Abstract
Intracellular Ca2+ signaling regulates diverse functions of the nervous system. Many of these neuronal functions, including learning and memory, are regulated by neuronal calcium sensor-1 (NCS-1). However, the pathways by which NCS-1 regulates these functions remain poorly understood. Consistent with the findings of previous reports, we revealed that NCS-1 deficient (Ncs1-/-) mice exhibit impaired spatial learning and memory function in the Morris water maze test, although there was little change in their exercise activity, as determined via treadmill-analysis. Expression of brain-derived neurotrophic factor (BDNF; a key regulator of memory function) and dopamine was significantly reduced in the Ncs1-/- mouse brain, without changes in the levels of glial cell-line derived neurotrophic factor or nerve growth factor. Although there were no gross structural abnormalities in the hippocampi of Ncs1-/- mice, electron microscopy analysis revealed that the density of large dense core vesicles in CA1 presynaptic neurons, which release BDNF and dopamine, was decreased. Phosphorylation of Ca2+/calmodulin-dependent protein kinase II-α (CaMKII-α, which is known to trigger long-term potentiation and increase BDNF levels, was significantly reduced in the Ncs1-/- mouse brain. Furthermore, high voltage electric potential stimulation, which increases the levels of BDNF and promotes spatial learning, significantly increased the levels of NCS-1 concomitant with phosphorylated CaMKII-α in the hippocampus; suggesting a close relationship between NCS-1 and CaMKII-α. Our findings indicate that NCS-1 may regulate spatial learning and memory function at least in part through activation of CaMKII-α signaling, which may directly or indirectly increase BDNF production.
Highlights
Spatial learning and navigation are critical to the survival of non-sessile animals
In WT mice, the escape latency to the hidden platform as well as the total path length in each session continued to decrease after the first trial, with significant differences observed between day 1 and days 2–5 (P
KO mice exhibited less improvement in total path length: No significant difference in total path length was observed between day 1 and day 2, a significant difference was noted between day 1 and days 3–5, with much larger P values than those observed for WT mice (Fig 1B)
Summary
Extensive research has documented that such higher-order brain functions are associated with intracellular Ca2+ regulation, which plays major roles in both neurotransmitter release and synaptic plasticity through processes such as signal transduction, gene expression, and ion channel activity. Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been proposed as a key molecule in the mediation of learning and memory processes through potentiation of Ca2+-permeable ion channels [1] and phosphorylation of AMPA-type glutamate receptors, resulting in increased excitatory postsynaptic currents [2]. BDNF positively regulates synaptic transmission and plasticity in mature neurons [7], thereby contributing to learning and memory formation [8]. Dopamine modulates the transcription of a variety of genes, thereby promoting neuronal differentiation and survival [10] and long-term synaptic plasticity [11]. Emerging evidence suggests that a positive relationship exists between BDNF and dopamine signaling [12], and that this interaction appears to be mediated by a Ca2+-dependent cascade [13]
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