Deletion of the amyloid precursor‐like protein 1 (APLP1) enhances excitatory synaptic transmission, reduces network inhibition but does not impair synaptic plasticity in the mouse dentate gyrus

Abstract

Amyloid precursor-like protein 1 (APLP1) is a transmembrane synaptic protein belonging to the amyloid precursor protein (APP) gene family. Although the role of this gene family-in particular of APP-has been intensely studied in the context of Alzheimer's disease, the physiological roles of its family members remain poorly understood. In particular, the function of APLP1, which is predominantly expressed in the nervous system, has remained enigmatic. Since APP has been implicated in synaptic plasticity, we wondered whether APLP1 could play a similar role. First, using in situ hybridization and laser microdissection combined with reverse transcription-quantitative polymerase chain reaction (PCR) we observed that Aplp1 mRNA is highly expressed in dentate granule cells. Having this examined, we studied synaptic plasticity at the perforant path-granule cell synapses in the dentate gyrus of APLP1-deficient mice in vivo. Analysis of field excitatory postsynaptic potentials evoked by stimulation of perforant path fibers revealed increased excitatory transmission in APLP1-deficient mice. Moreover, we observed decreased paired-pulse inhibition of population spikes indicating a decrease in network inhibition upon deletion of APLP1. In contrast, short-term presynaptic plasticity (STP) as well as long-term synaptic plasticity (LTP) was unchanged in the absence of APLP1. Based on these results we conclude that APLP1 deficiency on its own does not lead to defects in synaptic plasticity, but affects synaptic transmission and network inhibition in the dentate gyrus.

Region-Specific Differences in Amyloid Precursor Protein Expression in the Mouse Hippocampus

“…In addition to the above discussed differences in APP levels, differences in APP processing and thus the abundance of specific fragments such as sAPPα between brain regions may also play an important role. Likewise, regional differences in the expression of APP-like proteins, i.e., APLP1 or APLP2, which can partially compensate for a loss of APP could affect the interpretation of loss-of-function experiments (von Koch et al, 1997; Heber et al, 2000; Weyer et al, 2011; Hick et al, 2015; Vnencak et al, 2015). Regardless of all these considerations, however, APP can only play a role in synaptic plasticity of a synapse if it is present.…”

Novel Insights into the Physiological Function of the APP (Gene) Family and Its Proteolytic Fragments in Synaptic Plasticity

“…However, during the behavioral paradigm it has been noted that depletion of APLP1 resulted in an improvement of acquisition learning. The in vivo analysis at the perforant path-granule cell synapse (PP-DG) in young adult mice (16–20 weeks old) revealed unaltered STP and LTP, associated to enhanced excitatory transmission (Vnencak et al, 2015). The authors argued that maybe a larger number of perforant path synapses or an increased synaptic strength in APLP1-deficient mice may cause this enhancement, but final clarification is missing.…”

“…Several studies suggest that the hyperactivity is caused by APP overexpression (Born et al, 2014) while others assume Aß to be the trigger (Busche et al, 2008; Minkeviciene et al, 2009). The APP family proteins seem to be closely involved in regulating GABAergic transmission as both APLP1-KO and aged APP-KO mice exhibit reduced GABAergic mediated PPD responses (Seabrook et al, 1999; Vnencak et al, 2015) and in addition increased susceptibility for kainite-induced seizures (Steinbach et al, 1998). Moreover, supporting the role of APP within the GABAergic network are the chronic reduction of GABA A receptors and the lowered number of GABA B autoreceptors mediating PPD of inhibition in the absence of APP (Fitzjohn et al, 2000) as well as the identified interaction of APP with GABA B receptors in vitro (Norstrom et al, 2010) as well as recently in vivo (Schwenk et al, 2016).…”

“…In that study, Lassek and colleagues further show that APP deletion disturbs Ca 2+ homeostasis, due to a misregulation of calmodulin and neuromodulin but not of the expression of CaMKII or Ca 2+ channels. APLP1 is also localized at the presynaptic active zone (Laßek et al, 2016), but beside the function as mediator of neuronal adhesion (Kaden et al, 2009; Mayer et al, 2016) and its potential involvement in GABAergic neurotransmission (Vnencak et al, 2015) no other role or interaction partners have been attributed so far.…”

Amyloid-precursor Like Proteins APLP1 and APLP2 Are Dispensable for Normal Development of the Neonatal Respiratory Network

“…Similar to APP-KO mice, APLP1-KO mice show reduced body weight but normal locomotor activity and grip strength (Heber et al, 2000). Electrophysiological analysis of perforant path-granule cell synapses of the dentate gyrus revealed decreased network inhibition but no alterations in LTP in APLP1-KO mice (Vnencak et al, 2015). In line with this, morphological analysis of CA1 neurons in organotypic hippocampal cultures revealed normal spine density and dendritic branching (Weyer et al, 2014).…”