Alzheimer’s disease (AD) exhibits a complex etiology that simultaneously manifests as a complex cellular, neurobiological, molecular, anatomic–physiological and clinical entity. Other significant psychiatric conditions, such as depression and schizophrenia, may also present with complex and concurrent clinical and/or molecular phenotypes. These neuropsychiatric pathologies also originate from both environmental and genetic factors. We analyzed the molecular phenotypes of AD and discuss them with respect to the classical theories, which we integrated into mechanisms that share molecular and/or anatomical connections. Based on these mechanisms, we propose an interaction model and discuss the model in light of studies that refute or support it. Given the spectrum of AD phenotypes, we limit the scope of our discussion to a few, which facilitates concrete analysis. In addition, the study of specific, individual pathogenic phenotypes may be critical to defining the complex mechanisms leading to AD, thereby improving strategies for developing novel therapies.

CRMP2, also known as DPYSL2/DRP2, Unc-33, Ulip or TUC2, is a cytosolic phosphoprotein that mediates axon/dendrite specification and axonal growth. Mapping the CRMP2 interactome has revealed previously unappreciated functions subserved by this protein. Together with its canonical roles in neurite growth and retraction and kinesin-dependent axonal transport, it is now known that CRMP2 interacts with numerous binding partners to affect microtubule dynamics; protein endocytosis and vesicular cycling, synaptic assembly, calcium channel regulation and neurotransmitter release. CRMP2 signaling is regulated by post-translational modifications, including glycosylation, oxidation, proteolysis and phosphorylation; the latter being a fulcrum of CRMP2 functions. Here, the putative roles of CRMP2 in a panoply of neurodegenerative, sensory and motor neuron, and central disorders are discussed and evidence is presented for therapeutic strategies targeting CRMP2 functions.

Neurodegenerative disorders lead to disability and death in a significant proportion of the world’s population. However, many disorders of the nervous system remain with limited effective treatments. Kinase pathways in the nervous system that involve phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), and the mammalian target of rapamycin (mTOR) offer exciting prospects for the understanding of neurodegenerative pathways and the development of new avenues of treatment. PI 3-K, Akt, and mTOR pathways are vital cellular components that determine cell fate during acute and chronic disorders, such as Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, epilepsy, stroke, and trauma. Yet, the elaborate relationship among these kinases and the variable control of apoptosis and autophagy can lead to unanticipated biological and clinical outcomes. Crucial for the successful translation of PI 3-K, Akt, and mTOR into robust and safe clinical strategies will be the further elucidation of the complex roles that these kinase pathways hold in the nervous system.

Accumulation of senile plaques consisting of amyloid-β peptide (Aβ) aggregates is a prominent pathological feature in Alzheimer’s disease. Effective clearance of Aβ from the brain parenchyma is thought to regulate the development and progression of the disease. Macrophages in the brain play an important role in Aβ clearance by a variety of phagocytic and digestive mechanisms. Subpopulations of macrophages are heterogeneous such that resident microglia in the parenchyma, blood macrophages infiltrating from the periphery, and perivascular macrophages residing along cerebral vessels make functionally distinct contributions to Aβ clearance. Despite phenotypic similarities between the different macrophage subsets, a series of in vivo models have been derived to differentiate their relative impacts on Aβ dynamics as well as the molecular mechanisms underlying their activities. This review discusses the key findings from these models and recent research efforts to selectively enhance macrophage clearance of Aβ.

Alzheimer’s disease (AD) and epilepsy are separated in the medical community, but seizures occur in some patients with AD, and AD is a risk factor for epilepsy. Furthermore, memory impairment is common in patients with epilepsy. The relationship between AD and epilepsy remains an important question because ideas for therapeutic approaches could be shared between AD and epilepsy research laboratories if AD and epilepsy were related. Here we focus on one of the many types of epilepsy, temporal lobe epilepsy (TLE), because patients with TLE often exhibit memory impairment, depression and other comorbidities that occur in AD. Moreover, the seizures that occur in patients with AD may be nonconvulsive, which occur in patients with TLE. Here we first compare neuropathology in TLE and AD with an emphasis on the hippocampus, which is central to both AD and TLE research. Then we compare animal models of AD pathology with animal models of TLE. Although many aspects of the comparisons are still controversial, there is one conclusion that we suggest is clear: some animal models of TLE could be used to help address questions in AD research, and some animal models of AD pathology are bona fide animal models of epilepsy.

