Myristoylated alanine rich C kinase substrate (MARCKS) heterozygous mutant mice exhibit deficits in hippocampal mossy fiber-CA3 long-term potentiation

Abstract

The myristoylated alanine-rich C kinase substrate (MARCKS) is a primary protein kinase C (PKC) substrate in brain thought to transduce PKC signaling into alterations in the filamentous (F) actin cytoskeleton. Within the adult hippocampus, MARCKS is highly expressed in the dentate gyrus (DG)-CA3 mossy fiber pathway, but is expressed at low levels in the CA3-CA1 Schaffer collateral-CA1 pathway. We have previously demonstrated that 50% reductions in MARCKS expression in heterozygous Marcks mutant mice produce robust deficits in spatial reversal learning, but not contextual fear conditioning, suggesting that only specific aspects of hippocampal function are impaired by reduction in MARCKS expression. To further elucidate the role of MARCKS in hippocampal synaptic plasticity, in the present study we examined basal synaptic transmission, paired-pulse facilitation, post-tetanic potentiation, and long-term potentiation (LTP) in the hippocampal mossy fiber-CA3 and Schaffer collateral-CA1 pathways of heterozygous Marcks mutant and wild-type mice. We found that LTP is significantly impaired in the mossy fiber-CA3 pathway, but not in the Schaffer collateral-CA1 pathway, in heterozygous Marcks mutant mice, whereas basal synaptic transmission, paired-pulse facilitation, and posttetanic potentiation are unaffected in both pathways. These findings indicate that a 50% reduction in MARCKS expression impairs processes required for long-term, but not short-term, synaptic plasticity in the mossy fiber-CA3 pathway. The implications of these findings for the role of the mossy fiber-CA3 pathway in hippocampus-dependent learning processes are discussed.

Functional Role of the Interaction between Polysialic Acid and Myristoylated Alanine-rich C Kinase Substrate at the Plasma Membrane

“…In addition, MARCKS is involved in cell adhesion, lamellipodia formation, initiation of neuritogenesis, neurite outgrowth, growth cone adhesion, pathfinding, dendrite branching, dendritic spine morphogenesis, and synaptic plasticity (13,28,39,41,(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71). Knockdown of MARCKS by RNA interference and overexpression of MARCKS mutants revealed that non-phosphorylated MARCKS stabilizes growth cone adhesion, enhances branching and growth of dendrites, elongates dendritic spines, and enhances initiation of neuritogenesis and neurite outgrowth (65,66,68,69).…”

Angiotensin-II and MARCKS

“…At sites of cell adhesion, vinculin plays a role in physiological processes such as cell motility, migration, development, and wound healing (42). Loss of normal vinculin function has been associated with invasive cancer phenotypes, cardiovascular disease states, and derangements in embryogenesis that are also present in the embryonic lethal MARCKS knock-out mouse (9,11,42,43). Importantly, the tail domain of vinculin binds to acidic phospholipids, predominantly PIP 2 .…”

“…Indeed, the phosphorylation of MARCKS has been implicated in neuronal development (5,9) and in the migration of vascular endothelial cells (7,12) and neurons (14). The MARCKS null knock-out mouse is embryonic lethal (9,11,13), and no tissue-specific mouse knock-out models have been described. Much about the receptor-dependent modulation of MARCKS phosphorylation and its implications for vascular cell function remains incompletely understood.…”

Palmitic acid mediates hypothalamic insulin resistance by altering PKC-θ subcellular localization in rodents

“…Cytosolic myristoylated alanine-rich C kinase substrate (MARCKS) is phosphorylated by activation and translocation of many members of the PKC family, including PKC-θ (40). Therefore, to specifically test whether the fatty acids are impacting downstream targets of PKC-θ, we determined that i.c.v.…”