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Lipid dynamics at dendritic spines.

Dotti CG, Esteban JA, Ledesma MD - Front Neuroanat (2014)

Bottom Line: However, we know much less about the involvement of lipids, despite being major membrane components and structure determinants.Moreover, protein complexes that regulate spine plasticity depend on specific interactions with membrane lipids for proper function and accurate intracellular signaling.We pay particular attention to the influence that spine lipid dynamism has on glutamate receptors, which are key regulators of synaptic plasticity.

View Article: PubMed Central - PubMed

Affiliation: Centro Biología Molecular Severo Ochoa, CSIC-UAM Madrid, Spain.

ABSTRACT
Dynamic changes in the structure and composition of the membrane protrusions forming dendritic spines underlie memory and learning processes. In recent years a great effort has been made to characterize in detail the protein machinery that controls spine plasticity. However, we know much less about the involvement of lipids, despite being major membrane components and structure determinants. Moreover, protein complexes that regulate spine plasticity depend on specific interactions with membrane lipids for proper function and accurate intracellular signaling. In this review we gather information available on the lipid composition at dendritic spine membranes and on its dynamics. We pay particular attention to the influence that spine lipid dynamism has on glutamate receptors, which are key regulators of synaptic plasticity.

No MeSH data available.


Related in: MedlinePlus

Cholesterol regulation at spines upon glutamate stimulation. Acute glutamate stimulatory conditions lead to loss of membrane cholesterol. The mechanism proposed involves glutamate induced rise in intracellular Ca++ leading to the approximation/apposition of ER membranes to the synaptic plasma membrane. This allows Cyp46A1, whose active site is in the lumenal side of the ER, to oxidize cholesterol present in the exoplasmic leaflet that is released as hydroxycholesterol. In the aging context, constitutive high intracellular calcium and irreversible cholesterol loss due to lifelong lasting synaptic activity leads to reduced membrane-associated MARCKS, which affects synaptic plasticity by several mechanisms: (1) impaired MARCKS-mediated actin dynamics; (2) reduced membrane clustering of PIP2; and (3) high PI3K activity resulting in reduced glutamate-mediated Akt dephosphorylation and GSK3β activation. The later contributes to the impaired AMPARc internalization and LTD in aged neurons.
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Figure 1: Cholesterol regulation at spines upon glutamate stimulation. Acute glutamate stimulatory conditions lead to loss of membrane cholesterol. The mechanism proposed involves glutamate induced rise in intracellular Ca++ leading to the approximation/apposition of ER membranes to the synaptic plasma membrane. This allows Cyp46A1, whose active site is in the lumenal side of the ER, to oxidize cholesterol present in the exoplasmic leaflet that is released as hydroxycholesterol. In the aging context, constitutive high intracellular calcium and irreversible cholesterol loss due to lifelong lasting synaptic activity leads to reduced membrane-associated MARCKS, which affects synaptic plasticity by several mechanisms: (1) impaired MARCKS-mediated actin dynamics; (2) reduced membrane clustering of PIP2; and (3) high PI3K activity resulting in reduced glutamate-mediated Akt dephosphorylation and GSK3β activation. The later contributes to the impaired AMPARc internalization and LTD in aged neurons.

Mentions: Appropriate levels and clustering of phosphatidylinositol(4,5) diphosphate (PIP2) at the postsynaptic membrane, which are modulated by the activities of Phospholipase γ (PLCγ) and PIP5K, are important for synaptic plasticity, both LTP (Trovò et al., 2013) and LTD (Unoki et al., 2012). The PIP2-clustering molecule myristoylated alanine-rich C kinase substrate (MARCKS) critically contributes to this requirement. The effector domain of MARCKS reversibly sequesters PIP2 on the plasma membrane, which can be released in response to local increases in intracellular calcium (McLaughlin and Murray, 2005). Low levels of this protein, leading to PIP2 paucity at the membrane, promote the age-related impairment of synaptic plasticity (Figure 1). Hence, its overexpression in the hippocampus of old mice or intraventricular perfusion of MARCKS peptide result in enhanced LTP and improved memory (Trovò et al., 2013). On the other hand, MARCKs appears to be a key molecule in spine morphogenesis promoting the transition from thin immature dendritic spines to larger, more stable mushroom by controlling actin cytoskeleton (Calabrese and Halpain, 2005). In agreement, MARCKs deficient mice show impaired LTP and spatial cognition (McNamara et al., 1998; Hussain et al., 2006). Association of MARCKS to the membrane is necessary for its ability to crosslink F-actin (Calabrese and Halpain, 2005). Membrane levels of cholesterol, to which MARCKs can bind, would mediate this association. Evidence suggests that indeed defective MARCKs-induced PIP2 clustering in old synaptic membranes responds to the reduction of cholesterol levels during aging (Trovò et al., 2013; Martin et al., 2014; Figure 1).


