Platelet-derived Growth Factor Receptor-induced Feed-forward Inhibition of Excitatory Transmission between Hippocampal Pyramidal Neurons

Lei, Saobo; Lu, Wei‐Yang; Xiong, Zhi‐Gang; Orser, Beverley A.; Valenzuela, C. Fernando; MacDonald, John F.

doi:10.1074/jbc.274.43.30617

Cited by 45 publications

(42 citation statements)

References 46 publications

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“…Although NMDA receptors themselves are known to be both positively and negatively regulated by signaling pathways downstream of PLC, such as PKC, inhibition of PLC with U73122 on its own has no effect on NMDA receptor currents (Lei et al, 1999;Holohean and Hackman, 2004). Thus, U73122 inhibition of PLC is more likely preventing LTD induction by blocking signaling pathways downstream of NMDA receptors.…”

Section: Resultsmentioning

confidence: 99%

Phospholipase C Is Required for Changes in Postsynaptic Structure and Function Associated with NMDA Receptor-Dependent Long-Term Depression

2007

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AKAP79/150 is targeted to spines through binding F-actin and the phospholipid phosphatidylinositol-(4,5)-bisphosphate (PIP 2 ). Previous electrophysiological studies have demonstrated that inhibition of phospholipase C (PLC)-catalyzed hydrolysis of PIP 2 inhibits NMDAR-dependent LTD; however, the signaling mechanisms that link PLC activation to alterations in dendritic spine structure and AMPAR function in LTD are unknown. We show here that NMDAR stimulation of PLC in cultured hippocampal neurons is necessary for AKAP79/150 loss from spines and depolymerization of spine actin. Importantly, we demonstrate that NMDAR activation of PLC is also necessary for decreases in spine PSD95 levels and AMPAR internalization. Thus, PLC signaling is required for structural and functional changes in spine actin, PSD scaffolding, and AMPAR trafficking underlying postsynaptic expression of LTD.

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Section: Resultsmentioning

confidence: 99%

Phospholipase C Is Required for Changes in Postsynaptic Structure and Function Associated with NMDA Receptor-Dependent Long-Term Depression

2007

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“…In contrast, LTD of the NMDAR component at CA1 synapses is independent of clathrin and instead requires an intact actin cytoskeleton. The inhibition of NMDA-mediated currents in CA1 pyramidal neurons by PDGF-BB is also very long lasting and depends upon an intact actin cytoskeleton (17,18), however, it is not clathrin-dependent but is also blocked by inhibitors of serine-threonine phosphatases (17). Therefore it closely resembles LTD of NMDA synaptic currents.…”

Section: Discussionmentioning

confidence: 99%

“…Application of PDGF-BB to isolated or cultured hippocampal neurons caused a long-lasting decrease in peak NMDA-evoked currents (17,18). To test if the inhibition of NMDA receptor currents involved NR2B over NR2A receptors we applied NR2 subunit-selective antagonists to the bath (27,28).…”

Section: Pdgf␤ Receptors Are Activated By Dimers Of the Isoform Pdgf-mentioning

confidence: 99%

“…The most intense staining for PDGF␤ receptors is found in the pyramidal cells of the hippocampus (15), whereas PDGF␣ receptors are located primarily on glial cells in this region (16). We have previously demonstrated that the PDGF␤ receptor ligand PDGF-BB inhibits synaptic NMDA receptors at CA1 synapses (17) as well as NMDA-evoked currents of neurons acutely isolated from the CA1 region of the hippocampus (17,18) or from the prefrontal cortex (19).…”

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confidence: 99%

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Platelet-derived Growth Factor Selectively Inhibits NR2B-containing N-Methyl-D-aspartate Receptors in CA1 Hippocampal Neurons

