Differential expression of cytoskeletal regulatory factors in the adolescent prefrontal cortex: Implications for cortical development

Abstract

The prevalence of depression, anxiety, schizophrenia, and drug and alcohol use disorders peaks during adolescence. Further, up to 50% of “adult” mental health disorders emerge in adolescence. During adolescence, the prefrontal cortex undergoes dramatic structural reorganization, in which dendritic spines and synapses are refined, pruned, and stabilized. Understanding the molecular mechanisms that underlie these processes should help to identify factors that influence the development of psychiatric illness. Here we briefly discuss the anatomical connections of the medial and orbital prefrontal cortex (mPFC and OFC, respectively). We then present original findings suggesting that dendritic spines on deep-layer excitatory neurons in the mouse mPFC and OFC prune at different adolescent ages, with later pruning in the OFC. In parallel, we used western blotting to define levels of several cytoskeletal regulatory proteins during early, mid-, and late adolescence, focusing on tropomyosin-related kinase receptor B (TrkB) and β1-integrin-containing receptors and select signaling partners. We identified regional differences in the levels of several proteins in early and mid-adolescence that then converged in early adulthood. We also observed age-related differences in TrkB levels, both full-length and truncated isoforms, Rho-kinase 2 (ROCK2), and synaptophysin in both PFC subregions. Finally, we identified changes in protein levels in the dorsal and ventral hippocampus that were distinct from those in the PFC. We conclude with a general review of the manner in which TrkB- and β1-integrin-mediated signaling influences neuronal structure in the postnatal brain. Elucidating the role of cytoskeletal regulatory factors throughout adolescence may identify critical mechanisms of PFC development.

Adolescent maturation of the prefrontal cortex: Role of stress and sex in shaping adult risk for compromise

“…The frontal lobe of the brain is the last to fully develop across multiple species including rodents, nonhuman primates and humans . Although sex differences in the PFC have been showed in rodent and human studies, the critical nature of this region is apparent in both sexes . The PFC is particularly sensitive to adverse experiences during development and is poised for influence of sex‐specific hormonal changes during puberty .…”

“…The highly dynamic nature of cytoskeletal proteins allow growth and plasticity of neural cells for fast adaptation to novel scenarios, yet also introduces an additional level of susceptibility of neural cells to environmental insult, such as psychosocial stressors . For instance, psychosocial stress and increased circulating corticosterone levels alter actin microfilament, neurofilament and microtubule stability, as well as alterations in dendritic morphology via TrkB and β‐integrin mediated signaling in adolescence . Such changes have been shown to precipitate depressive‐like behaviors, decreased dendritic number and a reduction of vesicular release in the synaptic space of rodents.…”

“…Here, we focus on possible structural maturation of the brain that may give rise to sex differences and later life susceptibility to neural disorders either independently or in concert with these factors . Collectively, enhanced neural pruning, the completion of myelination and cytoskeletal alterations mark the completion of adolescence and represent the ontogeny of the adult brain . Therefore, these processes, and disruptions therein, are positioned to be at risk during the adolescent period.…”

“…23,30 Collectively, enhanced neural pruning, the completion of myelination and cytoskeletal alterations mark the completion of adolescence and represent the ontogeny of the adult brain. [30][31][32][33][34] Therefore, these processes, and disruptions therein, are positioned to be at risk during the adolescent period.…”

Corticosteroid-induced dendrite loss and behavioral deficiencies can be blocked by activation of Abl2/Arg kinase

“…Representative blots are below with the corresponding loading controls, HSP-70 (70 kDa) and GAPDH (37 kDa), which did not change as a function of CORT exposure. Protein levels in control mice were consistent with prior investigations ( e.g ., Shapiro et al, 2017). Further detailed results and comparisons to CA3-rich samples are presented in Suppl.…”