To define the physiological functions of GSK3α in adult brain in vivo, we aimed in first instance to generate mice with a conditional, post-natal and neuron-specific deficiency of GSK3α by the Cre-Lox system. Generation of two mouse strains with either neuron-specific or with total deficiency of GSK3α In line with their independent regulation and non-redundancy, both GSK3α and GSK3β contributed to the physiological and to the pathological phosphorylation of protein Tau. This effort allowed us to investigate physiological functions and pathological roles, whereby we concentrated on the neurobiological aspects to highlight the physiological functions of GSK3α in learning and memory, in mobility and behavior. In these perspectives, we studied GSK3α in brain in vivo, in two newly generated mouse strains deficient in GSK3α, either completely in all organs or neuron-specific. The contribution of GSK3β to phosphorylation of protein Tau is evident while that of GSK3α is hardly investigated. Neurobiological analysis of GSK3α, particularly in AD remains fragmented and debated. This extreme difference in outcome demonstrates their non-redundant physiological functions, which still need to be detailed in vivo. Nevertheless, GSK3β deficient mice die in utero in contrast with viability of GSK3α deficient mice. The structural similar kinase domains predict that GSK3 isozymes share physiological functions. Pre-synaptically, GSK3 controls activity-dependent bulk endocytosis. Experimental evidence, and localization in dendritic spines supports a post-synaptic role for GSK3β in LTP, and by extension in synaptic plasticity. Moreover, the mode of action of lithium ions is not understood, because they are neither very effective nor specific inhibitors of GSK3α/β. GSK3β was proposed as a therapeutic target based on the treatment of bipolar disorder with lithium salts, but this however seriously suffers from limited effectiveness, narrow therapeutic window and side-effects. Neurobiological focus on GSK3β stems from its demonstrated functions in neuronal differentiation and in cognition, and from its role as “tau-kinase I” in Alzheimer’s disease (AD). Combined with expression of both isozymes in most cells, and the wide diversity of substrates and molecular partners, complicates the estimation of activity and definition of functions in vivo. Consequently, each isozyme exists in four different phosphorylated isoforms, a molecular complexity that yet escapes analysis. Tyrosine phosphorylation appears an intramolecular autocatalytic event during synthesis and folding, which makes GSK3 dual-specificity kinases. Both are inherently active and controlled by phosphorylation at two levels: (i) inhibitory phosphorylation of serine residues S21/S9 in GSK3α/β and (ii) tyrosine phosphorylation at Y279/Y216 in GSK3α/β, which augments their activity and relieves substrate-priming by other kinases. Glycogen synthase kinase-3 (GSK3) comprises two structurally and functionally related serine-threonine kinases, active in many physiological processes. Moreover, GSK3α contributes to the pathological phosphorylation of protein Tau. GSK3α proved to be regulated independently from GSK3β, and to exert non-redundant physiological neurological functions in general behavior and in cognition. Consequently, practically all parameters and characteristics indicated that both GSK3 isoforms were regulated independently, but that they acted on the same physiological functions in learning and memory, in mobility and in behavior. Moreover, GSK3α contributed to the neuronal architecture of the hippocampal CA1 sub-region that is most vulnerable in AD. Interestingly, the passive inhibitory avoidance task proved to modulate the phosphorylation status of both GSK3 isozymes in wild-type mice, further implying both to function in cognition. Behavioral and electrophysiological analysis demonstrated the physiological importance of neuronal GSK3α, with GSK3β not compensating for impaired cognition and reduced LTP. We generated and characterized two mouse strains with neuron-specific or with total GSK3α deficiency. In contrast, the GSK3α isozyme remained largely ignored with respect to both aspects. GSK3β is involved in a wide range of physiological functions, and is presumed to act in the pathogenesis of neurological diseases, from bipolar disorder to Alzheimer’s disease (AD).
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