Neurobiology of rapid-acting antidepressants: convergent effects on GluA1-synaptic function.
Molecular psychiatry
Efforts to develop efficacious antidepressant agents with novel mechanisms have been largely unsuccessful since the 1950's until the discovery of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist that produces rapid and sustained antidepressant actions even in treatment-resistant patients. This finding has ushered in a new era for the development of novel rapid-acting antidepressants that act at the NMDA receptor complex, but without dissociative and psychotomimetic side effects of ketamine. Here, we review the current state of rapid-acting antidepressant drug development, including NMDA channel blockers, glycine site agents, and allosteric modulators, as well as ketamine stereoisomers and metabolites. In addition, we focus on the neurobiological mechanisms underlying the actions of these diverse agents and discuss evidence of convergent mechanisms including increased brain-derived neurotrophic factor signaling, increased synthesis of synaptic proteins, and most notably increased GluR1 and synaptic connectivity in the medial prefrontal cortex. These convergent mechanisms provide insight for potential additional novel targets for drug development (e.g., agents that increase synaptic protein synthesis and plasticity). Importantly, the convergent effects on synapse formation and plasticity also reverse the well-documented neuronal and synaptic deficits associated with stress and depression, and thereby target the underlying pathophysiology of major depressive disorder.
10.1038/s41380-019-0400-x
The AMPA Receptor Code of Synaptic Plasticity.
Diering Graham H,Huganir Richard L
Neuron
Changes in the properties and postsynaptic abundance of AMPA-type glutamate receptors (AMPARs) are major mechanisms underlying various forms of synaptic plasticity, including long-term potentiation (LTP), long-term depression (LTD), and homeostatic scaling. The function and the trafficking of AMPARs to and from synapses is modulated by specific AMPAR GluA1-GluA4 subunits, subunit-specific protein interactors, auxiliary subunits, and posttranslational modifications. Layers of regulation are added to AMPAR tetramers through these different interactions and modifications, increasing the computational power of synapses. Here we review the reliance of synaptic plasticity on AMPAR variants and propose "the AMPAR code" as a conceptual framework. The AMPAR code suggests that AMPAR variants will be predictive of the types and extent of synaptic plasticity that can occur and that a hierarchy exists such that certain AMPARs will be disproportionally recruited to synapses during LTP/homeostatic scaling up, or removed during LTD/homeostatic scaling down.
10.1016/j.neuron.2018.10.018
Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model.
Price Rebecca B,Duman Ronald
Molecular psychiatry
Chronic stress and depressive-like behaviors in basic neuroscience research have been associated with impairments of neuroplasticity, such as neuronal atrophy and synaptic loss in the medial prefrontal cortex (mPFC) and hippocampus. The current review presents a novel integrative model of neuroplasticity as a multi-domain neurobiological, cognitive, and psychological construct relevant in depression and other related disorders of negative affect (e.g., anxiety). We delineate a working conceptual model in which synaptic plasticity deficits described in animal models are integrated and conceptually linked with human patient findings from cognitive science and clinical psychology. We review relevant reports including neuroimaging findings (e.g., decreased functional connectivity in prefrontal-limbic circuits), cognitive deficits (e.g., executive function and memory impairments), affective information processing patterns (e.g., rigid, negative biases in attention, memory, interpretations, and self-associations), and patient-reported symptoms (perseverative, inflexible thought patterns; inflexible and maladaptive behaviors). Finally, we incorporate discussion of integrative research methods capable of building additional direct empirical support, including using rapid-acting treatments (e.g., ketamine) as a means to test this integrative model by attempting to simultaneously reverse these deficits across levels of analysis.
10.1038/s41380-019-0615-x
Major depressive disorder.
Nature reviews. Disease primers
Major depressive disorder (MDD) is a debilitating disease that is characterized by depressed mood, diminished interests, impaired cognitive function and vegetative symptoms, such as disturbed sleep or appetite. MDD occurs about twice as often in women than it does in men and affects one in six adults in their lifetime. The aetiology of MDD is multifactorial and its heritability is estimated to be approximately 35%. In addition, environmental factors, such as sexual, physical or emotional abuse during childhood, are strongly associated with the risk of developing MDD. No established mechanism can explain all aspects of the disease. However, MDD is associated with alterations in regional brain volumes, particularly the hippocampus, and with functional changes in brain circuits, such as the cognitive control network and the affective-salience network. Furthermore, disturbances in the main neurobiological stress-responsive systems, including the hypothalamic-pituitary-adrenal axis and the immune system, occur in MDD. Management primarily comprises psychotherapy and pharmacological treatment. For treatment-resistant patients who have not responded to several augmentation or combination treatment attempts, electroconvulsive therapy is the treatment with the best empirical evidence. In this Primer, we provide an overview of the current evidence of MDD, including its epidemiology, aetiology, pathophysiology, diagnosis and treatment.