Lipid dynamics at dendritic spines.

Dotti CG, Esteban JA, Ledesma MD - Front Neuroanat (2014)

Cholesterol regulation at spines upon glutamate stimulation. Acute glutamate stimulatory conditions lead to loss of membrane cholesterol. The mechanism proposed involves glutamate induced rise in intracellular Ca++ leading to the approximation/apposition of ER membranes to the synaptic plasma membrane. This allows Cyp46A1, whose active site is in the lumenal side of the ER, to oxidize cholesterol present in the exoplasmic leaflet that is released as hydroxycholesterol. In the aging context, constitutive high intracellular calcium and irreversible cholesterol loss due to lifelong lasting synaptic activity leads to reduced membrane-associated MARCKS, which affects synaptic plasticity by several mechanisms: (1) impaired MARCKS-mediated actin dynamics; (2) reduced membrane clustering of PIP2; and (3) high PI3K activity resulting in reduced glutamate-mediated Akt dephosphorylation and GSK3β activation. The later contributes to the impaired AMPARc internalization and LTD in aged neurons.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126552&req=5

Figure 1: Cholesterol regulation at spines upon glutamate stimulation. Acute glutamate stimulatory conditions lead to loss of membrane cholesterol. The mechanism proposed involves glutamate induced rise in intracellular Ca++ leading to the approximation/apposition of ER membranes to the synaptic plasma membrane. This allows Cyp46A1, whose active site is in the lumenal side of the ER, to oxidize cholesterol present in the exoplasmic leaflet that is released as hydroxycholesterol. In the aging context, constitutive high intracellular calcium and irreversible cholesterol loss due to lifelong lasting synaptic activity leads to reduced membrane-associated MARCKS, which affects synaptic plasticity by several mechanisms: (1) impaired MARCKS-mediated actin dynamics; (2) reduced membrane clustering of PIP2; and (3) high PI3K activity resulting in reduced glutamate-mediated Akt dephosphorylation and GSK3β activation. The later contributes to the impaired AMPARc internalization and LTD in aged neurons.
Mentions: Appropriate levels and clustering of phosphatidylinositol(4,5) diphosphate (PIP2) at the postsynaptic membrane, which are modulated by the activities of Phospholipase γ (PLCγ) and PIP5K, are important for synaptic plasticity, both LTP (Trovò et al., 2013) and LTD (Unoki et al., 2012). The PIP2-clustering molecule myristoylated alanine-rich C kinase substrate (MARCKS) critically contributes to this requirement. The effector domain of MARCKS reversibly sequesters PIP2 on the plasma membrane, which can be released in response to local increases in intracellular calcium (McLaughlin and Murray, 2005). Low levels of this protein, leading to PIP2 paucity at the membrane, promote the age-related impairment of synaptic plasticity (Figure 1). Hence, its overexpression in the hippocampus of old mice or intraventricular perfusion of MARCKS peptide result in enhanced LTP and improved memory (Trovò et al., 2013). On the other hand, MARCKs appears to be a key molecule in spine morphogenesis promoting the transition from thin immature dendritic spines to larger, more stable mushroom by controlling actin cytoskeleton (Calabrese and Halpain, 2005). In agreement, MARCKs deficient mice show impaired LTP and spatial cognition (McNamara et al., 1998; Hussain et al., 2006). Association of MARCKS to the membrane is necessary for its ability to crosslink F-actin (Calabrese and Halpain, 2005). Membrane levels of cholesterol, to which MARCKs can bind, would mediate this association. Evidence suggests that indeed defective MARCKs-induced PIP2 clustering in old synaptic membranes responds to the reduction of cholesterol levels during aging (Trovò et al., 2013; Martin et al., 2014; Figure 1).

Bottom Line: However, we know much less about the involvement of lipids, despite being major membrane components and structure determinants.Moreover, protein complexes that regulate spine plasticity depend on specific interactions with membrane lipids for proper function and accurate intracellular signaling.We pay particular attention to the influence that spine lipid dynamism has on glutamate receptors, which are key regulators of synaptic plasticity.

View Article: PubMed Central - PubMed

Affiliation: Centro Biología Molecular Severo Ochoa, CSIC-UAM Madrid, Spain.

ABSTRACT
Dynamic changes in the structure and composition of the membrane protrusions forming dendritic spines underlie memory and learning processes. In recent years a great effort has been made to characterize in detail the protein machinery that controls spine plasticity. However, we know much less about the involvement of lipids, despite being major membrane components and structure determinants. Moreover, protein complexes that regulate spine plasticity depend on specific interactions with membrane lipids for proper function and accurate intracellular signaling. In this review we gather information available on the lipid composition at dendritic spine membranes and on its dynamics. We pay particular attention to the influence that spine lipid dynamism has on glutamate receptors, which are key regulators of synaptic plasticity.

No MeSH data available.


Related in: MedlinePlus