Evolution of synaptic models: from neuronal communication to the role of glial cells in synaptic function and neurological disorders
| Era/Model | Key concepts | Key players | Main mechanisms | Notable findings | Implications for neurological disorders | References |
|---|---|---|---|---|---|---|
| Early synaptic model | Synapse as a site of communication between pre- and post-synaptic neurons | Neurons | Neurotransmitter release, receptor activation | Focus on direct synaptic communication via neurotransmitter release and downstream effects | Limited scope, failed to account for contributions from glial cells in synaptic function | [92, 93] |
| Tripartite synapse model (astrocytes and neurons) (2000s) | Inclusion of astrocytes as active participants in synaptic communication | Neurons, astrocytes | Gliotransmitter release, astrocyte involvement in synaptic plasticity | Astrocytes play an active role in synaptic activity by detecting and responding to neurotransmitter levels, modulating plasticity | Introduced the idea of glial cells’ involvement in synaptic modulation | [94–96] |
| Modified tripartite synapse model (neurons and microglia) (2000s–2010s) | Recognition of microglia as regulators of synaptic function and plasticity | Neurons, microglia | Microglial surveillance, synaptic pruning, cytokine-mediated signaling | Microglia monitor and eliminate weak synapses, playing a role in synaptic remodeling | Dysregulated microglial activity contributes to neurodevelopmental disorders and neurodegenerative diseases | [97, 98] |
| Quadripartite synapse model (2010s) | Extension to include microglia in synaptic function | Neurons, astrocytes, microglia | ATP-driven purinergic signaling, synaptic maintenance and pruning | Microglia actively participate in synaptic signaling and plasticity, contributing to both health and pathology | Provides a more holistic view of synaptic communication, involving immune and neuroinflammatory responses | [22, 99] |
| Purinergic signaling in quadripartite synapse | ATP as a key signaling molecule among neurons, astrocytes, and microglia | Neurons, astrocytes, microglia | ATP release during neuronal activity, microglial recruitment via P2Y12 receptors | ATP release directs microglial processes toward active synapses, influencing plasticity and hyperactivity in disorders like epilepsy | Disruption of ATP signaling and glial synchronization can lead to disorders like epilepsy and neurodegeneration | [75, 80, 100] |
| Astrocyte-microglial crosstalk | Dynamic interaction between astrocytes and microglia via ATP | Astrocytes, microglia | Modulation of microglial responses to neurotransmission (glutamatergic and GABAergic) | Astrocytes can enhance or suppress microglial activity, maintaining synaptic balance | Disruptions in crosstalk contribute to pathologies like epilepsy, and neurodegenerative diseases | [80, 101] |
| Neuroimmune modulation | Role of glial cells in neuroprotection and response to injury | Astrocytes, microglia | Release of protective molecules (IL-6) and ATP in response to inflammation or injury | Glial cells coordinate protective responses to neurotoxic stimuli and maintain neuronal health | Imbalances in glial responses contribute to inflammatory diseases and worsen neuronal damage in conditions like neurodegeneration and injury | [80, 102, 103] |
| Disruptions in synaptic homeostasis | Alterations in glial cell function contribute to disease | Neurons, astrocytes, microglia | Disruption of synaptic balance via glial dysfunction | Loss of synchrony between astrocytes and microglia can lead to hyperexcitable synapses, as in epilepsy | Implicates glial dysfunction in diseases such as epilepsy, neurodegeneration, and neuroinflammatory conditions | [74, 104, 105] |
IL-6: interleukin-6
