Intrinsic plasticity of neuronal excitability in the auditory brainstem and neocortex: nitrergic signalling to voltage-gated potassium channels

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Many people suffer from brain diseases caused by over-excitability (e.g. tinnitus, epilepsy or attention deficit hyperactivity disorder) exemplifying a fundamental problem: How does the brain keep a balance between too much and too little activity (e.g. epilepsy vs coma)? Maintaining this balance or equilibrium is known as "Homeostasis" (like keeping the correct body temperature: too hot or too cold is bad for you). In the brain too an imbalance of activity is associated with disease and dementia.Brain cells (neurons) receive information from their neighbours via chemical messengers (neurotransmitters) released at specialised contacts called synapses. We know a lot about how synapses work: excitatory synapses release a messenger called glutamate and this excites the target neuron to trigger an electrical pulse (action potential, AP). This AP then propagates along the neuronal process (axon) to the next set of synapses on other neurons. Thus networks of interconnected neurons pass information to each other; neurons use electrical pulses for internal information transmission and chemical messengers at synapses to communicate with each other. If a neuron receives lots of synapses then it should fire many APs, and scientists have shown that changing the strength of the synapses (giving more or less excitation) underlies learning and memory - this is often called synaptic plasticity. But how does a neuron know when to fire an AP? The action potential is generated by a class of proteins known as Voltage-Gated Ion Channels: sodium channels start the AP and potassium channels terminate it. Potassium channels are crucial regulators of neuronal excitability; they determine when it fires APs, how many it fires and how long they last. There are around 40 genes specifying different potasium channels, so they are difficult to study in 'real' neurons. The summed activity of all ion channels in a neuron determines its "intrinsic excitability" and changes in this are called "intrinsic plasticity" (in analogy with synaptic plasticity). So the brain can modify synaptic strength by a process of synaptic plasticity and adjust its ability to fire APs by changing intrinsic plasticity. Although scientists know a lot about synaptic plasticity, intrinsic plasticity has only recently been recognised as playing a significant role.We have shown that one messenger for this intrinsic plasticity is the chamical nitric oxide (NO). NO has many physiological roles in the immune, cardiovascular, reproductive and alimentary systems. NO acts on its receptor, guanylyl cyclase to generate cGMP and activates protein kinase G (PKG). These and other kinases change protein structure, activity or trafficking by adding phosphate groups.My laboratory has studies two channel families called Kv2 and Kv3 (KvX - stands for voltage-gated potassium channel family 2 or 3, respectively). These channels 'pull' the voltage back down to the resting voltage (around -70mV) after an AP so as to prepare the neuron for the next AP. We have discovered that an excitatory synaptic messenger (glutamate) causes some neurons to make NO and this signals to surrounding neurons to change from using Kv3 to Kv2 channels; i.e. the synapse has triggered intrinsic plasticity. We have spent 6 years tacking down how this is achieved at one type of synapse in the auditory pathway. Recently we showed that the same process is occurring in the hippocampus (which is the old part of the neocortex). We have developed many molecular tools and are now ready to determine the broader significance of this phenomenon for cortical function (using that part concerned with hearing - the auditory cortex) and how it contributes to disease and injury processes such as deafness (in the auditory brainstem) and tinnitus or epilepsy in the higher brain areas.Our work is an example of how fundamental research is necessary to understand mechanisms of disease.