Amyloid pathology impairs experience-dependent inhibitory synaptic plasticity

Abstract

Alzheimer's disease is associated with altered neuronal activity, presumably due to impairments in homeostatic synaptic plasticity. Neuronal hyper and hypoactivity are also observed in mouse models of amyloid pathology. Using multicolor two-photon microscopy, we test how amyloid pathology alters the structural dynamics of excitatory and inhibitory synapses and their homeostatic adaptation to altered experience-evoked activity in vivo in a mouse model. The baseline dynamics of mature excitatory synapses and their adaptation to visual deprivation are not altered in amyloidosis. Likewise, the baseline dynamics of inhibitory synapses are not affected. In contrast, despite unaltered neuronal activity patterns, amyloid pathology leads to a selective disruption of homeostatic structural disinhibition on the dendritic shaft. We show that excitatory and inhibitory synapse loss is locally clustered under the nonpathological state, but amyloid pathology disrupts it, indicating impaired communication of changes in excitability to inhibitory synapses.

Functional connectivity favors aberrant visual network c-Fos expression accompanied by cortical synapse loss in a mouse model of Alzheimer’s disease

“…However, prolonged visual deprivation (≥5 days) triggers reorganization of visual circuits in adult rodents, including increased NR2b/NR2a ratio, reduced GluR2/GABA A ratio (He, Hodos and Quinlan, 2006), and retraction of inhibitory dendrites or synapses (Chen et al, 2011; Keck et al, 2011; van Versendaal et al, 2012), which together may lower the threshold for neuronal activation (Bridi et al, 2018). Additionally, we recently found that one week of visual deprivation elicited accelerated inhibitory synapse loss in WT mice but not hAPP mice (Niraula, Yan and Subramanian, 2023). Here, we found that c-Fos + cell density consistently and sharply increased in WT but not hAPP mice.…”

“…The presented in vivo presynaptic structural data is an independent analysis performed from the same raw dataset acquired as previously described (Niraula et al, 2023a; Niraula et al, 2023b). TdTomato-filled axons were first identified based on branch morphology and absence of postsynaptic markers, then en passant and terminaux boutons were manually labeled based on morphology using a modified version of the ObjectJ plugin (Villa et al, 2016) for FIJI (Schindelin et al, 2012).…”

“…To further confirm that the reduction in VGluT1 in hAPP mice represents cortical excitatory synapse loss in the visual cortex, we analyzed the density and dynamics of presynaptic boutons in vivo. Datasets of excitatory layer 2/3 visual cortical neurons imaged from anesthetized headfixed mice in two sessions separated by one week of standard 12 h light/dark housing using twophoton microscopy were used for these analyses (Niraula et al, 2023a;Niraula et al, 2023b).…”

“…In these patients, cortical areas of the visual system frequently display irregular patterns of activation and functional connectivity (Gour et al, 2014; Hao et al, 2005; Wang et al, 2007). Mouse models of AD have also shown structural and functional visual system disruption (Chen et al, 2022; Chiquita et al, 2019; Criscuolo et al, 2018; Crowe and Ellis-Davies, 2014; Grienberger et al, 2012; Korzhova et al, 2021; Liebscher et al, 2016; Maya-Vetencourt et al, 2014; Niraula et al, 2023; Niraula, Yan and Subramanian, 2023; Papanikolaou et al, 2022; Rosales Jubal et al, 2021; Rudinskiy et al, 2012; van Veluw et al, 2020; William et al, 2012; William et al, 2021). Consistently, we also observed an increase in the expression of the immediate early gene c-Fos in the primary visual cortex of an amyloid mouse model (Niraula et al, 2023).…”