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Neurons adapt to long-lasting changes in network activity, both in vivo and in vitro, by adjusting their synaptic strengths to stabilize firing rates. We found that homeostatic scaling of excitatory synapses was impaired in hippocampal neurons derived from mice lacking presenilin 1 (Psen1(-/-) mice) or expressing a familial Alzheimer's disease-linked Psen1 mutation (Psen1(M146V)). These findings suggest that deficits in synaptic homeostasis may contribute to brain dysfunction in Alzheimer's disease.
Figure 2. PS1M146V neurons display synaptic scaling deficits that can be rescued by expression of constitutively active Akt(a) Cumulative probability plot showing the distribution of mEPSC amplitudes from wild-type (WT) and PS1M146V (M146V) control and TTX-treated neurons; (inset) average mEPSC amplitudes of the same neurons. Notice that TTX treatment failed to induce a significant increase in mEPSC amplitudes in PS1M146V neurons (ANOVA, P < 0.02; *Bonferroniâs Multiple Comparison Test, P < 0.05). (b) γ-secretase inhibitor (GSI) did not affect scaling up of mEPSC amplitudes in TTX-treated wild-type neurons (**unpaired t-test, P < 0.01). (c) Virally-mediated expression of CA-Akt in PS1M146V neurons had no effect on mEPSC amplitudes on its own, but restored the ability to scale up in response to TTX (ANOVA, P < 0.001; **Bonferroniâs Multiple Comparison Test, P < 0.01). Dashed line shows the average mEPSC amplitude of TTX-treated wild-type neurons (reported in Fig. 1b). All error bars, s.e.m.
