probably insufficient to explain activity-dependent development because it tends to destabilize the activity of neural circuits. How can complex circuits maintain stable activity states in the face of such destabilizing forces? An idea that is emerging from recent work is that average neuronal activity levels are maintained by a set of homeostatic plasticity mechanisms that dynamically adjust synaptic strengths in the correct direction to promote stability. Here we discuss evidence from a number of systems that homeostatic synaptic plasticity is crucial for processes ranging from memory storage to activity-dependent development.
Discoveries concerning the molecular mechanisms of cell differentiation and development have dictated the definition of a new sub-discipline of genetics known as epigenetics. Epigenetics refers to a set of self-perpetuating, post-translational modifications of DNA and nuclear proteins that produce lasting alterations in chromatin structure as a direct consequence, and lasting alterations in patterns of gene expression as an indirect consequence. The area of epigenetics is a burgeoning subfield of genetics in which there is considerable enthusiasm driving new discoveries. Neurobiologists have only recently begun to investigate the possible roles of epigenetic mechanisms in behaviour, physiology and neuropathology. Strikingly, the relevant data from the few extant neurobiology-related studies have already indicated a theme - epigenetic mechanisms probably have an important role in synaptic plasticity and memory formation.
Two organizing centres operate at long-range distances within the anterior
neural plate to pattern the forebrain, midbrain and hindbrain. Important progress
has been made in understanding the formation and function of one of these
organizing centres, the isthmic organizer, which controls the development
of the midbrain and anterior hindbrain. Here we review our current knowledge
on the identity, localization and maintenance of the isthmic organizer, as
well as on the molecular cascades that underlie the activity of this organizing
Postmitotic neurons are produced from a pool of cycling progenitors in
an orderly fashion during development. Studies of cell-fate determination
in the vertebrate retina have uncovered several fundamental principles by
which this is achieved. Most notably, a model for vertebrate cell-fate determination
has been proposed that combines findings on the relative roles of extrinsic
and intrinsic regulators in controlling cell-fate choices. At the heart of
the model is the proposal that progenitors pass through intrinsically determined
competence states, during which they are capable of giving rise to a limited
subset of cell types under the influence of extrinsic signals.
Converging evidence from electrophysiological, physiological and anatomical studies suggests that abnormalities in the synchronized oscillatory activity of neurons may have a central role in the pathophysiology of schizophrenia. Neural oscillations are a fundamental mechanism for the establishment of precise temporal relationships between neuronal responses that are in turn relevant for memory, perception and consciousness. In patients with schizophrenia, the synchronization of beta- and gamma-band activity is abnormal, suggesting a crucial role for dysfunctional oscillations in the generation of the cognitive deficits and other symptoms of the disorder. Dysfunctional oscillations may arise owing to anomalies in the brain's rhythm-generating networks of GABA (gamma-aminobutyric acid) interneurons and in cortico-cortical connections.
A plethora of discoveries relating to sex influences on brain function is rapidly moving this field into the spotlight for most areas of neuroscience. The domain of molecular or genetic neuroscience is no exception. The goal of this article is to highlight key developments concerning sex-based dimorphisms in molecular neuroscience, describe control mechanisms regulating these differences, address the implications of these dimorphisms for normal and abnormal brain function and discuss what these advances mean for future work in the field. The overriding conclusion is that, as for neuroscience in general, molecular neuroscience has to take into account potential sex influences that might modify signalling pathways.
Visual perceptual learning (VPL) is defined as a long-term improvement in performance on a visual task. In recent years, the idea that conscious effort is necessary for VPL to occur has been challenged by research suggesting the involvement of more implicit processing mechanisms, such as reinforcement-driven processing and consolidation. In addition, we have learnt much about the neural substrates of VPL and it has become evident that changes in visual areas and regions beyond the visual cortex can take place during VPL.