Of the various genetic factors contributing to the pathogenesis of Parkinson’s disease (PD), only mutations in α-synuclein (α-syn) and LRRK2 genes cause clinical and neuropathological phenotypes closely resembling the sporadic cases. Therefore, studying the pathophysiological functions of these two PD-related genes is particularly informative in understanding the underlying molecular pathogenic mechanism of the disease. PD-related missense and multiplication mutations in α-syn may cause both early- and late-onset PD, whereas various PD-related LRRK2 missense mutations may contribute to the more common late-onset PD. While intensive studies have been carried out to elucidate the pathogenic properties of PD-related mutant α-syn and LRRK2, our knowledge of their normal functions and their potential genetic interplay remains rudimental. In this review, we summarize the progress made regarding the pathophysiological functions of α-syn, LRRK2 and their interaction in PD, based on the available literature and our unpublished observations.

Reprogramming of somatic cells to an embryonic-like state has dramatically changed the landscape of stem cell research. Although still in its formative stages, the field of induced pluripotent stem cells (iPSCs) has the potential to advance the study of neurodegenerative and neurodevelopmental disorders at the molecular and cellular levels. The iPSC technology could be employed to establish in vitro experimental model systems for the identification of molecular lesions and to aid in the discovery of therapeutic targets and effective compounds. The derivation of patient-specific iPSCs has also opened up the possibility of generating disease-relevant cells for toxicity screening and for cellular therapy. In this article, we review the recent progress in the use of disease-specific iPSCs for in vitro and in vivo modeling of neurological diseases.

Cannabis is the most commonly used illicit substance among pregnant women. Human epidemiological and animal studies have found that prenatal cannabis exposure influences brain development and can have long-lasting impacts on cognitive functions. Exploration of the therapeutic potential of cannabis-based medicines and synthetic cannabinoid compounds has given us much insight into the physiological roles of endogenous ligands (endocannabinoids) and their receptors. In this article, we examine human longitudinal cohort studies that document the long-term influence of prenatal exposure to cannabis, followed by an overview of the molecular composition of the endocannabinoid system and the temporal and spatial changes in their expression during brain development. How endocannabinoid signaling modulates fundamental developmental processes such as cell proliferation, neurogenesis, migration and axonal pathfinding are also summarized.

Congenital CNS abnormalities have been targets for prenatal intervention since the founding of fetal surgery 30 years ago, but with historically variable results. Open fetal neurosurgery for myelomenigocele has demonstrated the most promising results of any CNS malformation. Improvements in the understanding of congenital diseases and in fetal surgical techniques have reopened the door to applying fetal surgery to other congenital CNS abnormalities. Advances in gene therapy, bioengineering and neonatal neuroprotection will aid in the future expansion of fetal neurosurgery to other CNS disorders.

Ischemic stroke triggers a massive, although transient, glutamate efflux and excessive activation of NMDA receptors (NMDARs), possibly leading to neuronal death. However, multiple clinical trials with NMDA antagonists failed to improve, or even worsened, stroke outcome. Recent findings of a persistent post-stroke decline in NMDAR density, which plays a pivotal role in plasticity and memory formation, suggest that NMDAR stimulation, rather than inhibition, may prove beneficial in the subacute period after stroke.

Aim

This study aims to examine the effect of the NMDAR partial agonist d-cycloserine (DCS) on long-term structural, functional and behavioral outcomes in rats subjected to transient middle cerebral artery occlusion, an animal model of ischemic stroke.

Materials & methods

Rats (n = 36) that were subjected to 90 min of middle cerebral artery occlusion were given a single injection of DCS (10 mg/kg) or vehicle (phosphate-buffered saline) 24 h after occlusion and followed up for 30 days. MRI (structural and functional) was used to measure infarction, atrophy and cortical activation due to electrical forepaw stimulation. Memory function was assessed on days 7, 21 and 30 postocclusion using the novel object recognition test. A total of 20 nonischemic controls were included for comparison.

Results

DCS treatment resulted in significant improvement of somatosensory and cognitive function relative to vehicle treatment. By day 30, cognitive performance of the DCS-treated animals was indistinguishable from nonischemic controls, while vehicle-treated animals demonstrated a stable memory deficit. DCS had no significant effect on infarction or atrophy.

Conclusion

These results support a beneficial role for NMDAR stimulation during the recovery period after stroke, most likely due to enhanced neuroplasticity rather than neuroprotection.

