Alzheimer?s disease (AD) is a highly prevalent neurodegenerative disease, characterized by learning and memory deficits and the pathological accumulation of amyloid beta (A?) protein. Accounting for 60-70% of cases of dementia, the disease has a rapidly expected increase in prevalence and cost to public health as world-wide life expectancy increases. The cause of memory dysfunction in the disease is poorly understood however, particularly at an early time-point of amyloid accumulation. In mouse models of AD, at ages preceding neuronal or synaptic loss, there have been observed alterations in hippocampal sharp wave ripples (SWRs), neuronal population events with a critical role in memory consolidation. The mechanisms underlying this disruption are relatively unexplored however, a critical gap that the research proposed in this fellowship will examine. While it is well-appreciated that amyloid accumulation impairs the synaptic function of excitatory pyramidal cells (PCs), there is growing evidence that inhibitory GABAergic cells are also compromised. Amyloid accumulation has been shown to disrupt the activity of parvalbumin (PV) expressing inhibitory basket cells (PVBCs), cells which have a critical role in regulating SWR events. PV cells are unique in that they are the major neuronal subtype ensheathed in peri-neuronal nets (PNNs), part of the extracellular matrix of proteins that regulate and support cellular activity. This proposal will explore if a preferential amyloid-induced disruption to PVBCs and the PNNs that surround them can account for alterations to SWR events. Parallel biochemical and electrophysiological studies will seek to determine if reduced excitatory input to this cell type results in decreased inhibitory drive to the hippocampal network, potentially causing the hyperexcitable activity often observed in early amyloid pathology. This mechanism will be further explored by monitoring the activity of excitatory PCs, both through patch clamp electrophysiology and calcium imaging to record ensemble dynamics. A biophysical computational model will determine if the proposed PVBC-PC mechanism is sufficient to explain observed SWR and ensemble disruption. The training proposed in the advanced techniques of whole-cell biocytin-injection and computational modeling will facilitate the determination of the neuronal mechanisms underlying hippocampal network disruption in early amyloid pathology. As this activity is critical for memory consolidation, these findings will provide a therapeutic target to potentially ameliorate memory decline.
The research proposed for this fellowship will determine the mechanisms underlying hippocampal network dysfunction in early amyloid pathology. The experiments will assess whether a preferential impairment of a specific inhibitory neuronal sub-type and the extracellular matrix of proteins surrounding them can account for dysregulation of ensemble activity that is critical for memory consolidation. The results will identify a target for therapeutic intervention to potentially ameliorate memory decline.