Beazely

Lim

et al. 2009

Journal of Biological Chemistry

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Platelet-derived growth factor (PDGF) ␤ receptor activation inhibits N-methyl-D-aspartate (NMDA)-evoked currents in hippocampal and cortical neurons via the activation of phospholipase C␥, PKC, the release of intracellular calcium, and a rearrangement of the actin cytoskeleton. In the hippocampus, the majority of NMDA receptors are heteromeric; most are composed of 2 NR1 subunits and 2 NR2A or 2 NR2B subunits. Using NR2B-and NR2A-specific antagonists, we demonstrate that PDGF-BB treatment preferentially inhibits NR2B-containing NMDA receptor currents in CA1 hippocampal neurons and enhances long-term depression in an NR2B subunit-dependent manner. Furthermore, treatment of hippocampal slices or cultures with PDGF-BB decreases the surface localization of NR2B but not of NR2A subunits. PDGF␤ receptors colocalize to a higher degree with NR2B subunits than with NR2A subunits. After neuronal injury, PDGF␤ receptors and PDGF-BB are upregulated and PDGF␤ receptor activation is neuroprotective against glutamate-induced neuronal damage in cultured neurons. We demonstrate that the neuroprotective effects of PDGF-BB are occluded by the NR2B antagonist, Ro25-6981, and that PDGF-BB promotes NMDA signaling to CREB and ERK1/2. We conclude that PDGF␤R signaling, by preferentially targeting NR2B receptors, provides an important mechanism for neuroprotection by growth factors in the central nervous system. N-Methyl-D-aspartate (NMDA)2 receptors are tetrameric, non-selective cation channels composed of two obligate NR1 and two variably expressed NR2 subunits (NR2A-D) although trimeric receptors (2NR1/NR2A/NR2B) are also likely to be present (1). In the hippocampus, NR2A and NR2B are the dominant NR2 forms (2, 3). The majority of synaptic receptors appear to contain the NR2A subunit, whereas NR2B-containing receptors are in greater density extrasynaptically (2, 4, 5), however, this paradigm has recently been challenged (6). Extrasynaptic NMDA receptors or, alternatively, the NR2B-containing NMDA receptors have been directly implicated in the Ca 2ϩ influx that causes excitotoxic cell death (7-10), whereas the synaptic, NR2A-containing receptors have paradoxically been linked to neuroprotection in ischemia (11, 12).Platelet-derived growth factor (PDGF) receptors are highly expressed in CA1 hippocampal neurons and are developmentally important but their functions in the mature CNS are largely unknown (13). There are two major PDGF receptor isoforms (PDGF␣ and PDGF␤ receptors) found in the hippocampus (14). The most intense staining for PDGF␤ receptors is found in the pyramidal cells of the hippocampus (15), whereas PDGF␣ receptors are located primarily on glial cells in this region (16). We have previously demonstrated that the PDGF␤ receptor ligand PDGF-BB inhibits synaptic NMDA receptors at CA1 synapses (17) as well as NMDA-evoked currents of neurons acutely isolated from the CA1 region of the hippocampus (17, 18) or from the prefrontal cortex (19).PDGF␤ receptors have been implicated in neuroprotection following ischemic events (20)...

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“…Similarly, PDGF-A and -B and their receptors (PDGFRa and PDGFRb) have a variety of roles in the brain. These include proliferation, migration, and differentiation of oligodendrocytes, neurite outgrowth (45), modulations of NMDA-receptor function (46), and neuroprotection (47). Elevation of these factors improves cognitive deficits and mental activity in aged animals (48).…”

Section: Vascular Endothelial Growth Factor (Vegf)/ Platelet-derived mentioning

confidence: 99%

Kampo Formulations, Chotosan, and Yokukansan, for Dementia Therapy: Existing Clinical and Preclinical Evidence

et al. 2013

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Abstract.Cognitive deficits and behavioral and psychological symptoms of dementia (BPSD) are typical features of patients with dementia such as Alzheimer's disease (AD), vascular dementia (VD), and other forms of senile dementia. Clinical evidence has demonstrated the potential usefulness of chotosan (CTS) and yokukansan (YKS), traditional herbal formulations called Kampo medicines, in the treatment of cognitive disturbance and BPSD in dementia patients, although the indications targeted by CTS and YKS in Kampo medicine differ. The availability of CTS and YKS for treating dementia patients is supported by preclinical studies using animal models of dementia that include cognitive/emotional deficits caused by aging and diabetes, dementia risk factors. These studies have led not only to the concept of a neuronal basis for the CTS-and YKS-induced amelioration of cognitive function and emotional/psychiatric symptom-related behavior in animal models, but also to a proposal that ingredient(s) of Uncariae Uncis cum Ramulus, a medicinal herb included in CTS and YKS, may play an important role in the actions of these formulae in dementia patients. Further studies are needed to clarify the active ingredients of these formulae and their target endogenous molecules implicated in the anti-dementia drug-like actions.

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Platelet-derived Growth Factor Receptor-induced Feed-forward Inhibition of Excitatory Transmission between Hippocampal Pyramidal Neurons

Cited by 45 publications

References 46 publications

Phospholipase C Is Required for Changes in Postsynaptic Structure and Function Associated with NMDA Receptor-Dependent Long-Term Depression

Phospholipase C Is Required for Changes in Postsynaptic Structure and Function Associated with NMDA Receptor-Dependent Long-Term Depression

Platelet-derived Growth Factor Selectively Inhibits NR2B-containing N-Methyl-D-aspartate Receptors in CA1 Hippocampal Neurons

Kampo Formulations, Chotosan, and Yokukansan, for Dementia Therapy: Existing Clinical and Preclinical Evidence

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