Impairments in cognition and neural precursor cell proliferation in mice expressing constitutively active glycogen synthase kinase-3 (original) (raw)
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Biological Psychiatry, 2014
Background-Identifying feasible therapeutic interventions is crucial for ameliorating the intellectual disability and other afflictions of Fragile X Syndrome (FXS), the most common inherited cause of intellectual disability and autism. Hippocampal glycogen synthase kinase-3 (GSK3) is hyperactive in the mouse model of FXS (FX mice), and hyperactive GSK3 promotes locomotor hyperactivity and audiogenic seizure susceptibility in FX mice, raising the possibility that specific GSK3 inhibitors may improve cognitive processes. Methods-We tested if specific GSK3 inhibitors improve deficits in N-methyl-D-aspartate receptor (NMDAR)-dependent long term potentiation (LTP) at medial perforant path synapses onto dentate granule cells (MPP-DGC) and dentate gyrus-dependent cognitive behavioral tasks. Results-GSK3 inhibitors completely rescued deficits in LTP at MPP-DGC synapses in FX mice. Furthermore, synaptosomes from the dentate gyrus of FX mice displayed decreased inhibitory serine-phosphorylation of GSK3β compared with wild-type littermates. The potential therapeutic utility of GSK3 inhibitors was further tested on dentate gyrus-dependent congnitive behaviors. In vivo administration of GSK3 inhibitors completely reversed impairments in several cognitive tasks in FX mice, including novel object detection, coordinate and categorical spatial processing, and temporal ordering for visual objects. Conclusions-These findings establish that synaptic plasticity and cognitive deficits in FX mice can be improved by intervention with inhibitors of GSK3, which may prove therapeutically beneficial in FXS.
Dual effects of increased glycogen synthase kinase-3 activity on adult neurogenesis
Human Molecular Genetics, 2012
Adult neurogenesis, the generation of new neurons during the adulthood, is a process controlled by several kinases and phosphatases among which GSK3b exerts important functions. This protein is particularly abundant in the central nervous system, and its activity deregulation is believed to play a key role in chronic disorders such as Alzheimer's disease. Previously, we reported that in vivo overexpression of GSK3b (Tet/ GSK3b mice) causes alterations in adult neurogenesis, leading to a depletion of the neurogenic niches. Here, we have further characterized those alterations, finding a delay in the switching-off of doublecortin marker as well as changes in the survival and death rates of immature precursors and a decrease in the total number of mature neurons. Besides, we have highlighted the importance of the inflammatory environment, identifying eotaxin as a possible modulator of the detrimental effects on adult neurogenesis. Taking advantage of the conditional system, we have also explored whether these negative consequences of increasing GSK3 activity are susceptible to revert after doxycycline treatment. We show that transgene shutdown in symptomatic mice reverts microgliosis, abnormal eotaxin levels as well as the aforementioned alterations concerning immature neurons. Unexpectedly, the decrease in the number of mature neurons and neuronal precursor cells of the subgranular zone of Tet/GSK3b mice could not be reverted. Thus, alterations in adult neurogenesis and likely in neurodegenerative disorders can be restored in part, although neurogenic niche depletion represents a non-reversible damage persisting during lifetime with a remarkable impact in adult mature neurons.
Frontiers in Molecular Neuroscience
Glycogen synthase kinase-3 (GSK3) mediates phosphorylation of several hundred proteins, and its aberrant activity is associated with an array of prevalent disorders. The two paralogs, GSK3α and GSK3β, are expressed ubiquitously and fulfill common as well as unique tasks throughout the body. In the CNS, it is established that GSK3 is involved in synaptic plasticity. However, the relative roles of GSK3 paralogs in synaptic plasticity remains controversial. Here, we used hippocampal slices obtained from adult mice to determine the role of each paralog in CA3−CA1 long-term potentiation (LTP) of synaptic transmission, a form of plasticity critically required in learning and memory. Conditional Camk2a Cre-driven neuronal deletion of the Gsk3a gene, but not Gsk3b, resulted in enhanced LTP. There were no changes in basal synaptic function in either of the paralog-specific knockouts, including several measures of presynaptic function. Therefore, GSK3α has a specific role in serving to limit ...