10.1038/nrdp.2016.65
The protocadherin 17 gene affects cognition, personality, amygdala structure and function, synapse development and risk of major mood disorders.
Chang H,Hoshina N,Zhang C,Ma Y,Cao H,Wang Y,Wu D-D,Bergen S E,Landén M,Hultman C M,Preisig M,Kutalik Z,Castelao E,Grigoroiu-Serbanescu M,Forstner A J,Strohmaier J,Hecker J,Schulze T G,Müller-Myhsok B,Reif A,Mitchell P B,Martin N G,Schofield P R,Cichon S,Nöthen M M, , ,Walter H,Erk S,Heinz A,Amin N,van Duijn C M,Meyer-Lindenberg A,Tost H,Xiao X,Yamamoto T,Rietschel M,Li M
Molecular psychiatry
Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.
10.1038/mp.2016.231
Targeting Homeostatic Synaptic Plasticity for Treatment of Mood Disorders.
Kavalali Ege T,Monteggia Lisa M
Neuron
Ketamine exerts rapid antidepressant action in depressed and treatment-resistant depressed patients within hours. At the same time, ketamine elicits a unique form of functional synaptic plasticity that shares several attributes and molecular mechanisms with well-characterized forms of homeostatic synaptic scaling. Lithium is a widely used mood stabilizer also proposed to act via synaptic scaling for its antimanic effects. Several studies to date have identified specific forms of homeostatic synaptic plasticity that are elicited by these drugs used to treat neuropsychiatric disorders. In the last two decades, extensive work on homeostatic synaptic plasticity mechanisms have shown that they diverge from classical synaptic plasticity mechanisms that process and store information and thus present a novel avenue for synaptic regulation with limited direct interference with cognitive processes. In this review, we discuss the intersection of the findings from neuropsychiatric treatments and homeostatic plasticity studies to highlight a potentially wider paradigm for treatment advance.
10.1016/j.neuron.2020.05.015
Genetic and cognitive windows into circuit mechanisms of psychiatric disease.
Arguello P Alexander,Gogos Joseph A
Trends in neurosciences
Accumulating evidence indicates substantial etiological and pathophysiological heterogeneity as well as overlap within and across psychiatric disorders. Moreover, it is uncertain at what level, besides gross behavior, mental illnesses can be differentiated. To advance our understanding of psychiatric disease, we advocate a more systematic approach in characterizing a small number of animal models by utilizing unequivocal rare disease mutations and targeted cognitive assessment to identify convergent disease circuits and mechanisms. Based on available data, we discuss the possibility that the temporal dynamics of synaptic plasticity play a central role in disease pathophysiology and that the extent and manner in which they are altered in specific neural circuits determine the exact clinical phenotype of diverse disorders.
10.1016/j.tins.2011.11.007
The complement system: a gateway to gene-environment interactions in schizophrenia pathogenesis.
Nimgaonkar V L,Prasad K M,Chowdari K V,Severance E G,Yolken R H
Molecular psychiatry
The pathogenesis of schizophrenia is considered to be multi-factorial, with likely gene-environment interactions (GEI). Genetic and environmental risk factors are being identified with increasing frequency, yet their very number vastly increases the scope of possible GEI, making it difficult to identify them with certainty. Accumulating evidence suggests a dysregulated complement pathway among the pathogenic processes of schizophrenia. The complement pathway mediates innate and acquired immunity, and its activation drives the removal of damaged cells, autoantigens and environmentally derived antigens. Abnormalities in complement functions occur in many infectious and autoimmune disorders that have been linked to schizophrenia. Many older reports indicate altered serum complement activity in schizophrenia, though the data are inconclusive. Compellingly, recent genome-wide association studies suggest repeat polymorphisms incorporating the complement 4A (C4A) and 4B (C4B) genes as risk factors for schizophrenia. The C4A/C4B genetic associations have re-ignited interest not only in inflammation-related models for schizophrenia pathogenesis, but also in neurodevelopmental theories, because rodent models indicate a role for complement proteins in synaptic pruning and neurodevelopment. Thus, the complement system could be used as one of the 'staging posts' for a variety of focused studies of schizophrenia pathogenesis. They include GEI studies of the C4A/C4B repeat polymorphisms in relation to inflammation-related or infectious processes, animal model studies and tests of hypotheses linked to autoimmune diseases that can co-segregate with schizophrenia. If they can be replicated, such studies would vastly improve our understanding of pathogenic processes in schizophrenia through GEI analyses and open new avenues for therapy.
10.1038/mp.2017.151
Mapping the Consequences of Impaired Synaptic Plasticity in Schizophrenia through Development: An Integrative Model for Diverse Clinical Features.
