Early synaptic pathophysiology in neurodegeneration: insights from Huntington's disease

Investigations of synaptic transmission and plasticity in mouse models of Huntington's disease (HD) demonstrate neuronal dysfunction long before the onset of classical disease indicators. Similarly, recent human studies reveal synaptic dysfunction decades before predicted clinical diagnosis in HD gene carriers. These studies guide premanifest tracking of disease and the development of treatment assessment tools. New discoveries of mechanisms underlying early neuronal dysfunction, including elevated pathogenic extrasynaptic NMDA receptor signaling, reduced synaptic connectivity and loss of brain-derived neurotrophic factor (BDNF) support have led to pharmacological interventions that can reverse or delay phenotype onset and disease progression in HD mice. Further understanding the primary effects of gene mutations associated with late-onset neurodegeneration should translate to novel treatments for HD families and guide therapeutic strategies for other neurodegenerative diseases.

Introduction

The prevention of cell death is a holy grail for neurodegenerative disease research. Even so, it is unlikely that cells in a diseased brain will perform adequately until the moment they expire. Cell death in classically degenerative conditions could be a result of protracted pathophysiology, and attempts to preserve dysfunctional elements of crucial neural circuits might be futile or even harmful. Current research into Huntington's disease (HD) demonstrates cognitive disturbances in HD patients long before onset of overt motor manifestations 1, 2, 3. Furthermore, neuronal and synaptic dysfunction precedes cell death by many years in humans 2, 3 and occurs long before, or in the absence of, cell death in HD animal models (Figure 1) 4, 5, 6, 7. Recent studies suggest that pharmacological interventions targeting early and putative pathophysiological disturbances in HD-like mouse models (hereafter referred to as HD mice) can reverse neuronal dysfunction 8, 9 and delay progression to neurodegeneration [10]. It is hoped that new insights in understanding the molecular and cellular dysfunction that takes place in HD will stimulate further investigation of early pathophysiological changes in this, and other, classically degenerative disorders.

This review is restricted to addressing recent advances in understanding synaptic dysfunction in HD; the rich literature concerning HD genetics, pathology and mouse models is excellently reviewed elsewhere 11, 12, 13, 14. This terminal disease is characterized by late-onset motor dysfunction, dementia and the prominent degeneration of medium-sized spiny neurons (MSNs) in the striatum and, to a lesser extent, of cortical pyramidal neurons. Although HD is a severe neurodegenerative disease for which there is currently no cure, recent studies suggest that early cognitive deficits occur years prior to cell death or overt neurological symptoms, probably due to synaptic and cellular dysfunction 1, 2, 3.