Regional and sub-regional differences in hippocampal GABAergic neuronal vulnerability in the TgCRND8 mouse model of Alzheimer's disease

Abstract

Hippocampal network activity is predominantly coordinated by γ-amino-butyric acid (GABA)ergic neurons. We have previously hypothesized that the altered excitability of hippocampal neurons in Alzheimer's disease (AD), which manifests as increased in vivo susceptibility to seizures in the TgCRND8 mouse model of AD, may be related to disruption of hippocampal GABAergic neurons. In agreement, our previous study in TgCRND8 mice has shown that hippocampal GABAergic neurons are more vulnerable to AD-related neuropathology than other types of neurons. To further explore the mechanisms behind the observed decrease of GABAergic neurons in 6 month-old TgCRND8 mice, we assessed the relative proportion of somatostatin (SOM), neuropeptide Y (NPY) and paravalbumin (PV) sub-types of GABAergic neurons at the regional and sub-regional level of the hippocampus. We found that NPY expressing GABAergic neurons were the most affected, as they were decreased in CA1-CA2 (pyramidal-, stratum oriens, stratum radiatum and molecular layers), CA3 (specifically in the stratum oriens) and dentate gyrus (specifically in the polymorphic layer) in TgCRND8 mice as compared to non-transgenic controls. SOM expressing GABAergic neurons were decreased in CA1-CA2 (specifically in the stratum oriens) and in the stratum radiatum of CA3, whereas PV neurons were significantly altered in stratum oriens sub-region of CA3. Taken together, these data provide new evidence for the relevance of hippocampal GABAergic neuronal network disruption as a mechanism underlying AD sequelae such as aberrant neuronal excitability, and further point to complex hippocampal regional and sub-regional variation in susceptibility to AD-related neuronal loss.

Phenotypic Alterations in Hippocampal NPY- and PV-Expressing Interneurons in a Presymptomatic Transgenic Mouse Model of Alzheimer’s Disease

“…Immunohistochemical staining for three neuronal markers (NeuN, NPY and PV) revealed distributional patterns in CA1/2, CA3, DG and subiculum (Figure 1A) that have been described previously (Albuquerque et al, 2015). Assessment of Aβ and amyloid-plaques using the FCA3340 antibody, which specifically recognizes human Aβ but not APP (Barelli et al, 1997), indicated no immunolabeling in hippocampus sections obtained from 1 month-old TgCRND8 mice, in contrast to the abundance of plaques present in the hippocampus of 11 month-old TgCRND8 mice, used as a positive control (Chishti et al, 2001; Figure 1B).…”

“…As with the aforementioned CA1 synaptic hyperexcitability, our results indicate that the change in the composition of certain GABAergic sub-populations may occur much earlier than previously believed. This is particularly striking for NPY-expressing GABAergic neurons that, by the age of 1 month (in the present study), have already decreased substantially in number, similar to 6 month-old TgCRND8 mice (Albuquerque et al, 2015) in all studied hippocampal regions. By contrast, the alteration of PV-expressing neurons appears more complex because the decreased expression of PV found in CA1 and subiculum at 1 month of age is not detectable in 6 month-old animals (Albuquerque et al, 2015).…”

“…This is particularly striking for NPY-expressing GABAergic neurons that, by the age of 1 month (in the present study), have already decreased substantially in number, similar to 6 month-old TgCRND8 mice (Albuquerque et al, 2015) in all studied hippocampal regions. By contrast, the alteration of PV-expressing neurons appears more complex because the decreased expression of PV found in CA1 and subiculum at 1 month of age is not detectable in 6 month-old animals (Albuquerque et al, 2015). Additionally, in another AD mouse model (APP/PS1), a significant loss of PV neurons was shown in CA1/2 region of 10 month-old mice (Takahashi et al, 2010).…”

“…A previous phenotypic analysis of hippocampal GABAergic neuronal populations at the overt stages of AD pointed to selective loss in number or function of specific sub-types, notably neurons expressing NPY (Ramos et al, 2006; Albuquerque et al, 2015), and PV (Verret et al, 2012; Albuquerque et al, 2015). As with the aforementioned CA1 synaptic hyperexcitability, our results indicate that the change in the composition of certain GABAergic sub-populations may occur much earlier than previously believed.…”

Major amyloid-β–degrading enzymes, endothelin-converting enzyme-2 and neprilysin, are expressed by distinct populations of GABAergic interneurons in hippocampus and neocortex

“…In AD, there is a clear loss of SOM innervation (reviewed in (Martel, et al, 2012) and several studies with APP transgenic mice support that SOM+ cells may be highly vulnerable to pathological Aβ accumulation (Albuquerque, et al, 2015,Ma and McLaurin, 2014,Perez-Cruz, et al, 2011,Ramos, et al, 2006). The sensitivity of these specific interneurons to AD pathology may relate to their putatively high capacity for intracellular Aβ metabolism via expression of ECE-2.…”