Many neurodegenerative disorders are characterized by conformational changes in proteins that result in misfolding, aggregation and intra- or extra-neuronal accumulation of amyloid fibrils. Molecular chaperones provide a first line of defence against misfolded, aggregation-prone proteins and are among the most potent suppressors of neurodegeneration known for animal models of human disease. Recent studies have investigated the role of molecular chaperones in amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and polyglutamine diseases. We propose that molecular chaperones are neuroprotective because of their ability to modulate the earliest aberrant protein interactions that trigger pathogenic cascades. A detailed understanding of the molecular basis of chaperone-mediated protection against neurodegeneration might lead to the development of therapies for neurodegenerative disorders that are associated with protein misfolding and aggregation.
In addition to their role in providing myelin for rapid impulse propagation, the glia that ensheath long axons are required for the maintenance of normal axon transport and long-term survival. This presumably ancestral function seems to be independent of myelin membrane wrapping. Here, I propose that ensheathing glia provide trophic support to axons that are metabolically isolated, and that myelin itself might cause such isolation. This glial support of axonal integrity may be relevant for a number of neurological and psychiatric diseases.
Dynamic aspects of interactions between astrocytes, neurons and the vasculature have recently been in the neuroscience spotlight. It has emerged that not only neurons but also astrocytes are organized into networks. Whereas neuronal networks exchange information through electrical and chemical synapses, astrocytes are interconnected through gap junction channels that are regulated by extra- and intracellular signals and allow exchange of information. This intercellular communication between glia has implications for neuroglial and gliovascular interactions and hence has added another level of complexity to our understanding of brain function.
Surviving in a world with hidden rewards and dangers requires choosing the appropriate behaviours. Recent discoveries indicate that the habenula plays a prominent part in such behavioural choice through its effects on neuromodulator systems, in particular the dopamine and serotonin systems. By inhibiting dopamine-releasing neurons, habenula activation leads to the suppression of motor behaviour when an animal fails to obtain a reward or anticipates an aversive outcome. Moreover, the habenula is involved in behavioural responses to pain, stress, anxiety, sleep and reward, and its dysfunction is associated with depression, schizophrenia and drug-induced psychosis. As a highly conserved structure in the brain, the habenula provides a fundamental mechanism for both survival and decision-making.
In the past 20 years, an extra layer of information processing, in addition to that provided by neurons, has been proposed for the CNS. Neuronally evoked increases of the intracellular calcium concentration in astrocytes have been suggested to trigger exocytotic release of the 'gliotransmitters' glutamate, ATP and D-serine. These are proposed to modulate neuronal excitability and transmitter release, and to have a role in diseases as diverse as stroke, epilepsy, schizophrenia, Alzheimer's disease and HIV infection. However, there is intense controversy about whether astrocytes can exocytose transmitters in vivo. Resolving this issue would considerably advance our understanding of brain function.
Recent studies are beginning to paint a clear and consistent picture of the impairments in psychological and cognitive competencies that are associated with microdeletions in chromosome 22q11.2. These studies have highlighted a strong link between this genetic lesion and schizophrenia. Parallel studies in humans and animal models are starting to uncover the complex genetic and neural substrates altered by the microdeletion. In addition to offering a deeper understanding of the effects of this genetic lesion, these findings may guide analysis of other copy-number variants associated with cognitive dysfunction and psychiatric disorders.
The classical concept of hypothalamus-pituitary-adrenal (HPA) homeostasis comprises a feedback system within which circulating levels of glucocorticoid hormones maintain the brain and body in an optimal steady state. However, studies involving new techniques for investigating the real-time dynamics of both glucocorticoid hormones and glucocorticoid receptor function paint a different picture--namely, of continuous dynamic equilibration throughout this neuroendocrine system. This dynamic state is dictated by feedforward and feedback regulatory loops and by stochastic interactions at the level of DNA binding. We propose that this continuous oscillatory activity is crucial for optimal responsiveness of glucocorticoid-sensitive neural processes.
The parieto-frontal cortical circuit that is active during action observation is the circuit with mirror properties that has been most extensively studied. Yet, there remains controversy on its role in social cognition and its contribution to understanding the actions and intentions of other individuals. Recent studies in monkeys and humans have shed light on what the parieto-frontal cortical circuit encodes and its possible functional relevance for cognition. We conclude that, although there are several mechanisms through which one can understand the behaviour of other individuals, the parieto-frontal mechanism is the only one that allows an individual to understand the action of others 'from the inside' and gives the observer a first-person grasp of the motor goals and intentions of other individuals.
