GSK-3β Is Required for Memory Reconsolidation in Adult Brain

Abstract

Activation of GSK-3β is presumed to be involved in various neurodegenerative diseases, including Alzheimer's disease (AD), which is characterized by memory disturbances during early stages of the disease. The normal function of GSK-3β in adult brain is not well understood. Here, we analyzed the ability of heterozygote GSK-3β knockout (GSK+/−) mice to form memories. In the Morris water maze (MWM), learning and memory performance of GSK+/− mice was no different from that of wild-type (WT) mice for the first 3 days of training. With continued learning on subsequent days, however, retrograde amnesia was induced in GSK+/− mice, suggesting that GSK+/− mice might be impaired in their ability to form long-term memories. In contextual fear conditioning (CFC), context memory was normally consolidated in GSK+/− mice, but once the original memory was reactivated, they showed reduced freezing, suggesting that GSK+/− mice had impaired memory reconsolidation. Biochemical analysis showed that GSK-3β was activated after memory reactivation in WT mice. Intraperitoneal injection of a GSK-3 inhibitor before memory reactivation impaired memory reconsolidation in WT mice. These results suggest that memory reconsolidation requires activation of GSK-3β in the adult brain.

The roles of protein kinases in learning and memory

“…Consistently, pharmacological inhibition of GSK-3b enhances fear LTM formation, whereas transgenic overexpression of GSK-3b impairs spatial memory formation (Hernandez et al 2002). Additionally, GSK-3b has also been implicated in reconsolidation (Kimura et al 2008b;Wu et al 2011) and memory retrieval (Hong et al 2012).…”

Tumor Necrosis Factor-Induced Cerebral Insulin Resistance in Alzheimer's Disease Links Numerous Treatment Rationales

“…Over the years, those arguing for a primary role for hyperphosphorylated in AD pathogenesis have, as expected, focused on GSK-3␤ as the phosphorylating kinase that generates this form of (Mandelkow et al, 1992;Lovestone et al, 1994;Lovestone and Reynolds, 1997). Other have examined its effects on the brain itself and produced much compelling data suggesting that GSK-3␤, in its inhibited state, is essential for normal brain function, and its activated state leads to the array of functional loss seen in AD (Jope and Johnson, 2004;Balaraman et al, 2006;Engel et al, 2006;Hooper et al, 2007;Kimura et al, 2008;Salcedo-Tello et al, 2011;Smillie and Cousin, 2011). As noted in section VI, the argument that whenever GSK-3␤ activation is high, the hyperphosphorylated generated initiates disease (Goedert, 2004) has yet to explain the reported harmlessness of this protein in induced mammalian hibernation (Hä rtig et al, 2007).…”

Aggregation of Detergent-insoluble Tau Is Involved in Neuronal Loss but Not in Synaptic Loss

“…The formation of tau fibrils is believed to involve three sequential steps (20,21). First, monomeric tau binds together to form oligomers that are soluble in sarcosyl solution.…”