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Memory formation is a complex process involving changes in the synaptic activity and gene expression encoding the insulin-like growth factors. We analyzed changes in the expression of genes encoding the insulin/insulin-like growth factors' proteins at the early period of learning in the CA1 region and dentate gyrus of the dorsal and ventral hippocampus in mice 1 hour after presentation of a new context (contextual fear conditioning) with and without negative reinforcement. It was found that in addition to changes in the expression of immediate early genes c-Fos (in all studied hippocampal fields) and Arc (in dorsal and ventral CA1, as well as in dorsal dentate gyrus), exposure to a new context significantly altered expression of the insulin receptor substrate 2 gene (Irs2) in dorsal CA1 and ventral dentate gyrus irrespectively of the negative reinforcement, which suggests participation of the insulin/IGF system in the early stages of neural activation during learning.

The search for strategies for strengthening the synaptic efficiency in Aβ

The search for strategies for strengthening the synaptic efficiency in Aβ25-35-treated slices is a challenge for the compensation of amyloidosis-related pathologies. Here, we used the recording of field excitatory postsynaptic potentials (fEPSPs), nitric oxide (NO) imaging, measurements of serine/threonine protein phosphatase (STPP) activity, and the detection of the functional mitochondrial parameters in suspension of brain mitochondria to study the Aβ25-35-associated signaling in the hippocampus. Aβ25-35 aggregates shifted the kinase–phosphatase balance during the long-term potentiation (LTP) induction in the enhancement of STPP activity. The PP1/PP2A inhibitor, okadaic acid, but not the PP2B blocker, cyclosporin A, prevented Aβ25-35-dependent LTP suppression for both simultaneous and delayed enzyme blockade protocols. STPP activity in the Aβ25-35-treated slices was upregulated, which is reverted relative to the control values in the presence of PP1/PP2A but not in the presence of the PP2B blocker. A selective inhibitor of stress-induced PP1α, sephin1, but not of the PP2A blocker, cantharidin, is crucial for Aβ25-35-mediated LTP suppression prevention. A mitochondrial Na+/Ca2+ exchanger (mNCX) blocker, CGP37157, also attenuated the Aβ25-35-induced LTP decline. Aβ25-35 aggregates did not change the mitochondrial transmembrane potential or reactive oxygen species (ROS) production but affected the ion transport and Ca2+-dependent swelling of organelles. The staining of hippocampal slices with NO-sensitive fluorescence dye, DAF-FM, showed stimulation of the NO production in the Aβ25-35-pretreated slices at the dendrite-containing regions of CA1 and CA3, in the dentate gyrus (DG), and in the CA1/DG somata. NO scavenger, PTIO, or nNOS blockade by selective inhibitor 3Br-7NI partly restored the Aβ25-35-induced LTP decline. Thus, hippocampal NO production could be another marker for the impairment of synaptic plasticity in amyloidosis-related states, and kinase–phosphatase balance management could be a promising strategy for the compensation of Aβ25-35-driven deteriorations.