Sleep has been identified as a state that optimizes the consolidation of newly acquired information in memory, depending on the specific conditions of learning and the timing of sleep. Consolidation during sleep promotes both quantitative and qualitative changes of memory representations. Through specific patterns of neuromodulatory activity and electric field potential oscillations, slow-wave sleep (SWS) and rapid eye movement (REM) sleep support system consolidation and synaptic consolidation, respectively. During SWS, slow oscillations, spindles and ripples - at minimum cholinergic activity - coordinate the re-activation and redistribution of hippocampus-dependent memories to neocortical sites, whereas during REM sleep, local increases in plasticity-related immediate-early gene activity - at high cholinergic and theta activity - might favour the subsequent synaptic consolidation of memories in the cortex.
A free-energy principle has been proposed recently that accounts for action, perception and learning. This Review looks at some key brain theories in the biological (for example, neural Darwinism) and physical (for example, information theory and optimal control theory) sciences from the free-energy perspective. Crucially, one key theme runs through each of these theories - optimization. Furthermore, if we look closely at what is optimized, the same quantity keeps emerging, namely value (expected reward, expected utility) or its complement, surprise (prediction error, expected cost). This is the quantity that is optimized under the free-energy principle, which suggests that several global brain theories might be unified within a free-energy framework.
During the development of the nervous system, many different types of neuron are produced. As well as forming the correct type of neuron, each must also establish precise connections. Recent findings show that, because of shared gene programmes, neuronal identity is intimately linked to and coordinated with axonal behaviour. Peripheral sensory neurons provide an excellent system in which to study these interactions. This review examines how neuronal diversity is created in the PNS and describes proteins that help to direct the diversity of neuronal subtypes, cell survival, axonal growth and the establishment of central patterns of modality-specific connections.
Ca(2+) signals have profound and varied effects on growth cone motility and guidance. Modulation of Ca(2+) influx and release from stores by guidance cues shapes Ca(2+) signals, which determine the activation of downstream targets. Although the precise molecular mechanisms that underlie distinct Ca(2+)-mediated effects on growth cone behaviours remain unclear, recent studies have identified important players in both the regulation and targets of Ca(2+) signals in growth cones.
Understanding the patterning mechanisms that control head development--particularly the neural crest and its contribution to bones, nerves and connective tissue--is an important problem, as craniofacial anomalies account for one-third of all human congenital defects. Classical models for craniofacial patterning argue that the morphogenic program and Hox gene identity of the neural crest is pre-patterned, carrying positional information acquired in the hindbrain to the peripheral nervous system and the branchial arches. Recently, however, plasticity of Hox gene expression has been observed in the hindbrain and cranial neural crest of chick, mouse and zebrafish embryos. Hence, craniofacial development is not dependent on neural crest prepatterning, but is regulated by a more complex integration of cell and tissue interactions.
A fundamental question in memory research is how our brains can form enduring memories. In humans, memories of everyday life depend initially on the medial temporal lobe system, including the hippocampus. As these memories mature, they are thought to become increasingly dependent on other brain regions such as the cortex. Little is understood about how new memories in the hippocampus are transformed into remote memories in cortical networks. However, recent studies have begun to shed light on how remote memories are organized in the cortex, and the molecular and cellular events that underlie their consolidation.
Studies of human addicts and behavioural studies in rodent models of addiction
indicate that key behavioural abnormalities associated with addiction are
extremely long lived. So, chronic drug exposure causes stable changes in the
brain at the molecular and cellular levels that underlie these behavioural
abnormalities. There has been considerable progress in identifying the mechanisms
that contribute to long-lived neural and behavioural plasticity related to
addiction, including drug-induced changes in gene transcription, in RNA and
protein processing, and in synaptic structure. Although the specific changes
identified so far are not sufficiently long lasting to account for the nearly
permanent changes in behaviour associated with addiction, recent work has
pointed to the types of mechanism that could be involved.
