The amyloid precursor protein regulates synaptic transmission at medial perforant path synapses

The perforant path provides the primary cortical excitatory input to the
hippocampus. Due to its important role in information processing and
coding, entorhinal projections to the dentate gyrus have been studied in
considerable detail. Nevertheless, synaptic transmission between
individual connected pairs of entorhinal stellate cells and dentate
granule cells remains to be characterized. Here, we have used mouse
organotypic entorhino-hippocampal tissue cultures of either sex, in which
the entorhino-dentate (EC-GC) projection is present and EC-GC pairs can be
studied using whole-cell patch clamp recordings. By using cultures of
wildtype mice, the properties of EC-GC synapses formed by afferents from
the lateral and medial entorhinal cortex were compared and differences in
short-term plasticity were identified. Since the perforant path is
severely affected in Alzheimer´s disease, we used tissue cultures of
amyloid-precursor protein (APP)-deficient mice to examine the role of APP
at this synapse. APP deficiency altered excitatory neurotransmission at
medial perforant path synapses, which was accompanied by transcriptomic
and ultrastructural changes. Moreover, presynaptic but not postsynaptic
APP deletion through the local injection of Cre-expressing
adeno-associated viruses in conditional APPflox/flox tissue cultures
increased the neurotransmission efficacy at perforant path synapses. In
summary, these data suggest a physiological role for presynaptic APP at
medial perforant path synapses that may be adversely affected under
altered APP processing conditions.