For much of the past century the focus of neuroscience was on the role of neurons in brain function. This bias was based on technical limitations. In the first half of the 20th century electrical recording and stimulation techniques were available; consequently, scientists manipulated the electrically active neuron. Glia – from the Greek word for “glue” and which represent 90% of the human brain volume, are electrically silent. Glia were therefore mute in these experiments. They were considered to be merely support cells for neurons or packing material. However, the tide turned in the early 1990s with the development of dynamic imaging strategies that could be applied to study the chemical excitability of glia. Advances occurred on two fronts – the development of sensitive cameras and the development of fluorescent Ca2+ sensitive indicators. This permitted imaging of Ca2+ excitability and allowed laboratories to observe Ca2+ signals in glia in response to neurotransmitters. This breakthrough discovery began a change in emphasis as it was realized that glia are active and “listen to” synaptic activity. But do glia talk back? In 1994 co-founder of GliaCure, Phil Haydon, discovered that glia speak as well as listen. He showed that the Ca2+ signals induced by neurotransmitters stimulate the release of gliotransmitters that in turn provide a feedback loop to the neuron. This pivotal discovery set the stage for the formation of GliaCure 17 years later.
Different glia, different jobs
Glial cells are currently divided into several different classes based on structural and functional distinctions. In the peripheral nervous system myelination of axons is performed by Schwann cells. In the central nervous system (CNS), myelination is performed by oligodendrocytes. The CNS also controls NG2 glia, whose roles are still being defined. GliaCure’s focus is on two types of glia: astrocytes and microglia.
Astrocytes are the most plentiful glial cell in the CNS and serve many functions: they clear neurotransmitters from the synapse, regulate local blood flow in response to neuronal activity and provide energy substrates to neurons. Astrocytes also release numerous gliotransmitters including glutamate, ATP which gives rise to adenosine, D-serine, and TNFα.
Gliotransmission is now known to regulate many brain functions including synaptic plasticity, neural network activity and sleep. Their ability to control sleep gives them a significant behavioral role that is of fundamental importance to the GliaCure drug discovery pipeline.
Sleep is controlled by at least two processes: the circadian oscillator, which regulates the timing of sleep/wake cycles (jetlag results from an offset between the circadian clock and local time after travel across time zones), and the sleep homeostat, which controls the pressure to sleep. GliaCure scientists discovered that astrocytes regulate sleep homeostasis by regulating the extracellular concentration of adenosine.
Because sleep disorders are co-morbid with many disorders of the brain – Parkinson’s and Alzheimer’s disease, depression and relapse from alcohol withdrawal, for instance – GliaCure is focusing on astrocytic targets as a novel strategy to combat these sleep abnormalities.
Microglia are innate immune cells of the nervous system that play a variety of roles in brain function. In particular, and of greatest interest to GliaCure, is their ability to respond to tissue injury and to phagocytose material. In the Alzheimer’s brain, microglia surround amyloid plaques. GliaCure scientists are investigating the potential for directing therapeutics to microglial receptors in order to stimulate phagocytosis to clear the brain of these plaques. We are currently optimizing lead compounds and preparing this work for IND-enabling studies for Phase I clinical trials.