Voluntary running depreciates the requirement of Ca²⁺-stimulated cAMP signaling in synaptic potentiation and memory formation

Abstract

Mental health and cognitive functions are influenced by both genetic and environmental factors. Although having active lifestyle with physical exercise improves learning and memory, how it interacts with the specific key molecular regulators of synaptic plasticity is largely unknown. Here, we examined the effects of voluntary running on long-term potentiation (LTP) and memory formation in mice lacking type 1 adenylyl cyclase (AC1), a neurospecific synaptic enzyme that contributes to Ca 2+ -stimulated cAMP production. Following 1 mo of voluntary running-wheel exercise, the impaired LTP and object recognition memory in AC1 knockout (KO) mice were significantly attenuated. Running up-regulated exon II mRNA level of BDNF (brain-derived neurotrophic factor), though it failed to increase exon I and IV mRNAs in the hippocampus of AC1 KO mice. Intrahippocampal infusion of recombinant BDNF was sufficient to rescue LTP and object recognition memory defects in AC1 KO mice. Therefore, voluntary running and exogenous BDNF application overcome the defective Ca 2+ -stimulated cAMP signaling. Our results also demonstrate that alteration in Ca 2+

A selective adenylyl cyclase 1 inhibitor relieves pain without causing tolerance

“…Nevertheless, AC1-KO mice still display impaired performance in certain learning and memory tasks. 4,16,17 The use of a pharmacological agent will allow us to determine if those effects are a result of developmental issues (as AC1 expression is important for synaptic plasticity and development) 45,46 or if there is an acute dose-dependent effect. If ST034307 is to be used for those experiments, intrathecal or intracerebroventricular injections will be required to ensure that the compound reaches the brain.…”

“…AC1-KO mice were created as previously described and propagated using homozygous breeding using the C57BL/6J background. 17 This particular strain is commonly used in studies related to analgesic agents 18–20 and provides a way of comparing the activity of ST034307 with other compounds, given that morphine was used as a positive control. Mice were housed in groups (2-5 per cage) in cages covered with filter tops (micro barrier top from Allentown), in a temperature-controlled room under a 12-hour light/dark cycle.…”

“…While less severe deficits are observed in AC1-KO mice compared to the AC1/AC8 double KO, the former still displays reduced long-term potentiation (LTP) in the hippocampus and impairments in certain recognition memory as well as spatial and avoidance learning tasks. 16,17 Those studies highlight the importance of selectivity for AC1 inhibition versus AC8 for a novel compound to treat pain, but do not exclude the possibility of adverse effects that may result from selective AC1 inhibition in the hippocampus.…”

Fear renewal activates cyclic adenosine monophosphate signaling in the dentate gyrus

“…cAMP has widely been demonstrated to play a key role in the cellular mechanisms underlying LTP and memory. AC1 is a neuron‐specific synaptic enzyme that contributes to Ca 2+ ‐stimulated cAMP production (Zheng et al, ). LTP in AC1 knockout (AC1 −/− ) mice is significantly impaired, which is related to the decrease in cAMP concentration.…”

The Effects of Exercise on Long-Term Potentiation: A Candidate Mechanism of the Exercise-Memory Relationship

“…Relatedly, exercise-related, BDNF-induced neurogenesis influences synaptic development, and in turn, likely plays an important role in LTP production. Other candidate mechanisms include exercise-related alterations in cholinergic activity [27], mineralocorticoid/glucocorticoid receptor expression [29], cAMP signaling [37], and inflammatory cytokines [38].…”