Glial Contribution to Excitatory and Inhibitory Synapse Loss in Neurodegeneration

Abstract

Synapse loss is an early feature shared by many neurodegenerative diseases, and it represents the major correlate of cognitive impairment. Recent studies reveal that microglia and astrocytes play a major role in synapse elimination, contributing to network dysfunction associated with neurodegeneration. Excitatory and inhibitory activity can be affected by glia-mediated synapse loss, resulting in imbalanced synaptic transmission and subsequent synaptic dysfunction. Here, we review the recent literature on the contribution of glia to excitatory/inhibitory imbalance, in the context of the most common neurodegenerative disorders. A better understanding of the mechanisms underlying pathological synapse loss will be instrumental to design targeted therapeutic interventions, taking in account the emerging roles of microglia and astrocytes in synapse remodeling.

Keywords: E/I imbalance; astrocytes; microglia; neurodegeneration; synapse loss.

Figure 1

Glial control of synaptic homoeostasis. Synapses exists as tri- or even quad-partite structures with glial processes in direct contact with neuronal components. Glia play important roles in regulating efficient neurotransmitter release and clearance, as well as providing trophic factors to ensure healthy function. Furthermore, during development glia prune away excess synapses and by doing so, fine-tune the excitatory/inhibitory balance within developing neuronal networks.

Figure 2

Pathophysiology of Alzheimer’s disease (AD). The build-up of pathological amyloid and tau species leads to neurodegeneration via numerous autonomous and non-autonomous pathways. Glial cells release pro-inflammatory mediators and lose their ability to regulate glutamate homeostasis, leading to synaptic dysfunction. Furthermore, the synaptic accumulation of proteins from the complement system leads to glial-dependent synapse engulfment and loss.

Figure 3

Pathophysiology of Parkinson’s disease (PD). Anatomically, PD is characterized by a loss of striatal dopaminergic neurons. This can lead to disruption of excitatory and inhibitory circuits, resulting in the clinical motor symptoms. Loss of glutamatergic synapses is apparent in the striatum and aggregates of α-synuclein (α-syn) are observed in the brains of patients. Furthermore, evidence suggests α-syn accumulates at the synapse, where both astrocytes and microglia have been shown to engulf α-syn-containing synaptic material.

Figure 4

Pathophysiology of amyotrophic lateral sclerosis (ALS). ALS is characterized by the breakdown of motor neurons in the motor cortex and spinal cord. Gliosis and cortical hyperexcitability are early features of the ALS brain and aggregates of TDP-43 are found in almost all patients. TDP-43 has been found at human synapses in ALS and the removal of TDP-43 from microglia leads to hyperphagocytic cells that engulf synapses. Microglia have been shown to engulf neuronally-derived TDP43. Interestingly, synapse loss is an early feature of ALS and observed in both the central and peripheral nervous systems.

Figure 5

Pathophysiology of multiple sclerosis (MS). While myelin loss is a central feature of MS pathology, it is accompanied by neurodegeneration, gliosis and immune cell (B-cells and T-cells) infiltration. Release of pro-inflammatory mediators and disrupted glutamate handling by glial cells leads to a toxic neuronal milieu. Furthermore, there is evidence that microglia are involved in complement-dependent synapse engulfment.

Figure 6

Glial Influence on excitatory/inhibitory balance. Under physiological conditions, glial cells play important roles in the control of neuronal physiology, resulting in a well-controlled balance of excitatory/inhibitory neuronal networks. However, under pathological conditions as described in some of the diseases here, glial cells become hyperactive and damage surrounding neurons. This results in a dramatic tip of the balance depending on whether excitatory or inhibitory cells are disproportionally affected in the network.