Learning improvement after PI3K activation correlates with de novo formation of functional small spines

Abstract

PI3K activation promotes the formation of synaptic contacts and dendritic spines, morphological features of glutamatergic synapses that are commonly known to be related to learning processes. In this report, we show that in vivo administration of a peptide that activates the PI3K signaling pathway increases spine density in the rat hippocampus and enhances the animals’ cognitive abilities, while in vivo electrophysiological recordings show that PI3K activation results in synaptic enhancement of Schaffer and stratum lacunosum moleculare inputs. Morphological characterization of the spines reveals that subjecting the animals to contextual fear-conditioning training per se promotes the formation of large spines, while PI3K activation reverts this effect and favors a general change toward small head areas. Studies using hippocampal neuronal cultures show that the PI3K spinogenic process is NMDA-dependent and activity-independent. In culture, PI3K activation was followed by mRNA upregulation of glutamate receptor subunits and of the immediate-early gene Arc. Time-lapse studies confirmed the ability of PI3K to induce the formation of small spines. Finally, we demonstrate that the spinogenic effect of PI3K can be induced in the presence of neurodegeneration, such as in the Tg2576 Alzheimer’s mouse model. These findings highlight that the PI3K pathway is an important regulator of neuronal connectivity and stress the relationship between spine size and learning processes.

Enhanced memory consolidation in mice lacking the circadian modulators Sharp1 and -2 caused by elevated Igf2 signaling in the cortex

“…To further characterize the Acx-specific phenotype in S1/2 −/− mice, we analyzed a set of surrogate markers of several signaling pathways (i.e., phosphorylation/activation states of p44/ 42-MAPK, S6, PI3K, mTOR, AMPK, GSK3β, and AKT) implicated in neuronal plasticity and hippocampal learning (8)(9)(10)(11)(12)(13)(14). We speculated that activated pathways selectively operating in the ACx and not the Hi might be among the underlying processes of the cortex-selective enhancement of learning and memory formation in S1/2 −/− mice.…”

“…It is well known that many aspects of sleep-wakerelated behavior are controlled by clock genes and emerging evidence suggests an involvement of the circadian system in cognitive processes (7). Several signaling pathways have been studied in the context of hippocampal learning (8)(9)(10)(11)(12)(13)(14), among those, the circadian timing of mitogen-activated protein kinase (MAPK) activity might be important for proper memory consolidation in the hippocampus (15). Moreover, MAPK is involved in processes of longterm potentiation and memory formation (12,16,17).…”

Neurotrophin receptor p75NTR mediates Huntington’s disease–associated synaptic and memory dysfunction

“…Dendritic spine dying and SP5 confocal analysis. Neurons were labeled using the Helios Gene Gun System (Bio-Rad) as previously described (102,103). Briefly, a suspension containing 3 mg of DiI (Molecular Probes, Invitrogen) dissolved in 100 μl of methylene chloride (SigmaAldrich) and mixed with 50 mg of tungsten particles (1.7 mm diameter; Bio-Rad) was spread on a glass slide and air-dried.…”

β-Caryophyllene/Hydroxypropyl-β-Cyclodextrin Inclusion Complex Improves Cognitive Deficits in Rats with Vascular Dementia through the Cannabinoid Receptor Type 2 -Mediated Pathway

“…The CB2 signaling mechanism is associated with the activation of the phosphatidylinositol 3-kinase (PI3K–Akt) pathway (Molina-Holgado et al, 2002; Palazuelos et al, 2006; Fernández-Ruiz et al, 2007). The PI3K/Akt pathway exhibits neuroprotection against brain disorders (Enriquez-Barreto et al, 2014; Gross and Bassell, 2014) and is associated with learning and memory abilities.…”