Prefrontal Inositol Triphosphate Is Molecular Correlate of Working Memory in Nonhuman Primates

Abstract

Working memory (WM) is a process of actively maintaining information in the mind for a relatively short period of time, and prefrontal cortex (PFC) has been thought to play a central role in its function. However, our understanding of underlying molecular events that translate into WM behavior remains elusive. To shed light on this issue, we have used three distinct nonhuman primate models of WM where each model represents three WM conditions: normal control, WM-deficient, and recuperated to normal from WM deficiency. Based on the hypothesis that there is a common molecular substrate for the coding of WM behavior, we have studied the relationship of these animals' performance on a WM task with their PFC levels of molecular components associated with Gq-phospholipase C and cAMP pathways, with the idea of identifying the footprints of such biomolecules. We observed that in all of the primate models WM deficiency was strongly related to the reduced concentration of IP 3 in PFC, whereas recuperation of WM-deficient animals to normal condition was associated with the normalization in IP 3 level. However, this correlation was absent or weak for cAMP, active protein kinase A, dopamine D 1 receptor, and Gq protein. In addition, WM deficiency related not only to pharmacological conditions but also to aging. Thus, it is suggested that optimal IP 3 activity is essential for normal WM function and the maintenance of intracellular IP 3 -mediated Ca 2ϩ level in PFC may serve as biochemical substrate for the expression of WM behavior.

Latent epistatic interaction model identifies loci associated with human working memory

“…Among the 18 pairs are those involving PLCH1 , a member of the eta family of the phosphoinositide-specific phospholipase C (PLC), and PDE1A , a Ca 2+ /Calmodulin-dependent phosphodiesterase (PDE). Both PLCs and PDEs are strongly implicated in the molecular mechanisms of working memory, such as the G-protein-coupled responses to neurotransmitters, which lead to Ca 2+ release as the inositol trisphosphate concentration increases [26, 27], or cAMP/cGMP signaling in dopaminergic, cholinergic and serotonergic neurotransmission [28, 29]. Further significant interaction candidates include the zinc-dependent aminopeptidase LNPEP together with the xylosyltransferase GXYLT1 , neurexin NRXN1 , a cell adhesion molecule and receptor associated with schizophrenia [30] or RBFOX1 , which regulates human neuronal development [31].…”

Deletion of Gαq in the telencephalon alters specific neurobehavioral outcomes

“…Birnbaum et al noted that PKC overactivation via G aq -coupled receptors within the PFC impaired working memory function (2004). Other downstream effectors of the G aq signaling cascade have also been implicated in working memory function, such as IP 3 within the PFC (Lopez-Tellez et al, 2010). D1 receptors within the PFC also play a significant role in working memory (Sawaguchi and Goldman-Rakic, 1991;Williams and Goldman-Rakic, 1995).…”

A correlation of haloperidol-induced cognitive deficit with dysfunctional dopamine receptor activity in nonhuman primate

“…We, as well as others, have observed that chronic haloperidol administration induces WM deficit in both young and aged monkeys. 20,29 It has been shown that this cognitive func- 35,36 and that dysfunction in prefrontal cortex causes schizophrenia. [17][18][19] Our results of a correlation between cognitive dysfunction and abnormality in the function of dopamine receptors in haloperidol-treated monkeys suggest that dopamine receptor activity may play an important role in cognitive processing and that it may be a key to the schizophrenia.…”

“…20,29 Animals that showed significant reduction in performance on the spatial delayed response task after treatment with haloperidol were considered cognitively-deficient.…”