Friend or Foe? The Varied Faces of Homeostatic Synaptic Plasticity in Neurodegenerative Disease

Abstract

Homeostatic synaptic plasticity (HSP) regulates synaptic strength both pre- and postsynaptically to ensure stability and efficient information transfer in neural networks. A number of neurological diseases have been associated with deficits in HSP, particularly diseases characterised by episodic network instability such as migraine and epilepsy. Recently, it has become apparent that HSP also plays a role in many neurodegenerative diseases. In this mini review, we present an overview of the evidence linking HSP to each of the major neurodegenerative diseases, finding that HSP changes in each disease appear to belong to one of three broad functional categories: (1) deficits in HSP at degenerating synapses that contribute to pathogenesis or progression; (2) HSP induced in a heterosynaptic or cell non-autonomous manner to support the function of networks of which the degenerating synapses or cells are part; and (3) induction of HSP within the degenerating population of synapses to preserve function and to resist the impact of synapse loss. Understanding the varied manifestations of HSP in neurodegeneration will not only aid understanding mechanisms of disease but could also inspire much-needed novel approaches to therapy.

Association between theLRP1BandAPOEloci and the development of Parkinson’s disease dementia

“…The nearest genes of some of these variants are involved in pathways known to contribute to neurodegeneration, such as vesicle trafficking (VTI1A), ubiquitin signalling (DDB1), synaptic homeostasis (PTPRD), and endoplasmic reticulum protein quality control and translocation (UGGT2, SSR1). [59][60][61][62] Interestingly, SSR1 expression has recently been shown to be upregulated in an early Parkinson's disease mouse model and to be highly correlated with the loss of dopaminergic neurons. 63 An intronic variant in SLC6A3, which encodes the dopamine transporter (DAT), was also observed to be nominally associated with faster progression to dementia in Parkinson's disease.…”

ProSAAS is Preferentially Secreted from Neurons During Homeostatic Scaling and Reduces Amyloid Plaque Size in the 5xFAD Mouse Hippocampus

“…Homeostatic scaling is necessary to maintain synaptic function within a physiological limit; thus, this scaling capability is of great interest in the context of neurodegenerative diseases such as AD (4). As AD progresses, accumulation of toxic amyloid oligomers in the hippocampus results in altered thresholds for LTP and LTD; synapse loss; and impairment of homeostatic scaling (6,29,30).…”

“…Homeostatic plasticity is a widely accepted mechanism for long-term activity-dependent alterations in synaptic strength, and encompasses both long-term potentiation (LTP), and its analog, long-term depression (LTD) (3). Strong activity in both pre- and post-synaptic neurons is essential for reinforcement of these synapses; however, induced activity changes pose potential problems in terms of runaway excitation or uncontrolled synaptic pruning (reviewed in (4)). To prevent hyperactivity and uncontrolled synaptic refinement, neurons engage a negative feedback mechanism termed homeostatic synaptic plasticity to maintain neuronal activity within a physiological range.…”

“…Homeostatic mechanisms become defective in neurons expressing AD-related transgenes, as these neurons are unable to compensate for disruptions in network activity (6). The inability of neurons to constrain neuronal firing within a physiological limit leads to excessive strengthening or weakening of synapses, and eventually, neurological disorders (reviewed in (4)). Thus, the identification of the molecular players involved in synaptic plasticity is important not only for gaining insight into the maintenance of normal network activity, but for understanding homeostatic disturbances resulting from disease progression.…”

Brain DNA methylomic analysis of frontotemporal lobar degeneration revealsOTUD4in shared dysregulated signatures across pathological subtypes

“…DNA methylation has previously been suggested to be an important regulator of glutamatergic synaptic scaling (also known as homeostatic synaptic plasticity), with demethylation found to be associated with increased glutamatergic synapse strength in cultured neurons [52], we here find evidence supporting disruption of such processes in FTLD. Homeostatic synaptic plasticity has been linked to neurodegeneration, possibly with loss of function due to pathogenesis, or through an increase as a mechanism to preserve function despite neurodegenerative deficits [60]. There is a known link between RNA granule formation and synapse plasticity; with RNA-binding protein function known to be particularly important.…”