Recent years have witnessed the rise of the gut microbiota as a major topic of research interest in biology. Studies are revealing how variations and changes in the composition of the gut microbiota influence normal physiology and contribute to diseases ranging from inflammation to obesity. Accumulating data now indicate that the gut microbiota also communicates with the CNS - possibly through neural, endocrine and immune pathways - and thereby influences brain function and behaviour. Studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic bacteria or antibiotic drugs suggest a role for the gut microbiota in the regulation of anxiety, mood, cognition and pain. Thus, the emerging concept of a microbiota-gut-brain axis suggests that modulation of the gut microbiota may be a tractable strategy for developing novel therapeutics for complex CNS disorders.
Cooling can reduce primary injury and prevent secondary injury to the brain after insults in certain clinical settings and in animal models of brain insult. The mechanisms that underlie the protective effects of cooling - also known as therapeutic hypothermia - are slowly beginning to be understood. Hypothermia influences multiple aspects of brain physiology in the acute, subacute and chronic stages of ischaemia. It affects pathways leading to excitotoxicity, apoptosis, inflammation and free radical production, as well as blood flow, metabolism and blood-brain barrier integrity. Hypothermia may also influence neurogenesis, gliogenesis and angiogenesis after injury. It is likely that no single factor can explain the neuroprotection provided by hypothermia, but understanding its myriad effects may shed light on important neuroprotective mechanisms.
Optogenetic tools have provided a new way to establish causal relationships between brain activity and behaviour in health and disease. Although no animal model captures human disease precisely, behaviours that recapitulate disease symptoms may be elicited and modulated by optogenetic methods, including behaviours that are relevant to anxiety, fear, depression, addiction, autism and parkinsonism. The rapid proliferation of optogenetic reagents together with the swift advancement of strategies for implementation has created new opportunities for causal and precise dissection of the circuits underlying brain diseases in animal models.
mRNAs can be targeted to specific neuronal subcellular domains, which enables rapid changes in the local proteome through local translation. This mRNA-based mechanism links extrinsic signals to spatially restricted cellular responses and can mediate stimulus-driven adaptive responses such as dendritic plasticity. Local mRNA translation also occurs in growing axons where it can mediate directional responses to guidance signals. Recent profiling studies have revealed that both growing and mature axons possess surprisingly complex and dynamic transcriptomes, thereby suggesting that axonal mRNA localization is highly regulated and has a role in a broad range of processes, a view that is increasingly being supported by new experimental evidence. Here, we review current knowledge on the roles and regulatory mechanisms of axonal mRNA translation and discuss emerging links to axon guidance, survival, regeneration and neurological disorders.
The classical biogenic amine neurotransmitters — dopamine, noradrenaline, and 5-hydroxytryptamine — control a variety of functions including locomotion, autonomic function, hormone secretion, and the complex behaviours that are associated with affect, emotion and reward. A key step that determines the intensity and duration of monoamine signalling at synapses is the reuptake of the released transmitter into nerve terminals through high-affinity plasma membrane transporters. In recent years, molecular, pharmacological and genetic approaches have established the importance of monoamine transporters in the control of monoamine homeostasis and have provided insights into their regulation.
Dynamic regulation of synaptic efficacy is one of the mechanisms thought to underlie learning and memory. Many of the observed changes in efficacy, such as long-term potentiation and long-term depression, result from the functional alteration of excitatory neurotransmission mediated by postsynaptic glutamate receptors. These changes may result from the modulation of the receptors themselves and from regulation of protein networks associated with glutamate receptors. Understanding the interactions in this synaptic complex will yield invaluable insight into the molecular basis of synaptic function. This review focuses on the molecular organization of excitatory synapses and the processes involved in the dynamic regulation of glutamate receptors.
