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

ABSTRACT: The perforant path provides the main 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, a characterization of synaptic transmission between individual connected pairs of entorhinal stellate cells and dentate granule cells is still pending. Here, we have used organotypic entorhino-hippocampal tissue cultures, in which the entorhino-dentate (EC-GC) projection is present and EC-GC pairs can be studied using whole-cell patch clamp recordings. 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 revealed. Since the perforant path is severely affected in Alzheimer´s disease, we used cultures of APP-deficient mice to address the role of the amyloid-precursor protein (APP) at this synapse. APP-deficiency caused alterations in excitatory neurotransmission at medial perforant path synapses that were accompanied by transcriptomic and ultrastructural changes. Moreover, the deletion of pre- but not postsynaptic APP through the local injection of Cre-expressing AAVs in conditional APPflox/flox tissue cultures increased the efficacy of neurotransmission at perforant path synapses. Together, these data suggest a physiological role for presynaptic APP at medial perforant path synapses, which may be adversely affected under conditions of altered APP processing.

ORGANISM(S): Mus musculus

PROVIDER: GSE213284 | GEO | 2022/09/16

REPOSITORIES: GEO

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Project description:Sanfilippo syndrome type B (MPS III B) is an autosomal recessive, neurodegenerative disease of children, characterized by profound mental retardation and dementia. The primary cause is mutation in the NAGLU gene, resulting in deficiency of N-acetylglucosaminidase and lysosomal accumulation of heparan sulfate. In the mouse model of MPS III B, neurons and microglia display the characteristic vacuolation of lysosomal storage of undegraded substrate, but neurons in the medial entorhinal cortex (MEC) display accumulation of several additional substances. We used whole genome microarray analysis to examine differential gene expression in MEC neurons isolated by laser capture microdissection from Naglu -/- and Naglu +/- mice. Neurons from the lateral entorhinal cortex (LEC) were used as tissue controls. The highest increase in gene expression (6- to 7-fold between mutant and control) in MEC and LEC neurons was that of Lyzs, which encodes lysozyme, but accumulation of lysozyme protein was seen in MEC neurons only. Because of a report that lysozyme induced the formation of hyperphosphorylated tau (P-tau) in cultured neurons, we searched for P-tau by immunohistochemistry. P-tau was found in MEC of Naglu -/- mice, in the same neurons as lysozyme. In older mutant mice, it was also seen in the dentate gyrus, an area important for memory. Electron microscopy of dentate gyrus neurons showed cytoplasmic inclusions of paired helical filaments - P-tau aggregates characteristic of tauopathies, a group of age-related dementias that includes Alzheimer disease. Our findings indicate that the Sanfilippo syndrome type B should also be considered a tauopathy. Two-condition experiment, Naglu-/- (affected) vs. Naglu+/- (unaffected control) of neurons from two adjacent brain regions: medial entorhinal cortex (MEC) and lateral entorhinal cortex (LEC). Biological replicates: 3 MEC Naglu-/-, 3 MEC Naglu+/-, 3 LEC Naglu-/- and 3 LEC Naglu+/-. Comparisons were made between 3 pairs of mutant and control female littermates for MEC and LEC neurons with dye switch duplicates, for a total of 12 microarrays.