Hyper-Excitability of Corticothalamic PT Neurons in MPFC Promotes Irritability in the Mouse Model of Alzheimer's Disease

Neuropsychiatric symptoms in patients with Alzheimer’s disease (AD) are believed to be presented as early as mild cognitive impairment (MCI) stage. However, it remains unclear whether there is functional heterogeneity within individual neuropsychiatric symptoms, and whether separate neuronal populations encode distinct aspects of the neuropsychiatric symptoms and drive them differently. Here, we report that pyramidal tract (PT) neurons projecting to the thalamus but not pons or medulla in mPFC of the mouse model of AD show increased excitability, which is associated with increased irritability and aggressivity. Decreased Kv6.3 in corticothalamic PT projection neurons contributes to hyper-excitability, which is tightly associated with aggressive behaviors. Overexpression of Kv6.3 not only prevents abnormal excitability of corticothalamic PT neurons in mPFC, but also rescues aggressive behaviors of 3xTg model mice. Our study provides causal evidence for the contribution of corticothalamic PT neurons to irritability in 3xTg model of AD and reveals circuit mechanisms used by PT neurons to regulate neuropsychiatric symptoms in AD.