Role of signal transduction crosstalk between adenylyl cyclase and MAP kinase in hippocampus-dependent memory

Abstract

One of the intriguing questions in neurobiology is how long-term memory (LTM) traces are established and maintained in the brain. Memory can be divided into at least two temporally and mechanistically distinct forms. Short-term memory (STM) lasts no longer than several hours, while LTM persists for days or longer. A crucial step in the generation of LTM is consolidation, a process in which STM is converted to LTM. Hippocampus-dependent LTM depends on activation of Ca 2+ , Erk/MAP kinase (MAPK), and cAMP signaling pathways, as well as de novo gene expression and translation. One of the transcriptional pathways strongly implicated in LTM is the CREB/CRE (calcium, cAMP response element) transcriptional pathway. Interestingly, this transcriptional pathway may also contribute to other forms of neuroplasticity including adaptive responses to drugs. Evidence discussed in this review indicates that activation of the Erk1/2 MAP Kinase (MAPK)/ CRE transcriptional pathway during the formation of hippocampus-dependent memory depends on calmodulin (CaM)-stimulated adenylyl cyclases.

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…In view of the lack of isoform-specific inhibitors and isoform-specific antibodies, knockout and overexpression studies with mice have driven most of our current understanding (Table 4). Several reviews delve more deeply into the exact roles for different AC isoforms in a variety of systems Xia and Storm, 2012;Guellich et al, 2014;Nicol and Gaspar, 2014;Rieg and Kohan, 2014;Sabbatini et al, 2014;Lee, 2015). Overall, our knowledge on the role of specific AC isoforms in human pathophysiology is still very limited.…”

“…The rutabaga gene in flies is most closely related to AC1 and was named for its deficits in learning and memory (Tempel et al, 1983;Levin et al, 1992). Deletion of AC1 in invertebrates or mice leads to a reduction of long-term potentiation (Levin et al, 1992;Wu et al, 1995) and impairments in numerous learning tasks, including spatial learning and learning to avoid a neutral odor Xia and Storm, 2012;Lee, 2015). Mice with AC1 deletion have deficits in neural wiring during brain development, including enhanced projections and/or branching patterns in the somatosensory system, the visual system, and in the peripheral nervous system (Abdel-Majid et al, 1998;Nicol et al, 2006;Dhande et al, 2012;Nicol and Gaspar, 2014;Suzuki et al, 2015).…”

The impact of sleep loss on hippocampal function

“…These receptors allow the Sleep loss and hippocampal function www.learnmem.org expression of LTP through increased influx of Ca 2+ (Xia and Storm 2012). Sleep deprivation has been shown to impair proper activation of this glutamate receptor-type through altering receptor subunit composition, surface expression, and reduced Ca 2+ influx (Chang et al 2012).…”

“…A large body of work suggests that sleep is particularly beneficial to the consolidation stage of memory storage, and that this stage is vulnerable to sleep manipulation (Sagales and Domino 1973;Buzsáki 1998;Stickgold et al 2000;Graves et al 2003). Learning induces a transient increase in calcium (Ca 2+ ) and adenylyl cyclase, an enzyme responsible for production of the second messenger, cyclic adenosine monophosphate (cAMP) (Xia and Storm 2012). cAMP activates three downstream targets important for protein synthesis and eventual memory consolidation.…”

The roles of protein kinases in learning and memory

“…In the case of Ras activation of the ERK cascade, the calcium/ calmodulin-sensitive guanine nucleotide exchange factors Ras-GRF1 and Ras-GRF2 are important (Feig 2011). The ERK1/2-MSK1 pathway requires cAMP production by calcium/calmodulin-dependent adenylate cyclases (Sindreu et al 2007;Xia and Storm 2012; also see Ahi et al 2004). ERK1/2 activation by cAMP involves Rap1 and is independent of PKA (Morozov et al 2003;Obara et al 2007;Ravni et al 2008).…”