Glycogen synthase kinase-3 inhibition is integral to long-term potentiation
European Journal of Neuroscience, 2007
Glycogen synthase kinase-3 (GSK-3) is a serine ⁄ threonine kinase regulating diverse cellular functions including metabolism, transcription and cell survival. Numerous intracellular signalling pathways converge on GSK-3 and regulate its activity via inhibitory serine-phosphorylation. Recently, GSK-3 has been involved in learning and memory and in neurodegeneration. Here, we present evidence that implicates GSK-3 in synaptic plasticity. We show that phosphorylation at the inhibitory Ser9 site on GSK-3b is increased upon induction of long-term potentiation (LTP) in both hippocampal subregions CA1 and the dentate gyrus (DG) in vivo. The increase in inhibitory GSK-3b phosphorylation is robust and persists for at least one hour postinduction. Furthermore, we find that LTP is impaired in transgenic mice conditionally overexpressing GSK-3b. The LTP deficits can be attenuated ⁄ rescued by chronic treatment with lithium, a GSK-3 inhibitor. These results suggest that the inhibition of GSK-3 facilitates the induction of LTP and this might explain some of the negative effects of GSK-3 on learning and memory. It follows that this role of GSK-3b in LTP might underlie some of the cognitive dysfunction in diseases where GSK-3 dysfunction has been implicated, including Alzheimer's and other dementias.
Frontiers in Molecular Neuroscience, 2022
Glycogen synthase kinase 3 (GSK-3) is a Ser/Thr protein kinase that regulates many cellular processes, including synaptic plasticity. Previously, we reported that inhibition of GSK-3 prevents the induction of one of the major forms of synaptic plasticity, N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD), in hippocampal slices. In the present study, we have investigated the effects of inhibiting GSK-3 on learning and memory in healthy naïve animals. Systemic administration of a highly selective GSK-3 inhibitor, CT99021, reversibly blocked NMDAR-dependent LTD in the CA1 region of the hippocampus in anesthetized adult mice. In behavioral tasks, CT99021 had no effect on locomotor activity, anxiety, hippocampus-dependent contextual fear memory, and hippocampus-dependent reversal learning. However, CT99021 facilitated the rate of learning in the Morris water maze (MWM) and T-maze and enhanced the accuracy of long-term spatial memory in the MWM. These findings sug...
Neuropsychopharmacology
Hippocampal neurogenesis has widely been linked to memory and learning performance. New neurons generated from neural stem cells (NSC) within the dentate gyrus of the hippocampus (DG) integrate in hippocampal circuitry participating in memory tasks. Several neurological and neuropsychiatric disorders show cognitive impairment together with a reduction in DG neurogenesis. Growth factors secreted within the DG promote neurogenesis. Protein kinases of the protein kinase C (PKC) family facilitate the release of several of these growth factors, highlighting the role of PKC isozymes as key target molecules for the development of drugs that induce hippocampal neurogenesis. PKC activating diterpenes have been shown to facilitate NSC proliferation in neurogenic niches when injected intracerebroventricularly. We show in here that long-term administration of diterpene ER272 promotes neurogenesis in the subventricular zone and in the DG of mice, affecting neuroblasts differentiation and neurona...
GSK-3 is a master regulator of neural progenitor homeostasis
Nature Neuroscience, 2009
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Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2016
Schizophrenia (SZ) is a neurodevelopmental disorder in which the emergence of cognitive symptoms occurs during early adolescence. Glycogen synthase kinase-3β (GSK3β) plays a critical role in synaptic plasticity during development and is highly implicated in the etiology of SZ. However, how GSK3β activity affects synaptic plasticity and working memory function in the prefrontal cortex (PFC) during development remains unknown. Here we show a GSK3β hyperactivity during the early postnatal period in a neurodevelopmental rat SZ model that receives gestational exposure (E17) to the neurotoxin methylazoxymethanol (MAM). Accompanied with this change, adult MAM rats exhibited a significant decrease in spine density as well as impaired working memory, which was rescued by treatment with a GSK3β inhibitor during the juvenile period. Furthermore, the age-dependent hyperactive GSK3β caused a significant deficit in long-term potentiation (LTP) and facilitated long-term depression (LTD) in PFC pyr...