The number of dendritic spines is reduced in the postmortem brains of individuals with schizophrenia. Revealing a potential mechanism of such change, this study finds that the schizophrenia-associated protein DISC1 regulates the Rho GTPase pathway to modulate dendritic spine size. Synaptic spines are dynamic structures that regulate neuronal responsiveness and plasticity. We examined the role of the schizophrenia risk factor DISC1 in the maintenance of spine morphology and function. We found that DISC1 anchored Kalirin-7 (Kal-7), regulating access of Kal-7 to Rac1 and controlling the duration and intensity of Rac1 activation in response to NMDA receptor activation in both cortical cultures and rat brain in vivo. These results explain why Rac1 and its activator (Kal-7) serve as important mediators of spine enlargement and why constitutive Rac1 activation decreases spine size. This mechanism likely underlies disturbances in glutamatergic neurotransmission that have been frequently reported in schizophrenia that can lead to alteration of dendritic spines with consequential major pathological changes in brain function. Furthermore, the concept of a signalosome involving disease-associated factors, such as DISC1 and glutamate, may well contribute to the multifactorial and polygenetic characteristics of schizophrenia.

In rats self-administering cocaine, drug seeking behavior induced by a cocaine-paired cue increases progressively during cocaine withdrawal. The authors detected silent synapses in basolateral amygdala–to–nucleus accumbens projections during early withdrawal, but these synapses progressively disappeared during protracted withdrawal. Optogenetic 're-silencing' of these synapses decreased cue-induced cocaine seeking following withdrawal. In rat models of drug relapse and craving, cue-induced cocaine seeking progressively increases after withdrawal from the drug. This 'incubation of cocaine craving' is partially mediated by time-dependent adaptations at glutamatergic synapses in nucleus accumbens (NAc). However, the circuit-level adaptations mediating this plasticity remain elusive. We studied silent synapses, often regarded as immature synapses that express stable NMDA receptors with AMPA receptors being either absent or labile, in the projection from the basolateral amygdala to the NAc in incubation of cocaine craving. Silent synapses were detected in this projection during early withdrawal from cocaine. As the withdrawal period progressed, these silent synapses became unsilenced, a process that involved synaptic insertion of calcium-permeable AMPA receptors (CP-AMPARs). In vivo optogenetic stimulation–induced downregulation of CP-AMPARs at amygdala-to-NAc synapses, which re-silenced some of the previously silent synapses after prolonged withdrawal, decreased incubation of cocaine craving. Our findings indicate that silent synapse–based reorganization of the amygdala-to-NAc projection is critical for persistent cocaine craving and relapse after withdrawal.

The conditioned place preference (CPP) paradigm is a well-established model utilized to study the role of context associations in reward-related behaviors, including both natural rewards and drugs of abuse. In this review article, we discuss the basic history, various uses, and considerations that are tied to this technique. There are many potential takeaway implications of this model, including negative affective states, conditioned drug effects, memory, and motivation, which are all considered here. We also discuss the neurobiology of CPP including relevant brain regions, molecular signaling cascades, and neuromodulatory systems. We further examine some of our prior findings and how they integrate CPP with self-administration paradigms. Overall, by describing the fundamentals of CPP, findings from the past few decades, and implications of using CPP as a research paradigm, we have endeavored to support the case that the CPP method is specifically advantageous for studying the role of a form of Pavlovian learning that associates drug use with the surrounding environment.

Cocaine and morphine produce similar addiction-related behaviors, but different adaptations at accumbens synapses. The authors explain this paradox, showing that both drugs generate silent synapses in distinct neuronal types: cocaine in D1 type and morphine in D2 type. Withdrawal strengthens cocaine-generated silent synapses and weakens morphine-generated ones, producing common circuit effects. Exposures to cocaine and morphine produce similar adaptations in nucleus accumbens (NAc)-based behaviors, yet produce very different adaptations at NAc excitatory synapses. In an effort to explain this paradox, we found that both drugs induced NMDA receptor–containing, AMPA receptor-silent excitatory synapses, albeit in distinct cell types through opposing cellular mechanisms. Cocaine selectively induced silent synapses in D1-type neurons, likely via a synaptogenesis process, whereas morphine induced silent synapses in D2-type neurons via internalization of AMPA receptors from pre-existing synapses. After drug withdrawal, cocaine-generated silent synapses became 'unsilenced' by recruiting AMPA receptors to strengthen excitatory inputs to D1-type neurons, whereas morphine-generated silent synapses were likely eliminated to weaken excitatory inputs to D2-type neurons. Thus, these cell type–specific, opposing mechanisms produced the same net shift of the balance between excitatory inputs to D1- and D2-type NAc neurons, which may underlie certain common alterations in NAc-based behaviors induced by both classes of drugs.

Disrupted in schizophrenia 1 (DISC1), a genetic risk factor for multiple serious psychiatric diseases including schizophrenia, bipolar disorder and autism, is a key regulator of multiple neuronal functions linked to both normal development and disease processes. As these diseases are thought to share a common deficit in synaptic function and architecture, we have analyzed the role of DISC1 using an approach that focuses on understanding the protein–protein interactions of DISC1 specifically at synapses. We identify the Traf2 and Nck-interacting kinase (TNIK), an emerging risk factor itself for disease, as a key synaptic partner for DISC1, and provide evidence that the DISC1–TNIK interaction regulates synaptic composition and activity by stabilizing the levels of key postsynaptic density proteins. Understanding the novel DISC1–TNIK interaction is likely to provide insights into the etiology and underlying synaptic deficits found in major psychiatric diseases.