Hippocampal place cell dysfunction and the effects of muscarinic M₁ receptor agonism in a rat model of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease that disproportionately impacts memory and the hippocampus. However, it is unclear how AD pathology influences the activity of surviving neurons in the hippocampus to contribute to the memory symptoms in AD. One well-understood connection between spatial memory and neuronal activity in healthy brains is the activity of place cells, neurons in the hippocampus that fire preferentially in a specific location of a given environment (the place field of the place cell). In the present study, place cells were recorded from the hippocampus in a recently-developed rat model of AD (Tg-F344 AD) at an age (12-20 months) at which the AD rats showed marked spatial memory deficits. Place cells in the CA2 and CA3 pyramidal regions of the hippocampus in AD rats showed sharply reduced spatial fidelity relative to wild-type (WT) rats. In contrast, spiking activity of place cells recorded in region CA1 in AD rats showed good spatial fidelity that was similar to CA1 place cells in WT rats. Oral administration of the M muscarinic acetylcholine receptor agonist VU0364572 impacted place cell firing rates in CA1 and CA2/3 hippocampal regions, but did not improve the spatial fidelity of CA2/3 hippocampal place cells in AD rats. The results indicated that, to the extent the spatial memory impairment in AD rats was attributable to hippocampal dysfunction, the memory impairment was more attributable to dysfunction in hippocampal regions CA2 and CA3 rather than CA1.

Anti-NMDAR encephalitis antibodies cause long-lasting degradation of the hippocampal neural representation of memory

“…Increase in neuronal activity does not necessarily lead to a decrease in information, but we observed that the hyperactivity led to an increase of the noise and decrease in the signal components, creating a net decrease in SNR, which translates into a decrease in information. This is consistent with previous studies showing that CA1 neuronal activity degradation associated with lower performance in spatial navigation (Cacucci et al 2008, Wikenheiser & Redish 2011), and it has also been reported in several animal models of cognitive alterations (Mesbah-Oskui et al, 2015, Zaremba et al, 2017, Galloway et al, 2018, Lin et al, 2022). In addition, we observed a reduction of neuronal response stability over time – a measurement of memory strength – (Agnihotri et al, 2004, Benna & Fusi 2021).…”

“…This is consistent with previous studies showing that CA1 neuronal activity degradation associated with lower performance in spatial navigation, 42,43 and it has also been reported in several animal models of cognitive alterations. [44][45][46][47] In addition, we observed a reduction of neuronal response stability over time -a measurement of memory strength. 48,49 The current findings provide evidence of retrograde amnesia, a cognitive dysfunction that has not been explored in anti-NMDARe patients but has been observed in other synaptopathies.…”

Task-dependent learning and memory deficits in the TgF344-AD rat model of Alzheimer’s disease: three key timepoints through middle-age in females

“…Notably, other studies have reported no significant differences in spatial reference memory between TgF344-AD and WT rats in the Barnes maze at 12–13 months of age, nor impairments in spatial or non-spatial recognition memory via two variants of the novel object recognition task in 12 month-old TgF344-AD rats 8 , 12 . TgF344-AD rats between 9 and 12 months of age showed impaired spatial memory, but intact non-spatial recognition memory, relative to WT rats, suggesting a dissociation of effects depending on task type 13 . Importantly, the initial characterizations of the TgF344-AD rat model by Cohen and colleagues found no observable sex differences on the tasks assessed, and consequently, a majority of the subsequent studies on this model combined male and female rats 5 .…”

Stereological Changes in Microvascular Parameters in Hippocampus of a Transgenic Rat Model of Alzheimer’s Disease

“…Local diffusion changes could promote transient fluctuation of the blood pressure [71] that may induce or exacerbate cerebrovascular damage and progression resulting from A␤ deposition [73,74]. Furthermore, trophic disbalance of the granular cells layer in DG may lead to synaptic disruptions [17,60,75] and weakened effectiveness of synaptic transmission to projections in CA subregions [76].…”