Structural analysis of the microglia–interneuron interactions in the CA1 hippocampal area of the APP/PS1 mouse model of Alzheimer's disease

Abstract

Microglia can interact with glutamatergic neurons and, through control of synaptic elements, regulate their physiological function. Much less is known about the partnership between microglia and GABAergic inhibitory interneurons. Here, we compared the interactions between microglia and parvalbumin (PV+) and somatostatin (SOM+) expressing interneurons in the CA1 hippocampal area of APP/PS1 transgenic mice that mimic certain aspects of the Alzheimer's disease (AD). We first uncovered a high level of interactions between microglia and two types of interneurons, with 98% of SOM+ and 90% of PV+ cells receiving different types of putative microglial contacts. The latter included the microglia soma to the interneuron soma (SomaMG‐to‐SomaIN), the microglia process to the interneuron soma (ProcessMG‐to‐SomaIN) and the microglia process to the interneuron dendrite (ProcessMG‐to‐DendIN) interactions. Moreover, we found significantly larger areas of interaction for the SomaMG‐to‐SomaIN and the ProcessMG‐to‐DendIN type of contacts between microglia and SOM+ cells. In contrast, PV+ cells exhibited larger areas for the ProcessMG‐to‐SomaIN interactions. Second, in APP/PS1 mice, although the overall microglia interactions with interneurons remained preserved, the fraction of interneurons receiving putative microglia contacts on their dendrites was reduced, and larger areas of interactions were observed for somatic contacts, suggesting a stronger modulation of the interneuron output by microglia in AD. In summary, these results reveal microglia as important partners of hippocampal PV+ and SOM+ GABAergic cells, with interneuron type‐specific pattern of interactions. Thus, microglia may play an essential role in the operation of interneurons under normal conditions and their dysfunction in disease.

Neuroinflammation triggers microglial phagocytosis of synapses via induction of synaptic filopodia

“…We observed that the enhanced and prolonged recruitment of activated microglia processes to the site of photodamage was directly involved in synaptic elimination. This is in line with accumulated evidence obtained in animal models of ischemia (Wake et al, 2009), systemic in ammation (Chen et al, 2014;Gallo et al, 2022), stress (Liu et al, 2021) and AD (Gervais et al, 2021;Gratuze et al, 2021;Wright et al, 2013). Together, these ndings complement previous studies and support the hypothesis that early in ammatory changes may lead to synaptic loss and therefore contribute to the cognitive impairment in neurodegenerative diseases such as AD.…”

Modelling the contributions to hyperexcitability in a mouse model of Alzheimer’s disease

“…Both enhanced excitatory glutamatergic (Busche and Konnerth, 2016; Zott et al ., 2019) as well as impaired inhibitory GABAergic transmission have been shown to contribute to neuronal network dysfunction in AD (Busche et al ., 2008; Schmid et al ., 2016; Palop and Mucke, 2016; Ambrad Giovannetti and Fuhrmann, 2019; Xu et al ., 2020; Hijazi et al ., 2020; Gervais et al ., 2021). Based on these observations, we tested whether increased E/I ratio due to reduced GABAergic inhibition combined with enhanced glutamatergic network input can reproduce experimental data.…”

“…However, importantly, the combination of these intrinsic ion channel modifications together with extrinsic network changes in the form of increased input frequency and input correlations in excitatory connections (AMPA/NMDA) and decreased inhibitory synaptic activity (25% reduction) led not only to elevated firing rates but also to an output mode switch from solitary to burst firing in the APP/PS1 morphology group ( Figure 4E ). Such changes in E/I balance as a result of reduced inhibition and increased excitation have been shown previously in AD mouse models (Busche et al ., 2008; Schmid et al ., 2016; Palop et al ., 2007; Palop and Mucke, 2016; Ambrad Giovannetti and Fuhrmann, 2019; Xu et al ., 2020; Hijazi et al ., 2020; Gervais et al ., 2021). Our results show that joint alterations in E/I balance and ion channels can explain not only qualitatively but also quantitatively the AD-related hyperexcitability including the shift from single spikes to bursts of spikes.…”

“…Both enhanced excitatory glutamatergic (Busche and Konnerth, 2016;Zott et al, 2019) as well as impaired inhibitory GABAergic transmission have been shown to contribute to neuronal network dysfunction in AD (Busche et al, 2008;Schmid et al, 2016;Palop and Mucke, 2016;Ambrad Giovannetti and Fuhrmann, 2019;Xu et al, 2020;Hijazi et al, 2020;Gervais et al, 2021).…”

“…Evidently, the modification of intrinsic excitability due to alterations in ion channel expression is well documented in AD. However, its interplay with synaptic and dendritic changes has not yet been fully clarified. Several studies have provided evidence for enhanced glutamatergic excitation (Busche and Konnerth, 2016; Zott et al ., 2019) and impaired inhibition during AD (Busche et al ., 2008, 2012; Takahashi et al ., 2010; Schmid et al ., 2016; Palop and Mucke, 2016; Ambrad Giovannetti and Fuhrmann, 2019; Xu et al ., 2020; Gervais et al ., 2021). This includes decreased perisomatic inhibition (Verret et al ., 2012) which can alter the firing pattern towards more bursts (Pouille and Scanziani, 2004).…”