Thalamic Reticular Nucleus Excitability and Cholinergic Signaling are Disrupted in a Mouse Model of Alzheimer’s Disease Neuropathology
Year: 2026
Type: article
Abstract: The thalamic reticular nucleus (TRN) forms powerful GABAergic connections with thalamic nuclei that regulate sleep, attention, and sensory processing. TRN neurons receive dense cholinergic innervation from the basal forebrain and brainstem, dynamically shaping TRN function across brain states. We previously showed reduced TRN activity and sleep deficits in amyloid precursor protein transgenic mice (APP mice), implicating TRN dysfunction as an early contributor to Alzheimer’s disease (AD) pathophysiology. Here, using slice electrophysiology in mice of both sexes, we determined whether changes in intrinsic membrane properties or cholinergic synaptic transmission contribute to TRN hypoactivity in APP mice. We found that TRN neurons located in the inner core and outer shell regions undergo substantial increases in excitability after the first postnatal month. In mature animals, core neurons exhibited higher firing rates and diverse firing patterns, including persistent firing, whereas shell neurons fired at lower rates and displayed more homogeneous firing patterns without persistent activity. Firing diversity in core neurons was mediated in part by low-threshold T-type Ca²⁺ channels. Cholinergic synaptic activation, mediated predominantly by basal forebrain afferents, produced biphasic excitatory-inhibitory postsynaptic responses in both core and shell neurons, with the ratio of postsynaptic excitation and inhibition varying across postsynaptic targets. Overall, cholinergic activation suppressed TRN firing. In APP mice, core neurons showed reduced intrinsic excitability and cholinergic afferents evoked postsynaptic responses with a larger muscarinic receptor-mediated inhibitory component, leading to delayed TRN firing. Together, these findings identify both intrinsic and cholinergic synaptic mechanisms that may contribute to TRN dysfunction during early AD. Significance Statement Alzheimer’s disease (AD) is typically diagnosed after cognitive symptoms emerge when treatments are less effective, highlighting the need to understand preclinical disease mechanisms. Cholinergic signaling and slow-wave sleep are disrupted before symptom onset, but the mechanisms underlying these changes remain poorly understood. Because the thalamic reticular nucleus (TRN) receives strong cholinergic input and mediates sleep-related rhythms, it is well positioned to contribute to early AD pathophysiology. We previously found reduced TRN activity and disrupted sleep in an AD mouse model. Here, we show that intrinsic excitability and cholinergic synaptic signaling are altered in TRN neurons during preclinical AD. These changes may contribute to thalamic dysfunction and sleep disturbances, providing a potential circuit mechanism linking early AD pathology to disease progression.
Source: Journal of Neuroscience
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W7225772345
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