Zhang, DaweiZhang, ChenHo, AngelaKirkwood, AlfredoSuedhof, Thomas C.Shen, Jie2020-05-052020-05-052010-12-01Dawei Zhang, Chen Zhang, Angela Ho, Alfredo Kirkwood, Thomas C Suedhof, Jie Shen. 2010. "Inactivation of presenilins causes pre-synaptic impairment prior to post-synaptic dysfunction." JOURNAL OF NEUROCHEMISTRY, Volume 115, Issue 5, pp. 1215 - 1221 (7). https://doi.org/10.1111/j.1471-4159.2010.07011.x0022-3042https://hdl.handle.net/2144/40570Synaptic dysfunction is widely thought to be a pathogenic precursor to neurodegeneration in Alzheimer’s disease (AD), and the extent of synaptic loss provides the best correlate for the severity of dementia in AD patients. Presenilins 1 and 2 are the major causative genes of early‐onset familial AD. Conditional inactivation of presenilins in the adult cerebral cortex results in synaptic dysfunction and memory impairment, followed by age‐dependent neurodegeneration. To characterize further the consequence of presenilin inactivation in the synapse, we evaluated the temporal development of pre‐synaptic and post‐synaptic deficits in the Schaeffer‐collateral pathway of presenilin conditional double knockout (PS cDKO) mice prior to onset of neurodegeneration. Following presenilin inactivation at 4 weeks, synaptic facilitation and probability of neurotransmitter release are impaired in PS cDKO mice at 5 weeks of age, whereas post‐synaptic NMDA receptor (NMDAR)‐mediated responses are normal at 5 weeks but impaired at 6 weeks of age. Long‐term potentiation induced by theta burst stimulation is also reduced in PS cDKO mice at 6 weeks of age. These results show that loss of presenilins results in pre‐synaptic deficits in short‐term plasticity and probability of neurotransmitter release prior to post‐synaptic NMDAR dysfunction, raising the possibility that presenilins may regulate post‐synaptic NMDAR function in part via a trans‐synaptic mechanism.p. 1215 - 1221en-US"© 2010 The Authors. Re-use of this article is permitted in accordance with the Terms and Conditions set out at http://www.wileyauthors.com/onlineopen"Science & technologyLife sciences & biomedicineBiochemistry & molecular biologyNeurosciences & neurologyAlzheimer's diseaseConditional knockoutLTPNeurodegenerationNeurotransmitter releaseNMDA receptorSynaptic dysfunctionSynaptic facilitationFamilial Alzheimer's diseaseSynaptic plasticityMissense mutationsDopamine releaseGeneMiceNeurodegenerationStriatumKnockoutProteinAgingAnimalsBiophysicsCalciumCerebral cortexElectric stimulationLong-term potentiationMice, inbred C57BLMice, knockoutNeuronsPresenilinsProbabilityReceptors, AMPAReceptors, N-methyl-D-aspartateSynapsesNeurology & neurosurgeryNeurosciencesArticle10.1111/j.1471-4159.2010.07011.x93778