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.

Keywords: Alzheimer’s; Huntington’s; Parkinson’s; amyotrophic lateral sclerosis; neurodegeneration; synaptic plasticity; synaptic scaling.

Figure 1

A potential role for homeostatic synaptic plasticity (HSP) in Alzheimer’s disease (AD) pathogenesis. The left panel shows a glutamatergic synapse under normal physiological conditions. The right panel shows a synapse during the early stages of AD. There is enhanced synaptic activity in affected networks, with increased synaptic glutamate release. This would normally be compensated by one or more mechanisms of HSP but if these fail, as many appear to in the context of AD, then elevated synaptic release persists and can drive a downregulation of postsynaptic strength via various mechanisms including postsynaptic mechanisms of HSP that remain intact, or potentially even recruitment of Hebbian plasticity (LTD). This internalization of glutamate receptors (AMPAR/NMDAR) could alter the ability of the synapse to support (further) Hebbian plasticity, with resultant effects on learning and cognition. Image created with Biorender.com. LTD, long term depression.

Figure 2

Induction of homeostatic synaptic plasticity (HSP) can support the functioning of neuronal networks and/or populations of synapses in the context of synaptic degeneration. (A) Heterosynaptic and cell non-autonomous induction of HSP supports the function of basal ganglia circuits following degeneration of dopaminergic synapses in Parkinson’s disease (PD). One example of this is shown involving synapses of the indirect pathway, which serves to negatively regulate voluntary movement. In models of PD, the strength of glutamatergic corticostriatal synapses onto medium spiny neurons is scaled down via mechanisms of HSP to compensate for the loss of D2 receptor-dependent inhibition (conceptually represented in the left panel as an inhibitory potential) of the same neuron by the degenerating nigrostriatal dopaminergic projections (right panel). Thus, heterosynaptic induction of HSP ensures that the overall strength of excitatory postsynaptic potentials (EPSPs) measured at the medium spiny neuron soma is preserved. (B) Induction of HSP at the degenerating neuromuscular junction (NMJ) supports motor function and opposes disease progression in amyotrophic lateral sclerosis (ALS) pathogenesis. The left panel shows the NMJ under physiological conditions. The right panel represents early stage ALS, in which innervation of the muscle and motor function is compromised by the loss of motor neuron synapses. This results in the induction of presynaptic HSP in remaining synaptic terminals via the membrane insertion of epithelial sodium channels (ENaC) that constitutively depolarise the presynaptic membrane (ΔV_m) and augment neurotransmitter release. This serves to: (1) preserve the strength of degenerating synapses; and/or (2) maintain normal or near-normal levels of postsynaptic depolarisation and end plate potentials (EPP) despite the loss of synaptic terminals, as shown here. Image created with Biorender.com.