Long-Term Potentiation Promotes Proliferation/Survival and Neuronal Differentiation of Neural Stem/Progenitor Cells

Abstract

Neural stem cell (NSC) replacement therapy is considered a promising cell replacement therapy for various neurodegenerative diseases. However, the low rate of NSC survival and neurogenesis currently limits its clinical potential. Here, we examined if hippocampal long-term potentiation (LTP), one of the most well characterized forms of synaptic plasticity, promotes neurogenesis by facilitating proliferation/survival and neuronal differentiation of NSCs. We found that the induction of hippocampal LTP significantly facilitates proliferation/survival and neuronal differentiation of both endogenous neural progenitor cells (NPCs) and exogenously transplanted NSCs in the hippocampus in rats. These effects were eliminated by preventing LTP induction by pharmacological blockade of the N-methyl-D-aspartate glutamate receptor (NMDAR) via systemic application of the receptor antagonist, 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phosphonic acid (CPP). Moreover, using a NPC-neuron co-culture system, we were able to demonstrate that the LTP-promoted NPC neurogenesis is at least in part mediated by a LTP-increased neuronal release of brain-derived neurotrophic factor (BDNF) and its consequent activation of tropomysosin receptor kinase B (TrkB) receptors on NSCs. Our results indicate that LTP promotes the neurogenesis of both endogenous and exogenously transplanted NSCs in the brain. The study suggests that pre-conditioning of the host brain receiving area with a LTP-inducing deep brain stimulation protocol prior to NSC transplantation may increase the likelihood of success of using NSC transplantation as an effective cell therapy for various neurodegenerative diseases.

Inhibition of phosphodiesterase 2 reverses impaired cognition and neuronal remodeling caused by chronic stress

“…Given that the primary role of BDNF is to promote the functional architecture of neurons in the brain (Cho et al, 2013), the present study investigated BDNF expression in the hippocampus in the presence of Bay 60-7550 after chronic stress. As shown in Fig.…”

LARGE, an AMPA receptor interactor, plays a large role in long-term memory formation by driving homeostatic scaling-down

“…To determine whether the LARGE could affect Hebbian synaptic plasticity in normally developed adult mouse brain, we investigated hippocampal synaptic plasticity via in vivo LTP after KD of LARGE after the stereotaxic injection of an AAV expressing LARGE shRNA with GFP. Theta-patterned stimulation (TPS) protocol ( Cho et al, 2013 ) readily induced long-lasting hippocampal CA1 LTP in control mice, but not in LARGE KD mice ( Figure 5A ). Despite this LTP impairment, LARGE KD exhibited dramatic increases in field excitatory postsynaptic potential (fEPSP) amplitudes ( Figure 5A ), leading us to analyze these amplitudes at different stimulation intensities.…”

“…The fEPSPs from the hippocampal CA1 region were recorded as previously described (Cho et al, 2013). C57BL/6 mice ( n = 11-12) were anesthetized with urethane (1.6 g/kg, i.p.…”

SIPA1L2 controls trafficking and signaling of TrkB-containing amphisomes at presynaptic terminals

“…Presynaptic LTP results in activation of Protein Kinase A (PKA) at MF boutons and enhanced synaptic function that is largely mediated by PKA-dependent phosphorylation of different components of the presynaptic release machinery (27,28,29,30,31). PKA-mediated phosphorylation of Snapin at Ser50 is crucial for its dissociation from the DIC and a phosphomimetic Snapin-S50D mutant is largely immobile (32).…”