Axons and Schwann cells exist in a highly interdependent relationship: damage to one cell type invariably leads to pathophysiological changes in the other. Greater understanding of communication between these cell types will not only give insight into peripheral nerve development, but also the reaction to and recovery from peripheral nerve injury. The type III isoform of neuregulin-1 (NRG1) has emerged as a key signaling factor that is expressed on axons and, through binding to erbB2/3 receptors on Schwann cells, regulates multiple phases of their development. In adulthood, NRG1 is dispensable for the maintenance of the myelin sheath; however, this factor is required for both axon regeneration and remyelination following nerve injury. The outcome of NRG1 signaling depends on interactions with other pathways within Schwann cells such as Notch, integrin and cAMP signaling. In certain circumstances, this signaling pathway may be maladaptive; for instance, direct binding of Mycobacterium leprae onto erbB2 receptors produces excessive activation and can actually promote demyelination. Attempts to modulate this pathway in order to promote nerve repair will therefore need to give consideration to the exact isoform used, as well as how it is processed and the context in which it is presented to the Schwann cell.

This article highlights the most recent findings regarding the rehabilitation interventions for the syndromes of visual neglect and anosognosia for hemiplegia that occur following right hemisphere stroke. We review papers published in the past 4 years pertaining to therapeutic approaches for these two syndromes in order to identify the trends in the development of effective interventions. Overall, it appears well recognized that visual neglect syndromes and awareness syndromes frequently co-occur and both include complex, multifaceted impairments leading to significant difficulties in daily life functioning following stroke. Thus, the interventions for these syndromes must be multifaceted in order to address the complex interplay of cognitive–behavioral–emotional components. There appears to be a trend for using combination therapeutic interventions that address these components.

Huntington’s disease (HD) is a noncurable and progressive autosomal-dominant neurodegenerative disorder that results from a polyglutamine expansion in the amino-terminal region of the huntingtin protein. The generation of rodent HD models has revealed that cellular dysfunction, rather than cell death alone, occurs early in the disease progression, appearing even before overt symptom onset. Much evidence has now established that dysfunction of the corticostriatal circuit is key to HD symptomology. In this article, we summarize the most current findings that implicate glutamate, dopamine and calcium signaling in this system and discuss how they work in concert to disrupt corticostriatal function. In addition, we highlight therapeutic strategies related to altered corticostriatal signaling in HD.

Mice are increasingly overtaking the rat model organism in important aspects of anxiety research, including drug development. However, translating the results obtained in mouse studies into information that can be applied in clinics remains challenging. One reason may be that most of the studies so far have used animals displaying ‘normal’ anxiety rather than ‘psychopathological’ animal models with abnormal (elevated) anxiety, which more closely reflect core features and sensitivities to therapeutic interventions of human anxiety disorders, and which would, thus, narrow the translational gap. Here, we discuss manipulations aimed at persistently enhancing anxiety-related behavior in the laboratory mouse using phenotypic selection, genetic techniques and/or environmental manipulations. It is hoped that such models with enhanced construct validity will provide improved ways of studying the neurobiology and treatment of pathological anxiety. Examples of findings from mouse models of enhanced anxiety-related behavior will be discussed, as well as their relation to findings in anxiety disorder patients regarding neuroanatomy, neurobiology, genetic involvement and epigenetic modifications. Finally, we highlight novel targets for potential anxiolytic pharmacotherapeutics that have been established with the help of research involving mice. Since the use of psychopathological mouse models is only just beginning to increase, it is still unclear as to the extent to which such approaches will enhance the success rate of drug development in translating identified therapeutic targets into clinical trials and, thus, helping to introduce the next anxiolytic class of drugs.

Suicide is a major public health concern; however, its neurobiology is unclear. Post-mortem brain tissue obtained from suicide victims and normal controls offers a useful method for studying the neurobiology of suicide. Despite several limitations, these studies have offered important leads in the neurobiology of suicide. In this article, we discuss some important findings resulting from these studies, focusing on serotonergic mechanisms, signal transduction systems, neuroendocrine studies and immune function abnormalities in suicide. These studies suggest that abnormalities of certain receptor subtypes, components of signaling systems such as protein kinase C and protein kinase A, transcription factors such as cyclic AMP response element-binding protein and neurotrophins may play an important role in the pathophysiology of suicide. These studies also suggest abnormalities of hypothalamic–pituitary–adrenal axis system components, feedback mechanisms and cytokines, which are chemical mediators of the immune functions. Post-mortem brain tissue offers an opportunity for future studies, such as genetic and epigenetic studies.