The quantity of neurotransmitter released into the synaptic cleft, the reliability with which it is released, and the response of the postsynaptic cell to that transmit- ter all contribute to the strength of a synaptic connection. The presynaptic nerve terminal is a major regulatory site for activity-dependent changes in synaptic func- tion. Ionotropic receptors for the inhibitory amino acid GABA, expressed on the presynaptic terminals of crustacean motor axons and vertebrate sensory neurons, were the first well-defined mechanism for the heterosynaptic transmitter-mediated regulation of transmitter release. Recently, presynaptic ionotropic receptors for a large range of transmitters have been found to be widespread throughout the central and peripheral nervous systems. In this review, we first consider some general theoretical issues regarding whether and how presynaptic ionotropic re- ceptors are important regulators of presynaptic function. We consider the criteria that should be met to identify a presynaptic ionotropic receptor and its regulatory function and review several examples of presynaptic receptors that meet at least some of those criteria. We summarize the classic studies of presynaptic inhibition mediated by GABA-gated Cl channels and then focus on presynaptic nicotinic ACh receptors and presynaptic glutamate receptors. Finally, we briefly discuss evidence for other types of presynaptic ionotropic receptors.
All available antidepressant medications are based on serendipitous discoveries of the clinical efficacy of two classes of antidepressants more than 50 years ago. These tricyclic and monoamine oxidase inhibitor antidepressants were subsequently found to promote serotonin or noradrenaline function in the brain. Newer agents are more specific but have the same core mechanisms of action in promoting these monoamine neurotransmitters. This is unfortunate, because only approximately 50% of individuals with depression show full remission in response to these mechanisms. This review summarizes the obstacles that have hindered the development of non-monoamine-based antidepressants, and provides a progress report on some of the most promising current strategies.
Many psychoactive drugs are used recreationally, particularly by young people. This use and its perceived dangers have led to many different classes of drugs being banned under national laws and international conventions. Indeed, the possession of cannabis, 3,4-methylenedioxy-N-methylamphetamine (MDMA; also known as ecstasy) and psychedelics is stringently regulated. An important and unfortunate outcome of the controls placed on these and other psychoactive drugs is that they make research into their mechanisms of action and potential therapeutic uses - for example, in depression and post-traumatic stress disorder - difficult and in many cases almost impossible.
Conduct disorder is a childhood behaviour disorder that is characterized by persistent aggressive or antisocial behaviour that disrupts the child's environment and impairs his or her functioning. A proportion of children with conduct disorder have psychopathic traits. Psychopathic traits consist of a callous-unemotional component and an impulsive-antisocial component, which are associated with two core impairments. The first is a reduced empathic response to the distress of other individuals, which primarily reflects reduced amygdala responsiveness to distress cues; the second is deficits in decision making and in reinforcement learning, which reflects dysfunction in the ventromedial prefrontal cortex and striatum. Genetic and prenatal factors contribute to the abnormal development of these neural systems, and social-environmental variables that affect motivation influence the probability that antisocial behaviour will be subsequently displayed.
14-3-3 proteins are abundantly expressed in the brain and have been detected in the cerebrospinal fluid of patients with different neurological disorders. Although the function of this family of highly conserved proteins is not completely known, recent evidence indicates their involvement in multiple cellular processes. By their interaction with more than 100 binding partners, 14-3-3 proteins modulate the action of proteins that are involved in cell cycle and transcriptional control, signal transduction, intracellular trafficking and regulation of ion channels. The study of some of these interactions is sheding light on the role of 14-3-3 proteins in processes such as apoptosis and neurodegeneration.
The generation and targeting of appropriate numbers and types of neurons to where they are needed in the brain is essential for the establishment, maintenance and modification of neural circuitry. This review aims to summarize the patterns, mechanisms and functional significance of neuronal migration in the postnatal brain, with an emphasis on the migratory events that persist in the mature brain.
The behavioural adjustment that follows the experience of conflict has been extensively studied in humans, leading to influential models of executive-control adjustment. Recent studies have revealed striking similarities in conflict-induced behavioural adjustment between humans and monkeys, indicating that monkeys can provide a model to study the underlying neural substrates and mechanisms of such behaviour. These studies have advanced our knowledge about the role of different prefrontal brain regions, including the anterior cingulate cortex (ACC) and the dorsolateral prefrontal cortex (DLPFC), in executive-control adjustment and suggest a pivotal role for the DLPFC in the dynamic tuning of executive control and, consequently, in behavioural adaptation to changing environments.
