Biophysical Basis of Alpha Rhythm Disruption in Alzheimer's Disease

Occipital alpha is a prominent rhythm (∼10 Hz) detected in electroencephalography (EEG) during wakeful relaxation with closed eyes. The rhythm is generated by a subclass of thalamic pacemaker cells that burst at the alpha frequency, orchestrated by the interplay of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) and calcium channels in response to elevated levels of ambient acetylcholine (ACh). These oscillations are known to have a lower peak frequency and coherence in the early stages of Alzheimer's disease (AD). Interestingly, calcium signaling, HCN channel expression and ACh signaling, crucial for orchestrating the alpha rhythm, are also known to be aberrational in AD. In a biophysically detailed network model of the thalamic circuit, we investigate the changes in molecular signaling and the causal relationships between them that lead to a disrupted thalamic alpha in AD. Our simulations show that lowered HCN expression leads to a slower thalamic alpha, which can be rescued by increasing ACh levels, a common therapeutic target of AD drugs. However, this rescue is possible only over a limited range of reduced HCN expression. The model predicts that lowered HCN expression can modify the network activity in the thalamic circuit leading to increased GABA release in the thalamus and disrupt the calcium homeostasis. The changes in calcium signaling make the network more susceptible to noise, causing a loss in rhythmic activity. Based on our results, we propose that reduced frequency and coherence of the occipital alpha rhythm seen in AD may result from downregulated HCN expression, rather than modified cholinergic signaling.