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The Pak Lab's work focuses on understanding how synapses change, maintain stability, and fail in disease, with the goal of revealing the molecular basis of cognition and cognitive decline.
SYNAPTIC PLASTICITY AND MEMORY
The ability of synapses to undergo lasting changes in strength is fundamental to learning and memory. The Pak Lab investigates the molecular mechanisms underlying this plasticity, with a particular interest in how synaptically localized transcriptional regulators contribute to long-lasting changes in neuronal connectivity.
Our current work focuses on the transcription factor CREB (cAMP response element-binding protein) and its localization to excitatory synapses in hippocampal neurons during long-term potentiation (LTP). We are investigating the activity-dependent movement of CREB to and from the synapse and the signaling pathways that regulate its localization. Using molecular and cellular approaches, we are also defining the protein interactions and phosphorylation events that may govern synaptic CREB function.
By uncovering mechanisms that regulate CREB outside of its well-established nuclear role, we aim to understand how synaptically localized transcription factors contribute to long-lasting plasticity. Synaptic CREB may play an important role in communication between activated synapses and the nucleus during LTP, providing new insight into the molecular processes underlying learning and memory.
Neural circuits must remain both adaptable and stable despite continual changes in activity. The Pak Lab investigates the molecular mechanisms that enable neurons to maintain this balance, with a particular focus on Polo-like kinase 2 (Plk2), an activity-inducible regulator of homeostatic synaptic plasticity.
Our work has shown that Plk2 acts as a molecular brake on excessive neuronal activity by coordinating pathways that reduce excitatory synaptic strength. In response to elevated activity, Plk2 regulates Ras and Rap signaling, promotes dendritic spine remodeling, and reduces synaptic AMPA receptors. More recent work has identified additional Plk2-dependent mechanisms that destabilize excitatory synapses during homeostatic adaptation.
By defining how Plk2 coordinates these compensatory responses, we aim to understand how neurons maintain circuit stability while preserving the capacity for plasticity and memory. These mechanisms may also reveal how failures of neuronal homeostasis contribute to neurological and neurodegenerative disease.
HOMEOSTATIC REGULATION OF NEURAL CIRCUITS
SYNAPTIC DYSFUNCTION IN AGING AND DISEASE
Synaptic dysfunction is an early and critical feature of many neurodegenerative disorders. The Pak Lab investigates how pathways that regulate neuronal activity and synaptic stability become altered during disease, with a particular focus on the relationship between neuronal hyperexcitability, Polo-like kinase 2 (Plk2), and tau.
Our recent work identified a cluster of phosphorylation sites within the C-terminal region of tau that is rapidly modified during neuronal hyperexcitation. These modifications influence tau localization to dendrites and alter excitatory postsynaptic sites. We further found that Plk2 inhibition blocks hyperexcitation-induced phosphorylation of this region, linking neuronal homeostatic signaling to activity-dependent changes in tau biology.
Building on these findings, we are investigating how neuronal activity and homeostatic signaling influence tau phosphorylation, localization, and propagation between neurons. By defining mechanisms that regulate the generation and spread of pathogenic tau, we aim to understand how altered responses to neuronal activity contribute to the progression of tau pathology and cognitive decline in Alzheimer’s disease and related neurodegenerative disorders.
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