Persistent dendritic spine enlargement is associated with stable long-term potentiation (LTP), and the latter is thought to underlie long-lasting memories. Extracellular proteolytic remodeling of the synaptic microenvironment could be important for such plasticity, but whether or how proteolytic remodeling contributes to persistent modifications in synapse structure and function is unknown. Matrix metalloproteinase-9 (MMP-9) is an extracellular protease that is activated perisynaptically after LTP induction and required for LTP maintenance. Here, by monitoring spine size and excitatory postsynaptic potentials (EPSPs) simultaneously with combined 2-photon time-lapse imaging and whole-cell recordings from hippocampal neurons, we find that MMP-9 is both necessary and sufficient to drive spine enlargement and synaptic potentiation concomitantly. Both structural and functional MMP-driven forms of plasticity are mediated through ␤1-containing integrin receptors, are associated with integrin-dependent cofilin inactivation within spines, and require actin polymerization. In contrast, postsynaptic exocytosis and protein synthesis are both required for MMP-9-induced potentiation, but not for initial MMP-9-induced spine expansion. However, spine expansion becomes unstable when postsynaptic exocytosis or protein synthesis is blocked, indicating that the 2 forms of plasticity are expressed independently but require interactions between them for persistence. When MMP activity is eliminated during theta-stimulation-induced LTP, both spine enlargement and synaptic potentiation are transient. Thus, MMP-mediated extracellular remodeling during LTP has an instructive role in establishing persistent modifications in both synapse structure and function of the kind critical for learning and memory.actin ͉ cofilin ͉ integrin ͉ synaptic plasticity ͉ protein synthesis L ong-lasting memory is based on long-term modifications of synapse structure and function. In hippocampal area CA1, naturalistic patterns of theta-stimulation readily induce long-term potentiation (LTP) of the excitatory, glutamatergic Schaffer collateral afferent inputs that target dendritic spines (1), which are small, actin-rich dendritic protrusions that harbor the majority of the excitatory synapses (2). Studies show that dendritic spines undergo significant morphological remodeling in association with long-lasting plasticity (3). Spine growth, for example, is associated with the induction of LTP and is thought to be important for supporting persistent changes in synaptic strength (4-6). However, little is known about signals that instruct and coordinate persistent modifications in synapse structure and function during LTP.Dendritic spine morphology and synaptic potentiation can both be dynamically modulated by proteins of the extracellular matrix (ECM) and the cell-surface proteins with which they interact, which has long fueled the idea that regulated ECM remodeling has an important role in synaptic plasticity (7). How precisely such remodeling could occur is not u...

Individuals with autism spectrum disorder (ASD) often have co-morbid anxiety and depression. Alexithymia and emotion regulation difficulties are commonly seen in individuals with ASD and in mood disorders. We hypothesized that alexithymia and emotional regulation would mediate the relationship between autistic features and anxiety/depression symptom severity. We collected data about emotional regulation, alexithymia, autistic symptoms and depression/anxiety in a sample of 64 young adults with ASD. We constructed two serial multiple mediator models, using autistic features as the independent variable and anxiety/depression symptoms as outcome variables. The serial relationship between alexithymia and emotional regulation mediated associations between autistic features and depression and anxiety, separately. The findings suggest that targeting alexithymia may benefit therapies designed to alleviate mood disorders in ASD.

Purpose The study systematically examined the relative relationships between perceived family and peer gambling and adolescent at-risk/problem gambling and binge-drinking. It also determined the likelihood of at-risk/problem gambling and binge-drinking as a function of the number of different social groups with perceived gambling. Methods A multi-site high-school survey assessed gambling, alcohol use, presence of perceived excessive peer gambling (Peer Excess – PE), and family gambling prompting concern (Family Concern – FC) in 2,750 high-school students. Adolescents were separately stratified into: 1) low-risk, at-risk, and problem/pathological gambling groups; and, 2) non-binge-drinking, low-frequency -binge-drinking, and high-frequency-binge-drinking groups. Results Multinomial logistic regression showed that relative to each other, FC and PE were associated with greater likelihoods of at-risk and problem/pathological gambling. However, only FC was associated with binge-drinking. Logistic regression revealed that adolescents who endorsed either FC or PE alone, compared to no endorsement, were more likely to have at-risk and problem/pathological gambling, relative to low-risk gambling. Adolescents who endorsed both FC and PE, compared to PE alone, were more likely to have problem/pathological gambling relative to low-risk and at-risk gambling. Relative to non-binge-drinking adolescents, those who endorsed both FC and PE were more likely to have low- and high-frequency-binge-drinking compared to FC alone or PE alone, respectively. Conclusions Family and peer gambling individually contribute to adolescent at-risk/problem gambling and binge-drinking. Strategies that target adolescents as well as their closely affiliated family and peer members may be an important step towards prevention of harm-associated levels of gambling and alcohol use in youths.

Age at the time of first alcohol and cannabis use was investigated in relation to a measure of transmissible (intergenerational) risk for addiction in childhood and development of alcohol use disorder (AUD) and cannabis use disorder (CUD). It was hypothesized that age at the time of first experience with either substance mediates the association between transmissible risk and subsequent diagnosis of both disorders. The Transmissible Liability Index (TLI; (Vanyukov et al., 2009) was administered to 339 10- to 12-year-old boys (n = 254) and girls (n = 85). Age at the time of first alcohol and cannabis use, and diagnosis of AUD and CUD, were prospectively tracked to age 22. Each standard deviation unit increase in TLI severity corresponded to a reduction in age of alcohol and cannabis use onset by 3.2 months and 4.6 months, respectively. Age at the time of first alcohol use mediated the association of TLI with both AUD and CUD. Parallel results were obtained for cannabis. Whereas transmissible risk is congenerous to both AUD and CUD, its magnitude was 7 times greater in youths who initiated substance use with cannabis. TLI predicts age of first use of alcohol and cannabis that is common to developing both AUD and CUD. The ramifications of these findings for prevention are discussed.

Objective: The anterior cingulate cortex (ACC) is a critical for both stress and inhibitory control processes and has been implicated in childhood trauma. This prospective study tested the hypothesis that early trauma moderates the association between inhibitory control during late childhood and ACC stress reactivity during adolescence.Method-Sixty-four adolescents were stratified into higher-or lower-childhood-trauma groups. Inhibitory control was indicated by fewer errors on a Stroop Color-Word task. Personalized stress cues during functional magnetic resonance imaging assessed neural correlates of stress in adolescents.