Synaptic spines are dynamic structures that regulate neuronal responsiveness and plasticity. Here we describe a role for the schizophrenia risk factor, Disrupted-in-Schizophrenia 1 (DISC1), in the maintenance of spine morphology and function. We show that DISC1 anchors Kalirin-7 (Kal-7) thereby regulating access of Kal-7 to Rac1 and so controlling the duration and intensity of Rac1 activation in response to NMDA receptor activation in cortical culture as well as in vivo brain. This offers explanation for why Rac1 and its activator (Kal-7) serve as key mediators of spine enlargement and that constitutive Rac1 activation decreases spine size. This novel mechanism likely underlies disturbances in glutamatergic neurotransmission 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 rat models of drug relapse and craving, cue-induced cocaine seeking progressively increases after drug withdrawal. This ‘incubation of cocaine craving’ is partially mediated by time-dependent adaptations at glutamatergic synapses in nucleus accumbens. However, the circuit-level adaptations mediating this plasticity remain elusive. Here we studied silent synapses—often regarded as immature synapses that express stable NMDA receptors with AMPA receptors either absent or labile—in basolateral amygdala-to-accumbens projection in incubation of cocaine craving. Silent synapses were detected within this projection during early withdrawal from cocaine. As the withdrawal period progressed, these silent synapses became ‘unsilenced’, a process involving 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 cocaine incubation. Our finding indicates that silent synapse-based reorganization of the amygdala-to-accumbens projection is critical for persistent cocaine craving and relapse after withdrawal.

SummaryExposures to cocaine and morphine produce similar adaptations in nucleus accumbens (NAc)-based behaviors, yet produce very different adaptations at NAc excitatory synapses. Here, we explain this paradox by showing that both drugs induce NMDA receptor-containing, AMPA receptor (AMPAR)-silent excitatory synapses, but in distinct cell types through opposing cellular mechanisms: cocaine selectively induces silent synapses in D1-type neurons likely via a synaptogenesis process, whereas morphine induces silent synapses in D2-type neurons via internalization of AMPARs from pre-existing synapses. After drug withdrawal, cocaine-generated silent synapses become ‘unsilenced’ by recruiting AMPARs to strengthen excitatory inputs to D1-type neurons, while morphine-generated silent synapses are likely eliminated to weaken excitatory inputs to D2-type neurons. Thus, these cell-type specific, opposing mechanisms produce 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.

Summary Stress facilitates reinstatement of addictive drug-seeking in animals and promotes relapse in humans. Acute stress has marked and long-lasting effects on plasticity at both inhibitory and excitatory synapses on dopamine neurons in the ventral tegmental area (VTA), a key region necessary for drug reinforcement. Stress blocks long-term potentiation at GABAergic synapses on dopamine neurons in the VTA (LTPGABA), potentially removing a normal brake on activity. Here we show that blocking kappa opioid receptors (KORs) prior to forced-swim stress rescues LTPGABA. In contrast, blocking KORs does not prevent stress-induced potentiation of excitatory synapses nor morphine-induced block of LTPGABA. Using a kappa receptor antagonist as a selective tool to test the role of LTPGABA in vivo, we find that blocking KORs within the VTA prior to forced-swim stress prevents reinstatement of cocaine-seeking. These results suggest that KORs may represent a useful therapeutic target for treatment of stress-triggered relapse in substance abuse.