2025/04/04 by Francisco Arias-Aragón, Ana C. Sánchez-Hidalgo, Agnès Gruart +5 · 1 citation
Neuroscience · Medicine · #Neuroscience and Neuropharmacology Research #Biochemical effects in animals
paper · doi:10.1016/j.expneurol.2025.115241
Mutations in presenilin ( PSEN1/2 ) genes are the main cause of familial Alzheimer's disease (fAD). Presenilin (PS) form the active component of the gamma-secretase complex, a protease that cleaves the C-terminal fragment (CTF) of multiple membrane proteins. The generation of mice lacking Psen1/2 genes in adult forebrain and of knockin mice expressing fAD-linked PSEN1 mutations favored a loss of function mechanism for PS/gamma-secretase in AD. In vitro , inactivation of PS impairs short- and long-term plasticity, but if PS regulates synaptic plasticity in vivo is not known, nor is it known the contribution of specific gamma-secretase substrates. In this study, we performed electrophysiological recordings at medial prefrontal cortex-basolateral (mPFC-BLA) synapse of behaving mice during fear conditioning, a type of associative memory . In controls, fear-conditioning decreases paired-pulse facilitation of the mPFC-BLA synapse, likely reflecting a memory-dependent increase in release probability. In contrast, PScKO tam mice lacking Psen1 / 2 genes in forebrain neurons in a tamoxifen-regulated manner show decreased paired-pulse facilitation at mPFC-BLA synapse along with impaired memory. Neurexins (Nrxns) are presynaptic membrane proteins processed by PS/gamma-secretase. Importantly, paired-pulse facilitation is further decreased in PScKO tam ;NrxnCTF mice expressing increased NrxnCTF levels in PS-deficient neurons. Moreover, high-frequency stimulation induces long-term potentiation (LTP) at mPFC-BLA synapse of control mice, but LTP is impaired in PScKO tam mice and fully inhibited in PScKO tam ;NrxnCTF mice. These findings suggest that PS enables learning-dependent adaptations in short and long-term synaptic plasticity by, at least in part, preventing the accumulation of NrxnCTF, pointing at NrxnCTF as a relevant factor downstream of PS dysfunction in AD. • Fear memory changes short-term plasticity of mPFC-BLA synapse in behaving mice. • Impaired fear-induced changes in short-term plasticity in mice lacking Presenilin. • In vivo long-term potentiation at mPFC-BLA synapse fails in Presenilin deficient mice. • Generation of mice with increased Neurexin-CTF levels in Presenilin-deficient neurons. • Neurexin-CTF exacerbates the synaptic plasticity deficits of mice lacking Presenilin.