Björn Granseth

Dynamic control of synaptic strength in a neuronal network

The human brain is a vast and complicated communications-network where more than one hundred billion neurons process information essential for our survival. The neuronal regulation of respiration and circulation are obvious examples of the brain’s direct role in upholding life. But one must not forget that neuronal activity that manifest as emotions and abstract reasoning is also life-upholding: they have a direct role for healthy interpersonal interactions in family and society.

The processing of information by the neuronal networks of the brain depends on the arrangement of excitatory and inhibitory neurons, the active and passive electrochemical integration of excitatory and inhibitory input for these neurons and the signal transfer from one neuron to the next. The specialised structures for communication between nerve cells are called synapses. A nerve cell use electricity to transmit a signal to a remote location with its nerve fibre but the communication to the next is usually chemical in nature. At the terminal end of the nerve fibre there are swellings, called pre-synaptic boutons, that are filled with hundreds of small vesicles. These vesicles contains neurotransmitter molecules and when the presynaptic bouton is depolarized by an action potential, voltage gated calcium ion channels open and the resulting increase of calcium in the bouton makes the vesicles release neurotransmitter to the receiving cell.

Since Katz discovered that exocytosis of synaptic vesicles is the basic mechanism for communication between nerve cells, an abundance of membrane-bound proteins have been identified at this organelle. These molecules have many interaction-partners in the cytosol and at the pre-synaptic membrane that regulate and coordinate neurotransmitter release. Even though all synapses in the nervous system share the same basic mechanism of communication, vesicle release, they can vary considerably with regard to how much transmitter is released. Some synapses reliably release transmitter every time they are depolarised by an action potential. Other synapses are more reluctant to do so.

This difference most likely comes from differences in the molecular reactions that regulate vesicle availability and trigger exocytosis. When a synapse is reached by many action potentials in a short period of time other molecular reactions, such as those that supply new vesicles to be released and remove vesicle membrane from the release site, become important for the capacity of the synapse to release transmitter. Some synapses increase in strength during bursts of action potentials, other release transmitter only for the first few action potentials but cannot maintain this for the remainder in the burst. This dynamic change in synaptic strength during repetitive action potential firing is known as short-term plasticity. The molecular mechanisms are not known but it seems likely that the different dynamics in transmitter release between synapse-types comes from the fact that different reactions are rate limiting in triggering exocytosis and making new vesicles available for exocytosis.

The neuronal networks of the brain process information encoded as action potentials. Short-term synaptic plasticity regulates how the signal is transferred from one neuron to the next but the response in the receiving cell is ultimately under the control of the molecular properties of this neuron. Ion channels regulated by neurotransmitter binding, membrane voltage or molecules inside or outside the cell decide when and how the neuron will fire an action potential. Some neurons fire a burst of action potentials when depolarised, other neurons send off only a few. The dynamic nature of network activity is thus dependent on the kinetics of molecular reactions in both pre- and post-synaptic neurons. The overall objective for the laboratory I am currently setting-up at Linköping University is to study the dynamic regulation of neuronal activity in the circuit that connects the thalamus to the primary sensory areas of the neocortex.

Almost all input to the neocortex, except for olfaction, pass through the thalamus before reaching the cerebral cortex. Even though the specific neuronal mechanism for sensory perception and consciousness remains unknown, most neuroscientists agree that neocortical processing is an absolute requirement for this to occur. The strategic position of the thalamus, at the entrance to the cerebral cortex, has produced the idea that it functions as a gate to consciousness. Crick gave formal structure to this idea in the “searchlight hypothesis”, where the thalamic gate is under the control of a gatekeeper: the neuronal circuit that connects the thalamus and cortex. The recurrent excitatory feedback from pyramidal neurons in layer 6 of primary sensory areas would enhance the transfer to cortex and recurrent inhibition from neurons residing in the thalamic reticular nucleus would reduce the relay.