The role of neurabins in affective disorders
Affective disorders, a set of neuropsychiatric diseases also known as mood disorders, include depression and anxiety. These disorders are emerging as a major public health challenge and, despite efforts in the last two decades, the biological mechanisms underlying such diseases remain elusive and poorly understood. Indeed, altered synaptic functions as well as aberrant connectivity and plasticity have been proposed as critical players in the etiology of affective disorders. Importantly, disruption of synaptic proteins often occurs in these pathological conditions (Luscher and Isaac, 2009).
Neurabins and affective disorders
In a recent PLOS One article, Wu and colleagues (University of Alabama at Birmingham) decided to investigate the potential role of two synaptic proteins: neurabin and spinophilin. These two proteins, also known as neurabin I and II, are homologous scaffold proteins located at the synaptic level. However, a slight difference in their synaptic location exists. In fact, while neurabin has been shown to be located at both pre- and post-synaptic levels, the other homologue protein spinophillin is primarily located at the post-synaptic site, more specifically in dendritic spines. Evidence suggests that both scaffold proteins are involved in cellular processes such as spinogenesis, dendritic spine maturation and cytoskeletal regulation. At the molecular level, neurabin and spinophilin regulate AMPA receptor trafficking, a key phenomenon able to affect fast excitatory synaptic transmission.
Using knock-out (KO) animal models for neurabin and spinophilin, Wu and colleagues aimed to understand their contribution in anxiety- and depression-related behaviors. “Our data reveal that, despite the structural similarities between neurabin and spinophilin, and their overlapping function in regulating the synaptic cytoskeleton, inactivation of each gene caused distinct behavioral phenotypes,” report the authors. Because aging is a physiological variable able to constantly reshape synapses and their molecular machineries, neurabin- and spinophilin-deficient mice were studied at different ages: young (3-5 months old) and middle-aged (11-13 months old) adults. To investigate the consequences of neurabin and/or spinophilin deficiency, Wu et al. used well-established behavioral paradigms known to reveal anxiety- and depression-like phenotypes, notably the elevated zero maze (anxiety) and the forced swim test (behavioral despair, depression).
Anxiety- and depression-like phenotype in neurabin-deficient mice.
Novel and stressful environments evoke conflicts in rodents between exploratory drive and fear/defensive behavior. When allowed to make a choice between two novel areas, closed areas are preferred. Because of the elevated nature of the platform in the elevated zero maze, rodents tend to spend more time in the closed regions than in the open ones. Interestingly, genetic ablation of neurabin, but not spinophilin, in young adult mice induced an anxiolytic-like effect.
Behavioral despair, a depression-like phenotype, was assessed using the forced swim test (FST). The FST has been described as rendering a situation in which behavioral despair is induced; that is, the animal loses hope to escape the stressful environment. In the FST mice are placed in an inescapable transparent tank that is filled with water and their mobility or immobility is measured. The lower the mobility (higher the immobility), the higher the despair. Surprisingly, a differential regulation of depression-like behavior was observed in neurabin KO and spinophilin KO mice. In fact, while spinophilin-deficient mice displayed a significantly increased immobility time (increased behavioral despair) during the first day of FST, neurabin-deficient mice showed a reduction of such behavior, thus suggesting a reduction of depression-like phenotype. “These data suggest that loss of neurabin leads to reduced depression-like behavior in young adult mice, and that neurabin and spinophilin play different roles in regulating depression-like behavior”, say Qin Wang, the senior author of the article.
Neurabins, aging and affective disorders
What about aged mice? As mentioned above, aging shapes synaptic functions. Thus, Wu and co-authors decided to perform the same behavioral investigations in middle-aged mice. Unexpectedly, middle-aged KO mice behaved differently compared to young adults. In fact, middle-aged spinophilin KO mice were less anxious, whereas the anxiolytic effect of genetic neurabin loss observed in the younger mice was absent in the older individuals. A similar scenario was observed during the characterization of depression-like behavior in middle-aged mice: loss of spinophilin imparted an apparent protective effect in terms of the depression-like behavior of swimming-induced learned helplessness at this age, whereas neurabin-deficient mice looked normal. It is worth mentioning that while neurabin KO mice display deficient long-term potentiation (LTP) but normal long-term depression (LTD), spinophilin KO mice show impaired LTD but normal LTP (Allen et al., 2006).
“Our data”, conclude the authors, “indicate that these two homologous proteins play important, yet distinct, roles in the regulation of anxiety- and depression-like behaviors, as well overall activity level, in an age-dependent manner. Our study therefore provides new insights into the complex neurobiology of affective disorders.”
Genetics and caveats
Although this study may help to dissect the molecular and functional mechanisms underlying affective disorders, several caveats arise from the genetic strategy used in the study. In particular, complete deletion of a gene (neurabin, spinophilin, or other) may trigger maladaptive and compensatory modifications which may lead to erroneous interpretations. In addition, developmental arrangements may occur, thus leading to abnormal phenotypes. Indeed, strategies using conditional, tissue- and cell type-specific engineered mice must be encouraged in order to clearly establish functional roles of specific molecular actors.
Any views expressed are those of the author, and do not necessarily reflect those of PLOS.
Giuseppe Gangarossa received his PhD in Biomedical Sciences, specialty Neuroscience, from the University of Bologna. He has been a visiting fellow at the Karolinska Institutet (Sotckholm, Sweden), the French Inserm (Montpellier, France) and the Collège de France (Paris, France). Giuseppe is currently Assistant Professor of Physiology at the University Paris Diderot. His main research topic is dopamine-related brain disorders. You can follow him on twitter @PeppeGanga