Cytoplasmic Polyadenylation Element Binding Proteins CPEB1 and CPEB3 Regulate the Translation of FosB and Are Required for Maintaining Addiction-Like Behaviors Induced by Cocaine.

A recurrent and devastating feature of addiction to a drug of abuse is its persistence, which is mediated by maladaptive long-term memories of the highly pleasurable experience initially associated with the consumption of the drug. We have recently found that members of the CPEB family of proteins (Cytoplasmic Polyadenylation Element-Binding Proteins) are involved in the maintenance of spatial memory. However, their possible role in the maintenance of memories that sustain addictive behavior has yet to be explored. Little is known about any of the mechanisms for maintaining memories for addictive behavior. To address the mechanisms whereby addictive behavior is maintained over time, we utilized a conditional transgenic mouse model expressing a dominant-negative version of CPEB1 that abolishes the activity in the forebrain of two of the four CPEB isoforms (CPEB1 and CPEB3). We found that, following cocaine administration, these dominant-negative (DN) CPEB mice showed a significant decrease, when compared to wild type (WT) mice, in both locomotor sensitizations and conditioned place preference (CPP), two indices of addictive behavior. Supporting these behavioral results, we also found a difference between WT and DN-CPEB1-3 mice in the cocaine-induced synaptic depression in the core of the Nucleus Accumbens (NAc). Finally, we found that (1) CPEB is reduced in transgenic mice following cocaine injections and that (2) FosB, known for its contribution to establishing the addictive phenotype, when its expression in the striatum is increased by drug administration, is a novel target of CPEBs molecules. Thus, our study highlights how CPEB1 and CPEB3 act on target mRNAs to build the neuroadaptative implicit memory responses that lead to the development of the cocaine addictive phenotypes in mammals.

Proximodistal Heterogeneity of Hippocampal CA3 Pyramidal Neuron Intrinsic Properties, Connectivity, and Reactivation during Memory Recall.

The hippocampal CA3 region is classically viewed as a homogeneous autoassociative network critical for associative memory and pattern completion. However, recent evidence has demonstrated a striking heterogeneity along the transverse, or proximodistal, axis of CA3 in spatial encoding and memory. Here we report the presence of striking proximodistal gradients in intrinsic membrane properties and synaptic connectivity for dorsal CA3. A decreasing gradient of mossy fiber synaptic strength along the proximodistal axis is mirrored by an increasing gradient of direct synaptic excitation from entorhinal cortex. Furthermore, we uncovered a nonuniform pattern of reactivation of fear memory traces, with the most robust reactivation during memory retrieval occurring in mid-CA3 (CA3b), the region showing the strongest net recurrent excitation. Our results suggest that heterogeneity in both intrinsic properties and synaptic connectivity may contribute to the distinct spatial encoding and behavioral role of CA3 subregions along the proximodistal axis.

Social Involvement Modulates the Response to Novel and Adverse Life Events in Mice.

Epidemiological findings suggest that social involvement plays a major role in establishing resilience to adversity, however, the neurobiology by which social involvement confers protection is not well understood. Hypothesizing that social involvement confers resilience by changing the way adverse life events are encoded, we designed a series of behavioral tests in mice that utilize the presence or absence of conspecific cage mates in measuring response to novel and adverse events. We found that the presence of cage mates increased movement after exposure to a novel environment, increased time spent in the open arms of the elevated plus maze, and decreased freezing time after a foot shock as well as expedited fear extinction, therefore significantly changing the response to adversity. This is a first description of a mouse model for the effects of social involvement on adverse life events. Understanding how social involvement provides resilience to adversity may contribute to the future treatment and prevention of mental and physical illness.

SUMOylation Is an Inhibitory Constraint that Regulates the Prion-like Aggregation and Activity of CPEB3.

Protein synthesis is crucial for the maintenance of long-term-memory-related synaptic plasticity. The prion-like cytoplasmic polyadenylation element-binding protein 3 (CPEB3) regulates the translation of several mRNAs important for long-term synaptic plasticity in the hippocampus. Here, we provide evidence that the prion-like aggregation and activity of CPEB3 is controlled by SUMOylation. In the basal state, CPEB3 is a repressor and is soluble. Under these circumstances, CPEB3 is SUMOylated in hippocampal neurons both in vitro and in vivo. Following neuronal stimulation, CPEB3 is converted into an active form that promotes the translation of target mRNAs, and this is associated with a decrease of SUMOylation and an increase of aggregation. A chimeric CPEB3 protein fused to SUMO cannot form aggregates and cannot activate the translation of target mRNAs. These findings suggest a model whereby SUMO regulates translation of mRNAs and structural synaptic plasticity by modulating the aggregation of the prion-like protein CPEB3.