Introduction: Glycogen synthase kinase 3 (GSK3) is at the center of cellular signaling and controls various aspects of brain functions, including development of the nervous system, neuronal plasticity and onset of neurodegenerative disorders. Areas covered: In this review, recent efforts in elucidating the roles of GSK3 in neuronal plasticity and development of brain pathologies; Alzheimer’s and Parkinson’s disease, schizophrenia, and age-related neurodegeneration are described. The effect of microglia and astrocytes on development of the pathological states is also discussed. Expert opinion: GSK3β and its signaling pathway partners hold great promise as therapeutic target(s) for a multitude of neurological disorders. Activity of the kinase is often elevated in brain disorders. However, due to the wide range of GSK3 cellular targets, global inhibition of the kinase leads to severe side-effects and GSK3 inhibitors rarely reach Phase-2 clinical trials. Thus, a selective modulation of a specific cellular pool of GSK3 or specific down- or upstream partners of the kinase might provide more efficient anti-neurodegenerative therapies.

Glycogen synthase kinase 3β (GSK3β), originally described as a negative regulator of glycogen synthesis, is a molecular hub linking numerous signaling pathways in a cell. Specific GSK3β inhibitors have anti-depressant effects and reduce depressive-like behavior in animal models of depression. Therefore, GSK3β is suggested to be engaged in the pathogenesis of major depressive disorder, and to be a target and/or modifier of anti-depressants’ action. In this review, we discuss abnormalities in the activity of GSK3β and its upstream regulators in different brain regions during depressive episodes. Additionally, putative role(s) of GSK3β in the pathogenesis of depression and the influence of anti-depressants on GSK3β activity are discussed.

In the central nervous system, several forms of experience-dependent plasticity, learning and memory require the activity-dependent control of synaptic efficacy. Despite substantial progress in describing synaptic plasticity, mechanisms related to heterogeneity of synaptic functions at local circuits remain elusive. Here we studied the functional and molecular aspects of hippocampal circuit plasticity by analyzing excitatory synapses at basal and apical dendrites of mouse hippocampal pyramidal cells (CA1 region) in acute brain slices. In the past decade, activity of metalloproteinases (MMPs) has been implicated as a widespread and critical factor in plasticity mechanisms at various projections in the CNS. However, in the present study we discovered that in striking contrast to apical dendrites, synapses located within basal dendrites undergo MMP-independent synaptic potentiation. We demonstrate that synapse-specific molecular pathway allowing MMPs to rapidly upregulate function of NMDARs in stratum radiatum involved protease activated receptor 1 and intracellular kinases and GTPases activity. In contrast, MMP-independent scaling of synaptic strength in stratum oriens involved dopamine D1/D5 receptors and Src kinases. Results of this study reveal that 2 neighboring synaptic systems differ significantly in extracellular and intracellular cascades that control synaptic gain and provide long-searched transduction pathways relevant for MMP-dependent synaptic plasticity.

Aging is believed to be the result of alterations of protein expression and accumulation of changes in biomolecules. Although there are numerous reports demonstrating changes in protein expression in brain during aging, only few of them describe global changes at the protein level. Here, we present the deepest quantitative proteomic analysis of three brain regions, hippocampus, cortex and cerebellum, in mice aged 1 or 12 months, using the total protein approach technique. In all the brain regions, both in young and middle-aged animals, we quantitatively measured over 5,200 proteins. We found that although the total protein expression in middle-aged brain structures is practically unaffected by aging, there are significant differences between young and middle-aged mice in the expression of some receptors and signaling cascade proteins proven to be significant for learning and memory formation. Our analysis demonstrates that the hippocampus is the most variable structure during natural aging and that the first symptoms of weakening of neuronal plasticity may be observed on protein level in middle-aged animals.

Fbp2 (muscle isozyme of fructose 1,6-bisphosphatase) is a glyconeogenesis-regulating enzyme and a multifunctional protein indispensable for long-term potentiation (LTP) formation in the hippocampus. Here, we present evidence that expression of Fbp2 in murine hippocampal cell cultures is regulated by crosstalk between neurons and astrocytes. Co-culturing of the two cell types results in a decrease in Fbp2 expression in astrocytes, and its simultaneous increase in neurons, as compared to monocultures. These changes are regulated by paracrine signaling using extracellular vesicle (EV)-packed factors released to the culture medium. It is well accepted that astrocyte–neuron metabolic crosstalk plays a crucial role in shaping neuronal function, and recently we have suggested that Fbp2 is a hub linking neuronal signaling with redox and/or energetic state of brain during the formation of memory traces. Thus, our present results emphasize the importance of astrocyte–neuron crosstalk in the regulation of the cells’ metabolism and synaptic plasticity, and bring us one step closer to a mechanistic understanding of the role of Fbp2 in these processes.