Table 2.
Summary of alterations in synaptic function by altering presenilin or γ-secretase activity.
| Age | Aβ | Basal synaptic transmission | Presynaptic function | LTP | LTD | Other | Reference | |
|---|---|---|---|---|---|---|---|---|
| PS1 cKO | 3–6 mo | Cortical Aβ 40 and Aβ 42 are decreased | Normal (CA1) | Normal PPF ratio (CA1) | Normal (CA1) (5x TBS) normal (CA1) (3x 100 Hz) | Normal (CA1) | [178] | |
|
| ||||||||
| 2 mo | Normal (CA1) | Decreased PPF ratio (CA1) | Decreased (CA1) (5x TBS) | Normal (CA1) | Reduced NMDAR function (CA1); decreased cortical synaptic levels of NR1, NR2A, αCaMKII, and CRE-dependent genes | [179] | ||
| 6 mo | Increased (CA1) | Decreased PPF ratio (CA1) | Decreased (CA1) (5x TBS) | Normal (CA1) | ||||
| PS cDKO | 2 mo | Increased expression of the NR2A subunit of NMDARs, specifically at postsynaptic density and presynaptic terminals of axo/dendritic synapses, trapped at synapses (CA1) | [180] | |||||
| 5 wk | Decreased Ca2+-dependent frequency facilitation and release probability (CA1) | Normal (CA1) (5x TBS) | Normal NMDAR-mediated synaptic response (CA1) | [181] | ||||
| 6 wk | Decreased (CA1) 5x TBS | Reduced NMDAR-mediated synaptic response (CA1) | ||||||
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| CA1-PS cDKO | 2 mo | Normal (CA1) | Normal (CA1) (5x TBS) | Normal NMDAR/AMPAR ratio | [182] | |||
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| CA3-PS cDKO | 2 mo | Decreased Ca2+-dependent frequency facilitation and release probability (CA1) | Decreased (CA1) (5x TBS) | Normal NMDAR/AMPAR ratio | [182] | |||
|
| ||||||||
| AppTg (Swe/Ind) | 3 mo | Normal (CA1) | Normal (CA1) | Increased (CA1) (5x TBS) | [183] | |||
| 6 mo | Age dependent increase in Aβ levels and plaque deposition | Decreased (CA1) | Normal (CA1) | Decreased (CA1) (5x TBS) | ||||
|
| ||||||||
| AppTg; PS1−/− | 3 mo | Normal (CA1) | Normal (CA1) | Increased (CA1) | [183] | |||
| 6 mo | Decreased cortical Aβ peptides and plaque formation | Decreased (CA1) | Normal (CA1) | Decreased (CA1) (5x TBS) | ||||
|
| ||||||||
| 3-4 mo | Normal (CA1) | Normal (CA1) | ||||||
| Tg2576 | 6-7 mo | 50% increase in soluble Aβ | Decreased (CA1)-stronger stimulus required to elicit similar sized postsynaptic responses | Decreased (CA1) | [184] | |||
| 14-15 mo | 1000% increase in soluble Aβ | Decreased (CA1) but similar to 6-7 months | Normal (CA1) | |||||
|
| ||||||||
| Tg2576 w/MRK-560 (γ-secretase inhibitor) | 6-7 mo | 1, 3, or 7 days of treatment reduced soluble Aβ levels | Partial recovery but not significant | Recovered (CA1) | [184] | |||
| 15 mo | 3 months of treatment reduced soluble Aβ levels | No improvement | ||||||
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| Tg2576 w/CHF5074 (γ-secretase modulator) | 6 mo | 4-week, subchronic, oral treatment reduced Aβ levels | Recovered (CA1) | [185] | ||||