Hippocampal Mossy Fibers Synapses in CA3 Pyramidal Cells Are Altered at an Early Stage in a Mouse Model of Alzheimer's Disease

Abstract

Early Alzheimer's disease (AD) affects the brain non-uniformly, causing hippocampal memory deficits long before widespread brain degeneration becomes evident. Here we addressed whether mossy fiber inputs from the dentate gyrus onto CA3 principal cells are affected in an AD mouse model before amyloid ␤ plaque deposition. We recorded from CA3 pyramidal cells in a slice preparation from 6-month-old male APP/PS1 mice, and studied synaptic properties and intrinsic excitability. In parallel we performed a morphometric analysis of mossy fiber synapses following viral based labeling and 3D-reconstruction. We found that the basal structural and functional properties as well as presynaptic short-term plasticity at mossy fiber synapses are unaltered at 6 months in APP/PS1 mice. However, transient potentiation of synaptic transmission mediated by activity-dependent release of lipids was abolished. Whereas the presynaptic form of mossy fiber long-term potentiation (LTP) was not affected, the postsynaptic LTP of NMDAR-EPSCs was reduced. In addition, we also report an impairment in feedforward inhibition in CA3 pyramidal cells. This study, together with our previous work describing deficits at CA3-CA3 synapses, provides evidence that early AD affects synapses in a projection-dependent manner at the level of a single neuronal population.

Impaired pattern separation in Tg2576 mice is associated with hyperexcitable dentate gyrus caused by Kv4.1 downregulation

“…Synaptic activity in the DG/CA3 network was proposed as an early target of amyloid pathology that leads to impaired pattern separation and episodic memory loss [ 21 ]. Consistently, impaired synaptic plasticity in MF-CA3 synapses at an early stage in AD model mice was reported [ 22 , 23 ]. However, it remains to be elucidated how alteration of intrinsic excitability contributes to impaired DG/CA3 network underlying AD-associated cognitive deficit.…”

Impaired pattern separation in Tg2576 mice is associated with hyperexcitable dentate gyrus caused by Kv4.1 downregulation

“…Synaptic activity in the DG/CA3 network was proposed as an early target of amyloid pathology that leads to impaired pattern separation and episodic memory loss (21). Consistently, impaired synaptic plasticity in MF-CA3 synapses at an early stage in AD model mice was reported (22, 23). However, it remains to be elucidated how alteration of intrinsic excitability contributes to impaired DG/CA3 network underlying AD-associated cognitive deficit…”

Hippocampal Deficits in Amyloid-β-Related Rodent Models of Alzheimer’s Disease

“…Synaptic plasticity has been well studied in AD as deficits in the ability of synapses to undergo changes in strength could be responsible for memory deficits. There is good consensus in the field that impaired synaptic strengthening is a key feature of AD as deficits in long-term potentiation (LTP) occur in many mouse models of AD (Nalbantoglu et al, 1997;Chapman et al, 1999;Gruart et al, 2008;Gengler et al, 2010;Klevanski et al, 2015;Gelman et al, 2018;Viana da Silva et al, 2019). Even transgenic mice expressing only the carboxy-terminal 104 amino acids of APP display deficits in the maintenance of LTP (Nalbantoglu et al, 1997).…”

“…In addition to alterations in neuronal excitability, mouse models of AD demonstrate deficits in γ-aminobutyric acid (GABA) pathways and altered excitation/inhibition balance leading to seizures. In APP/PS1 mice deficits in the GABAergic pathway and feed forward inhibition are age-dependent (Oyelami et al, Viana da Silva et al, 2019). In hAPP mice parvalbumin interneuron dysfunction and reduced levels of voltage-gated sodium channel subunit Nav1.1 have also been linked to abnormal oscillatory rhythms, network synchrony and cognitive function (Verret et al, 2012).…”