Neurogenesis is the process by which new neural cells are generated from a small population of multipotent stem cells in the adult CNS. This natural generation of new cells is limited in its regenerative capabilities and also declines with age. The use of stem cells in the treatment of neurodegenerative disease may hold great potential; however, the age-related incidence of many CNS diseases coincides with reduced neurogenesis. This review concisely summarizes current knowledge related to adult neurogenesis and its alteration with aging and examines the feasibility of using stem cell and gene therapies to combat diseases of the CNS with advancing age.

With Alzheimer’s disease increasing in prevalence and public awareness, more people are becoming interested in learning their chances of developing this condition. Disclosing Alzheimer’s disease risk has been discouraged because of the limited predictive value of available tests, lack of prevention and treatment options, and concerns regarding potential psychological and social harms. However, challenges to this status quo include the availability of direct-to-consumer health risk information (e.g., genetic susceptibility tests), as well as a growing literature suggesting that people seeking risk information for Alzheimer’s disease through formal education and counseling protocols generally find it useful and do not experience adverse effects. This paper reviews current and potential methods of risk assessment for Alzheimer’s disease, discusses the process and impact of disclosing risk to interested patients and consumers, and considers the practical and ethical challenges in this emerging area. Anticipated future directions are addressed.

Cross-country, longitudinal twin studies provide strong evidence for both the biological and environmental basis of dyslexia, and the stability of genetic influences on reading and spelling, even when skills improve in response to instruction. Although DNA studies aimed at identifying gene candidates in dyslexia and related phenotypes (behavioral expression of underlying genotypes); and imaging studies of brain differences between individuals with and without dyslexia and the brain’s response to instructional treatment are increasing, this review illustrates, with the findings of one multidisciplinary research center, an emerging trend to investigate the inter-relationships among genetic, brain and instructional treatment findings in the same sample, which are interpreted in reference to a working-memory architecture, for dyslexia (impaired decoding and spelling) and/or dysgraphia (impaired handwriting). General principles for diagnosis and treatment, based on research with children who failed to respond to the regular instructional program, are summarized for children meeting research criteria for having or being at risk for dyslexia or dysgraphia. Research documenting earlier emerging specific oral language impairment during preschool years associated with reading and writing disabilities during school years is also reviewed. Recent seminal advances and projected future trends are discussed for linking brain endophenotypes and gene candidates, identifying transchromosomal interactions, and exploring epigenetics (chemic al modifications of gene expression in response to developmental or environmental changes). Rather than providing final answers, this review highlights past, current and emerging issues in dyslexia research and practice.

The progression from recreational drug use to drug addiction impacts multiple neurobiological processes and can be conceptualized as a transition from positive to negative reinforcement mechanisms driving both drug-taking and drug-seeking behaviors. Neurobiological mechanisms for negative reinforcement, defined as drug taking that alleviates a negative emotional state, involve changes in the brain reward system and recruitment of brain stress (or antireward) systems within forebrain structures, including the extended amygdala. These systems are hypothesized to be dysregulated by excessive drug intake and to contribute to allostatic changes in reinforcement mechanisms associated with addiction. Points of intersection between positive and negative motivational circuitry may further drive the compulsivity of drug addiction but also provide a rich neurobiological substrate for therapeutic intervention.

During the last 20 years, our understanding of the mechanisms underlying Alzheimer's disease (AD) has considerably improved, in part owing to both in vitro and in vivo model systems. Studies in mice expressing both human amyloid precursor protein and human tau have provided clear evidence that amyloid-β and tau interact in the pathogenesis of AD. Moreover, amyloid-β toxicity has been shown to be tau-dependent since reducing tau levels prevents behavioral deficits and sudden death in amyloid precursor protein transgenic mice. As tau pathology preferentially develops in specific sites and spreads in a predictable manner across the brain, understanding the mechanism underlying tau dysfunction should be a focus in AD mouse modeling. A defined effort must be made to develop therapies that directly address the impact of tau dysfunction in the pathogenesis of AD. Finally, early diagnosis of AD is essential and this must be made possible by identification of early biomarkers, behavioral changes or use of novel imaging techniques.

