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

Abstract

Interneurons, key regulators of hippocampal neuronal network excitability and synchronization, are lost in advanced stages of Alzheimer’s disease (AD). Given that network changes occur at early (presymptomatic) stages, we explored whether alterations of interneurons also occur before amyloid-beta (Aβ) accumulation. Numbers of neuropeptide Y (NPY) and parvalbumin (PV) immunoreactive (IR) cells were decreased in the hippocampus of 1 month-old TgCRND8 mouse AD model in a sub-regionally specific manner. The most prominent change observed was a decrease in the number of PV-IR cells that selectively affected CA1/2 and subiculum, with the pyramidal layer (PY) of CA1/2 accounting almost entirely for the reduction in number of hippocampal PV-IR cells. As PV neurons were decreased selectively in CA1/2 and subiculum, and given that they are critically involved in the control of hippocampal theta oscillations, we then assessed intrinsic theta oscillations in these regions after a 4-aminopyridine (4AP) challenge. This revealed increased theta power and population bursts in TgCRND8 mice compared to non-transgenic (nTg) controls, suggesting a hyperexcitability network state. Taken together, our results identify for the first time AD-related alterations in hippocampal interneuron function as early as at 1 month of age. These early functional alterations occurring before amyloid deposition may contribute to cognitive dysfunction in AD.

Phosphorylation of Tau protein correlates with changes in hippocampal theta oscillations and reduces hippocampal excitability in Alzheimer's model

“…Importantly, our recordings were performed at 30 days of postnatal age (P30) in all groups (see "Experimental procedures"). In line with our previous findings (21,22), oscillatory activity from the non-Tg group showed rhythmic theta activity (3)(4)(5)(6)(7)(8) in the CA1 and subiculum areas, characterized by stable power and frequency ( Fig. 3A; see also magnification in Fig.…”

“…Blocking of Kv potassium channels with 4-AP, in TgCRND8 at early P30, increased theta power and induced seizure activity (22). Altogether, our data demonstrated for the first time that the CA1 hippocampal network in the TgCRND8 AD mouse model showed hyperexcitability preceding protein deposition and cognitive impairments (22). However, the blocking of Kv channels in the P30 3xTg-AD mouse model exerted the opposite effect; the CA1/subiculum hippocampal network showed sig- (G and H, respectively).…”

“…This mice is characterized by A␤ deposition at 20 weeks of age (6). Interestingly, in contrast to non-Tg mice, blocking of Kv potassium channels with 4-AP in TgCRND8 at postnatal developmental stages (P30) increased theta power and induced seizure activity (22). To examine the network excitability of 3xTg-AD mice in the same experimental conditions, we bath-applied 4-AP while recording the complete septo-hippocampal preparation obtained from non-Tg and 3xTg-AD mice.…”

“…We recently reported that hippocampal network excitability is increased in the TgCRND8 AD mice (22). This mice is characterized by A␤ deposition at 20 weeks of age (6).…”

Contribution of early Alzheimer's disease‐related pathophysiology to the development of acquired epilepsy

“…In mouse models of temporal lobe epilepsy, loss of parvalbumin‐, calbindin‐, somatostatin‐ and neuropeptide Y‐expressing interneurons occurs in CA1 and dentate gyrus early during epileptogenesis (Andre, Marescaux, Nehlig, & Fritschy, ; Bouilleret, Loup, Kiener, Marescaux, & Fritschy, ; Bouilleret, Schwaller, Schurmans, Celio, & Fritschy, ). Similarly, different mouse models of Alzheimer's disease show reduced numbers of interneurons in these regions (Mahar et al., ; Ramos et al., ); and functional impairments of parvalbumin‐expressing interneurons were directly related to network hypersynchrony in parietal cortex (Verret et al., ). In granule cells of the dentate gyrus, calbindin expression is disease stage‐dependently reduced in mouse models and patients with Alzheimer's disease (Palop et al., ; Stefanits, Wesseling, & Kovacs, ).…”