After injury to the adult central nervous system (CNS), injured axons cannot regenerate past the lesion. In this review, we present evidence that this is due to the formation of a glial scar. Chondroitin and keratan sulphate proteoglycans are among the main inhibitory extracellular matrix molecules that are produced by reactive astrocytes in the glial scar, and they are believed to play a crucial part in regeneration failure. We will focus on this role, as well as considering the behaviour of regenerating neurons in the environment of CNS injury.
The current view of brain organization supports the notion that there is a considerable degree of functional specialization and that many regions can be conceptualized as either 'affective' or 'cognitive'. Popular examples are the amygdala in the domain of emotion and the lateral prefrontal cortex in the case of cognition. This prevalent view is problematic for a number of reasons. Here, I will argue that complex cognitive-emotional behaviours have their basis in dynamic coalitions of networks of brain areas, none of which should be conceptualized as specifically affective or cognitive. Central to cognitive-emotional interactions are brain areas with a high degree of connectivity, called hubs, which are critical for regulating the flow and integration of information between regions.
The control of cell movement during development is essential for forming and stabilizing the spatial organization of tissues and cell types. During initial steps of tissue patterning, distinct regional domains or cell types arise at appropriate locations, and the movement of cells is constrained in order to maintain spatial relationships during growth. In other situations, the guidance of migrating cells or neuronal growth cones to specific destinations underlies the establishment or remodeling of a pattern. Eph receptor tyrosine kinases and their ephrin ligands are key players in controlling these cell movements in many tissues and at multiple stages of patterning.
Thomas Willis is considered to be one of the greatest neuroanatomists of all time. His name is usually associated with 'the circle of Willis', an anastomotic circle at the base of the brain, but his work also formed the foundation of basic neuroanatomical description and nomenclature, and comparative neuroanatomy. By combining his insightful clinical observations with his original pathological studies, his enquiring mind established links that are still astonishing 300 years on. For these reasons, Willis' name and achievements should be proclaimed to every new generation of neuroscientists.
It is anticipated that by 2040 neurodegeneration will affect 40 million people worldwide, more than twice as many as today. The traditional neurocentric view holds that neurodegeneration is caused primarily by intrinsic neuronal defects. However, recent evidence indicates that the millions of blood vessels that criss-cross the nervous system might not be the silent bystanders they were originally considered. Indeed, recent genetic studies reveal that insufficient production of angiogenic signals, which stimulate the growth of blood vessels, can cause neurodegeneration. Remarkably, some angiogenic factors can also regulate neuroregeneration, and have direct neuroprotective and other effects on various neural cell types. Here we provide an overview of the molecules that affect both neural and vascular cell processes--to underline their duality, we term them angioneurins. Unravelling the molecular mechanisms by which these angioneurins act might create opportunities for developing new neurovascular medicine.
The Rho family of small GTPases act as intracellular molecular switches
that transduce signals from extracellular stimuli to the actin cytoskeleton
and the nucleus. Recent evidence implicates Rho GTPases in the regulation
of neuronal morphogenesis, including migration, polarity, axon growth and
guidance, dendrite elaboration and plasticity, and synapse formation. Signalling
pathways from membrane receptors to Rho GTPases and from Rho GTPases to the
actin cytoskeleton are beginning to be discovered. Mutations in these signalling
pathways have been reported in human neurological diseases, which underscores
their importance in the development and function of the nervous system.
Long-term potentiation (LTP) in the CA1 region of the hippocampus has been the primary model by which to study the cellular and molecular basis of memory. Calcium/calmodulin-dependent protein kinase II (CaMKII) is necessary for LTP induction, is persistently activated by stimuli that elicit LTP, and can, by itself, enhance the efficacy of synaptic transmission. The analysis of CaMKII autophosphorylation and dephosphorylation indicates that this kinase could serve as a molecular switch that is capable of long-term memory storage. Consistent with such a role, mutations that prevent persistent activation of CaMKII block LTP, experience-dependent plasticity and behavioural memory. These results make CaMKII a leading candidate in the search for the molecular basis of memory.