Presenilins (PS) form the active subunit of the gamma-secretase complex, which 
mediates the proteolytic clearance of a broad variety of type-I plasma membrane 
proteins. Loss-of-function mutations in PSEN1/2 genes are the leading cause of 
familial Alzheimer's disease (fAD). However, the PS/gamma-secretase substrates 
relevant for the neuronal deficits associated with a loss of PS function are not 
completely known. The members of the neurexin (Nrxn) family of presynaptic 
plasma membrane proteins are candidates to mediate aspects of the synaptic and 
memory deficits associated with a loss of PS function. Previous work has shown 
that fAD-linked PS mutants or inactivation of PS by genetic and pharmacological 
approaches failed to clear Nrxn C-terminal fragments (NrxnCTF), leading to its 
abnormal accumulation at presynaptic terminals. Here, we generated transgenic 
mice that selectively recreate the presynaptic accumulation of NrxnCTF in adult 
forebrain neurons, leaving unaltered the function of PS/gamma-secretase complex 
towards other substrates. Behavioral characterization identified selective 
impairments in NrxnCTF mice, including decreased fear-conditioning memory. 
Electrophysiological recordings in medial prefrontal cortex-basolateral amygdala 
(mPFC-BLA) of behaving mice showed normal synaptic transmission and uncovered 
specific defects in synaptic facilitation. These data functionally link the 
accumulation of NrxnCTF with defects in associative memory and short-term 
synaptic plasticity, pointing at impaired clearance of NrxnCTF as a new mediator 
in AD.