Forsyth Jennifer K,Lewis David A
Trends in cognitive sciences
Schizophrenia is associated with alterations in sensory, motor, and cognitive functions that emerge before psychosis onset; identifying pathogenic processes that can account for this multi-faceted phenotype remains a challenge. Accumulating evidence suggests that synaptic plasticity is impaired in schizophrenia. Given the role of synaptic plasticity in learning, memory, and neural circuit maturation, impaired plasticity may underlie many features of the schizophrenia syndrome. Here, we summarize the neurobiology of synaptic plasticity, review evidence that plasticity is impaired in schizophrenia, and explore a framework in which impaired synaptic plasticity interacts with brain maturation to yield the emergence of sensory, motor, cognitive, and psychotic features at different times during development in schizophrenia. Key gaps in the literature and future directions for testing this framework are discussed.
10.1016/j.tics.2017.06.006
Using neuroplasticity-based auditory training to improve verbal memory in schizophrenia.
Fisher Melissa,Holland Christine,Merzenich Michael M,Vinogradov Sophia
The American journal of psychiatry
OBJECTIVE:Impaired verbal memory in schizophrenia is a key rate-limiting factor for functional outcome, does not respond to currently available medications, and shows only modest improvement after conventional behavioral remediation. The authors investigated an innovative approach to the remediation of verbal memory in schizophrenia, based on principles derived from the basic neuroscience of learning-induced neuroplasticity. The authors report interim findings in this ongoing study. METHOD:Fifty-five clinically stable schizophrenia subjects were randomly assigned to either 50 hours of computerized auditory training or a control condition using computer games. Those receiving auditory training engaged in daily computerized exercises that placed implicit, increasing demands on auditory perception through progressively more difficult auditory-verbal working memory and verbal learning tasks. RESULTS:Relative to the control group, subjects who received active training showed significant gains in global cognition, verbal working memory, and verbal learning and memory. They also showed reliable and significant improvement in auditory psychophysical performance; this improvement was significantly correlated with gains in verbal working memory and global cognition. CONCLUSIONS:Intensive training in early auditory processes and auditory-verbal learning results in substantial gains in verbal cognitive processes relevant to psychosocial functioning in schizophrenia. These gains may be due to a training method that addresses the early perceptual impairments in the illness, that exploits intact mechanisms of repetitive practice in schizophrenia, and that uses an intensive, adaptive training approach.
10.1176/appi.ajp.2009.08050757
Cognitive interventions targeting brain plasticity in the prodromal and early phases of schizophrenia.
Annual review of clinical psychology
Several important paradigm shifts have occurred in the field of schizophrenia treatment, including an increased focus on early detection, the development of preemptive interventions, and the view of schizophrenia as a neurodevelopmental disease characterized by decreased efficiency and abnormal connectivity in cortical and subcortical neural networks. In this review, we briefly describe some of the neural impairments that contribute to the development of schizophrenia, with an emphasis on the impact of stress and trauma on cognitively vulnerable neural systems. We then present current data on two behavioral interventions that target these critical risk factors and that aim to preempt the onset of schizophrenia in vulnerable individuals or improve the clinical course in recent-onset schizophrenia: cognitive therapy and computerized cognitive training.
10.1146/annurev-clinpsy-032511-143134
Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning.
Nature neuroscience
Synapse density is reduced in postmortem cortical tissue from schizophrenia patients, which is suggestive of increased synapse elimination. Using a reprogrammed in vitro model of microglia-mediated synapse engulfment, we demonstrate increased synapse elimination in patient-derived neural cultures and isolated synaptosomes. This excessive synaptic pruning reflects abnormalities in both microglia-like cells and synaptic structures. Further, we find that schizophrenia risk-associated variants within the human complement component 4 locus are associated with increased neuronal complement deposition and synapse uptake; however, they do not fully explain the observed increase in synapse uptake. Finally, we demonstrate that the antibiotic minocycline reduces microglia-mediated synapse uptake in vitro and its use is associated with a modest decrease in incident schizophrenia risk compared to other antibiotics in a cohort of young adults drawn from electronic health records. These findings point to excessive pruning as a potential target for delaying or preventing the onset of schizophrenia in high-risk individuals.
10.1038/s41593-018-0334-7
Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders.
Neniskyte Urte,Gross Cornelius T
Nature reviews. Neuroscience
The final stage of brain development is associated with the generation and maturation of neuronal synapses. However, the same period is also associated with a peak in synapse elimination - a process known as synaptic pruning - that has been proposed to be crucial for the maturation of remaining synaptic connections. Recent studies have pointed to a key role for glial cells in synaptic pruning in various parts of the nervous system and have identified a set of critical signalling pathways between glia and neurons. At the same time, brain imaging and post-mortem anatomical studies suggest that insufficient or excessive synaptic pruning may underlie several neurodevelopmental disorders, including autism, schizophrenia and epilepsy. Here, we review current data on the cellular, physiological and molecular mechanisms of glial-cell-dependent synaptic pruning and outline their potential contribution to neurodevelopmental disorders.
10.1038/nrn.2017.110