Modification of neuronal ion channels by Small Ubiquitin-like Modifiers (SUMOs) has been observed in brains of patients with Alzheimer’s Dementia (AD). However, the functional consequences of SUMOylation of neuronal ions channels, and the role of SUMOylation in alterations in neuronal electrophysiology observed in AD, remain largely unknown. Neuronal hyperexcitability contributes to the cognitive defects in AD. Neuronal voltage-gated sodium channels (Nav1.1/1.2/1.6) are integral to neuronal excitation. Moreover, β-amyloid (Aβ) peptides, which play a causal role in AD, alter the physiological properties and/or expression of neuronal voltage-gated sodium channels. Our prior work, which forms the basis of the parent grant, has shown that SUMOylation of the cardiac voltage-gated sodium channel Nav1.5 alters channel properties, leading to an increase in the inward sodium current. The functionally relevant SUMOylation motif we have identified in Nav1.5 is highly conserved among voltage-gated sodium channels, including neuronal voltage-gated sodium channels. This suggests that physiology of neuronal voltage-gated sodium channels is also subject to modification via SUMOylation. In this supplement we will investigate the role of SUMOylation in regulating the functional properties of neuronal voltage-gated sodium channels using state-of-the-art electrophysiological methodologies, as well as novel SUMO-modifying reagents generated in the parent grant. Therefore, this application falls within the scope of the parent grant. This supplement will also explore whether SUMOylation can modulate neuronal excitability in the context of β-amyloid toxicity through its impact on the post-translational landscape, surface expression, and conductance properties of neuronal voltage-gated sodium channels. These studies will open a new chapter in understanding how deregulation of neuronal excitability via SUMOylation of neuronal sodium channels contributes to the pathogenesis of cognitive impairment in AD.