Neurophysiological alterations in the nucleus reuniens of a mouse model of Alzheimer’s disease

Abstract

Key Points Alterations in the neurophysiology of hippocampal and cortical neurons has been linked to network hyperexcitability in mouse models of amyloidopathy.  The nucleus reuniens (Re) is part of a cognitive network involving the hippocampal formation and prefrontal cortex. Increased cellular activity in Re has been linked to the generation of hippocampal-thalamo-cortical seizure activity in J20 mice.  Re neurons display hyperpolarised resting membrane potentials in J20 mice. Passive membrane properties are unaffected by transgene expression. Re neurons recorded from J20 mice did not exhibit increased excitability in response to depolarising current stimuli but did exhibit an increased propensity to rebound burst following hyperpolarising current stimuli. This increased rebound firing was not a result of changes in T-type Ca 2+ conductances. Finally we observed a decrease in AP width.  These results help us understand how altered Re cellular neurophysiology may contribute to hippocampal-thalamo-cortical hyperexcitability in J20 mice. Abstract 1Transgenic mice that overproduce beta-amyloid (Aβ) peptides exhibit neurophysiological alterations 2 at the cellular, synaptic and network levels. Recently, increased neuronal activity in nucleus reuniens 3 (Re), has been linked to hyperexcitability within hippocampal-thalamo-cortical networks in the J20 4 mouse model of amyloidopathy. Here in vitro whole-cell patch clamp recordings were used to 5 compare old pathology-bearing J20 mice and wild-type controls to examine whether alterations to the 6 intrinsic electrophysiological properties of Re neurons could contribute to the amyloidopathy-7 associated Re hyperactivity. A greater proportion of Re neurons displayed a hyperpolarised membrane 8 potential in J20 mice without changes to the incidence or frequency of spontaneous action potential 9 (AP) generation. Passive membrane properties were independent of transgene expression. Re 10 neurons recorded from J20 mice did not exhibit increased AP generation in response to depolarising 11 current stimuli but did exhibit an increased propensity to rebound burst following hyperpolarising 12 current stimuli. This increase in rebound firing does not appear to result from alterations to T-type 13 calcium channels. Finally, in J20 mice there was an ~8% reduction in spike width, similar to what we 14 and others have reported in CA1 pyramidal neurons from multiple amyloidopathy mice. We conclude 15 that alterations to the intrinsic properties of Re neurons may contribute to the hyperexcitability 16 observed in hippocampal-thalmo-cortical circuits under pathological Aβ load. 17

Involvement of the Hypothalamic Nuclei in Forming Object–Place Associations in Neurons of Hippocampal Field CA2 (a hypothetical mechanism)

“…It was suggested that pharmacological actions with agonists for vasopressin Avpr1b receptors in fi eld CA2 might potentially be useful for improving social memory in various types of dementia [Smith et al, 2016]. Studies have shown that pathological β-amyloid loading also alters neuron activity in the reuniens nucleus [Walsh et al, 2020], with the result that the connection of the hippocampus with the prefrontal cortex must be degraded.…”