It is now well accepted that plasticity is a fundamental feature of the brain across the lifespan, and plays an important role in both the emergence and treatment of brain disorders. But what forms can disease-related plasticity take and what methods can we use to assess such plasticity and implement plasticity-based therapeutic approaches?

The starting point for most hypotheses about disease-related plasticity is centered on the best-characterized forms of synaptic plasticity, such as long-term potentiation (LTP), long-term depression (LTD), and homeostatic plasticity. For each of these classical forms of plasticity, however, there are many mechanistically distinct sub-varieties, and these often co-exist within a single neuron or even at a single set of synapses. Furthermore, experimentally eliciting LTP or LTD typically relies upon patterns of synaptic activities that differ from endogenous patterns, and eliciting homeostatic plasticity sometimes relies upon more extreme augmentation or reduction of excitatory input than a neuron will typically experience. It seems likely, therefore, that the brain’s palette of plasticity mechanisms, under normal conditions and certainly after disease processes have altered signaling pathways regulating synaptic function, is more varied than the classical forms of plasticity studied in slices or cultured neurons. In animal models of brain disorders, we have an ever-expanding array of tools to explore this palette. In the human brain, it remains challenging to detect synaptic changes let alone the antecedents of these changes. Yet, if plasticity underlies disease progression, coming to such an understanding is critical for developing approaches to target this progression.

The 2023 NPPR issue includes preclinical and clinical studies tackling disease-related plasticity and plasticity-informed interventions. On the preclinical side, we begin with updates on plasticity mechanisms and substrates that are likely to be cross-cutting across disorders. Drs. Brown and Sorg describe the role of perineuronal nets in plasticity related to motivated behavior and addiction. Drs. Kruyer, Kalivas, and Scofield focus on astrocytes as modulators of synaptic signaling in models of psychiatric disorders. Drs. Scheyer, Yasmin, Naskar and Patel broadly review emerging data on endocannabinoids in neuropsychiatric disease pathophysiology and treatment. Next, several articles provide cutting-edge updates on plasticity related to specific disorders or potential therapeutic approaches. Drs. Kavalali and Monteggia draw on preclinical data, focusing in particular on ketamine’s rapid antidepressant effect, that support a role for homeostatic plasticity in both disease-related plasticity and plasticity-informed interventions. Drs. Guo, Vaughan, Rojo, and Huang discuss recent work on modulation of the reward circuitry by sleep, and how this may be harnessed to treat substance use disorder. Drs. Walsh, Christoffel and Malenka review data on mapping and manipulating neural circuits that mediate prosocial behaviors, focusing on serotonin as a modulator of sociability and sociability deficits in models of neuropsychiatric disorders. Dr. Scott Thompson discusses converging preclinical and clinical evidence that the genesis of depression involves changes in the function of excitatory synapses and the mood-governing circuits in which they are embedded, along with the potential for restoring synaptic and circuit function through novel therapeutics. Finally, Drs. Calder and Hasler review evidence that psychedelics promote neuroplasticity, focusing on how and where this occurs in the brain, the doses required, the duration of such effects, and potential clinical applications.

The remainder of the issue focuses on neuroplasticity in the human brain and mechanisms to study and manipulate it. Plasticity can rarely be directly measured, but is more often inferred by linking multiple levels of analyses, for example, by combining imaging techniques, cognitive neuroscience approaches, and computational modeling. A few articles delve into the methodological aspects of measuring and inferring plasticity changes in the human brain. Drs. Appelbaum, Shenasa, Stolz, and Daskalakis highlight the view of plasticity in the brain as a multiscale series of changes that occur on a spectrum from microscale events at the synapse to morphological alterations that span the entire nervous system. Drs. Scott and Frank integrate across different systems of analyses, bridging neuroscience and computational modeling. They highlight the roles of calcium dynamics and neuromodulatory signals in controlling plasticity, as well as Hebbian mechanisms, which all converge to create a conditional and adaptive control of plasticity, or metaplasticity, which shapes reinforcement learning. Next, several articles tackle specific disease states or specific interventions that involve plasticity. Dr. Knudsen describes behavioral, biochemical, in vivo neuroimaging, and electrophysiological evidence for acute effects of psychedelics, often initiated by single use and yet long lasting, likely mediated by neuroplasticity. Drs. Howes, Cummings, Chapman, and Shatalina show evidence that schizophrenia is associated with lower regional levels of the synaptic protein SV2A measured with Positron Emission Tomography. These observations—in conjunction with findings of lower gray matter volumes and cortical thickness, accelerated gray matter loss over time, abnormal gyrification patterns, and lower metabolic markers in comparison to controls, with effect sizes ranging from ~ –0.11 to –1.0—suggest lower synaptic density in frontal, anterior cingulate, temporal cortices and the hippocampi. Drs. Vinogradov, Chafee, Lee, and Morishita discuss the evidence for progressive dysplastic changes in cortical circuits in psychosis spectrum illnesses, and the need for pharmacologic or neuromodulatory interventions to be supplemented by plasticity-harnessing corrective learning experiences, and provide illustrations for these interventions. Dr. Holmes, Abdallah and Esterlis describe the use of neuroimaging techniques in the evaluation of synaptic alterations associated with depression in humans, as well as measurement of synaptic changes after administration of the fast-acting antidepressant ketamine, assessed with SV2A and mGluR5 PET imaging, making the case for synaptic loss in depression and suggesting therapeutic remediation by ketamine. Drs. Jannati, Oberman, Rotenberg and Pascual-Leone present evidence for neuromodulatory effects of transcranial magnetic stimulation (TMS) involving synaptic plasticity and discuss measures of plasticity in brain disorders and their translational relevance.

Overall, the goal of this issue is to highlight the complexity of plasticity that accompanies psychiatric disorders and the rapid advances in approaches to harness plasticity as a therapeutic approach. Much work is needed to improve available methods to measure synaptic structure and function, especially in vivo in the human brain, and to link it to behavioral changes. We hope that this set of articles will promote further interest and sharpen the focus on plasticity as the most fundamental tool for psychiatric therapies, and the need to bridge the disparity between our understanding of synaptic complexity from preclinical studies with the paucity of studies in humans.