Our brain is constantly changing, adjusting to the environment based on input. At the same time, there seems to be mechanisms in place to resist change. At the junctions between neurons and their targets, known as “synapses”, there are mechanisms to ensure that the amount of signal sent from neurons and the sensitivity of the target cells are in constant balance. There is increased interest in how this homeostatic mechanism changes with age, as disruption in synaptic homeostasis may be causal to disease. Hence it may be possible to increase lifespan via interventions that restore optimal activity of synapses.
Drosophila melanogaster (fruit fly) is an attractive model organism for looking at synaptic regulation. Many of the genes involved in synaptic transmission and development are conserved between the fly and vertebrates. The neuromuscular junctions (synaptic formation between motor neurons and muscle cells) are easy to identify, and allow for direct recording of electrical activity in neurons and in muscle. An added bonus is the ability to genetically manipulate the post-synaptic cell separately from the presynaptic cell (and vice versa), thanks to availability of genetic switches specific to the muscle and the neuron.
In 2012, Dr. Pejmun Haghighi’s lab at the Buck Institute reported the role of TOR (target of rapamycin), a well-known gene in the aging field, in synaptic regulation. Normally, flies lacking a component of the glutamate receptor in muscle show reduced sensitivity to glutamate release. Neurons compensate for this by increasing the amount of neurotransmitter (NT) released. This change in the presynaptic function in response to postsynaptic deficit suggests some sort of retrograde signaling to maintain synaptic homeostasis. This homeostatic maintenance was disrupted in flies lacking TOR in the muscle. In contrast, over-expression of TOR in the muscle increased the amount of NT released. The researchers suggested that activation of TOR (and its downstream target S6K) results in retrograde signaling that leads to an increase in NT release.
Involvement of TOR in increasing synaptic function is particularly interesting in light of the association of TOR inhibition and longevity. Disruption of the TOR pathway in yeast, nematodes, fruit flies, and mice increases lifespan significantly. Could the benefits of reducing TOR activity in part be explained by TOR’s role in increasing synaptic function?
While it may sound paradoxical, increased synaptic function is not necessarily better for the organism. Synaptic transmission is energetically demanding; ATP is required for vesicular sorting of NTs, docking and release of NT vesicles, maintenance of ionic balance in the cells, and the list goes on. Additionally, release of neurotransmitters is calcium dependent; a wave of depolarization (called the action potential) increases the local membrane potential in the presynaptic axon terminal, opening calcium gated ion channels. Calcium ions can activate components of the exocytosis mechanism to release NTs into the synapse. Increased energy demands and calcium concentration can be toxic to cells, and continued stress over lifetime may prove to be harmful. This idea of increased synaptic function contributing to neuronal damage may underlie some of the neurological disorders associated with age.
In a Drosophila model of Huntington’s Disease, Romero et al. reported that flies expressing the expanded form of the huntingtin protein (the mutant form associated with disease) had increased NTs at the neuromuscular junction and faster decline in motor abilities. However, introducing a second mutation in genes involved in NT release brought back the synaptic function to the wild type fly level and rescued the motor decline phenotype. Increased synaptic function has also been reported in mouse Parkinson’s Disease models.
The model is still in its infancy, and doesn’t necessarily cover all neurodegenerative disorders. For example, reports are rather mixed for Amyotrophic Lateral Sclerosis (ALS) models, with data for both increased and decreased synaptic functions. There seems to be an overarching theme of disrupted synaptic function in neurodegenerative diseases, but whether this synaptic dysfunction is causal or consequential is still unknown.
For now, we can rest assured that increased synaptic function is not necessarily the same as increased cognitive activity. So we can continue to enjoy our Sudoku games without worrying about potentially damaging our neurons.