Microglia are resident CNS immune cells that are active sensors in healthy brain and versatile effectors under pathological conditions. Cerebral ischemia induces a robust neuroinflammatory response that includes marked changes in the gene-expression profile and phenotype of a variety of endogenous CNS cell types (astrocytes, neurons and microglia), as well as an influx of leukocytic cells (neutrophils, macrophages and T-cells) from the periphery. Many molecules and conditions can trigger a transformation of surveying microglia to microglia of an alerted or reactive state. Here we review recent developments in the literature that relate to microglial activation in the experimental setting of in vitro and in vivo ischemia. We also present new data from our own laboratory demonstrating the direct effects of in vitro ischemic conditions on the microglial phenotype and genomic profile. In particular, we focus on the role of specific molecular signaling systems, such as hypoxia inducible factor-1 and Toll-like receptor-4, in regulating the microglial response in this setting. We then review histological and novel radiological data that confirm a key role for microglial activation in the setting of ischemic stroke in humans. We also discuss recent progress in the pharmacologic and molecular targeting of microglia in acute ischemic stroke. Finally, we explore how recent studies on ischemic preconditioning have increased interest in pre-emptively targeting microglial activation in order to reduce stroke severity.

Language deficits represent the core diagnostic characteristics of autism, and some of these individuals never develop functional speech. The language deficits in autism may be due to structural and functional abnormalities in certain language regions (e.g., frontal and temporal), or due to altered connectivity between these brain regions. In particular, a number of anatomical pathways that connect auditory and motor brain regions (e.g., the arcuate fasciculus, the uncinate fasciculus and the extreme capsule) may be altered in individuals with autism. These pathways may also provide targets for experimental treatments to facilitate communication skills in autism. We propose that music-based interventions (e.g., auditory–motor mapping training) would take advantage of the musical strengths of these children, and are likely to engage, and possibly strengthen, the connections between frontal and temporal regions bilaterally. Such treatments have important clinical potential in facilitating expressive language in nonverbal children with autism.

It has been reported for more than 100 years that patients with severe nonfluent aphasia are better at singing lyrics than they are at speaking the same words. This observation led to the development of melodic intonation therapy (MIT). However, the efficacy of this therapy has yet to be substantiated in a randomized controlled trial. Furthermore, its underlying neural mechanisms remain unclear. The two unique components of MIT are the intonation of words and simple phrases using a melodic contour that follows the prosody of speech and the rhythmic tapping of the left hand that accompanies the production of each syllable and serves as a catalyst for fluency. Research has shown that both components are capable of engaging fronto–temporal regions in the right hemisphere, thereby making MIT particularly well suited for patients with large left hemisphere lesions who also suffer from nonfluent aphasia. Recovery from aphasia can happen in two ways: either through the recruitment of perilesional brain regions in the affected hemisphere, with variable recruitment of right-hemispheric regions if the lesion is small, or through the recruitment of homologous language and speech-motor regions in the unaffected hemisphere if the lesion of the affected hemisphere is extensive. Treatment-associated neural changes in patients undergoing MIT indicate that the unique engagement of right-hemispheric structures (e.g., the superior temporal lobe, primary sensorimotor, premotor and inferior frontal gyrus regions) and changes in the connections across these brain regions may be responsible for its therapeutic effect.

The dopamine transporter (DAT) is a primary determinant of the concentration of dopamine in the synapse and is involved in a number of psychiatric and neurological diseases. The transporter actively takes up its physiological substrate, dopamine, when it is on the surface of the plasmalemmal membrane, but the concentration of DAT in the membrane is highly regulated by substrate. Substrates initially, and very rapidly, recruit more DAT into the membrane for greater function, but continued presence of substrate downregulates the activity of DAT and even membrane DAT content. This biphasic regulation is orchestrated by numerous signal transduction mechanisms, including a palette of protein kinases. Understanding the mechanisms of rapid regulation of DAT could provide new therapeutic strategies to improve transporter function and modulate responses to its more notorious substrates, amphetamine and methamphetamine.

Stroke is a sexually dimorphic disease, with differences between males and females observed both clinically and in the laboratory. While males have a higher incidence of stroke throughout much of the lifespan, aged females have a higher burden of stroke. Sex differences in stroke result from a combination of factors, including elements intrinsic to the sex chromosomes as well as the effects of sex hormone exposure throughout the lifespan. Research investigating the sexual dimorphism of stroke is only in the beginning stages, but early findings suggest that different cell death pathways are activated in males and females after ischemic stroke. A greater understanding of the mechanisms underlying sex differences in stroke will lead to more appropriate treatment strategies for patients of both sexes.