User:CorinneMarieClifford/Low-threshold spikes

Project Proposal This is the proposal for our group project that will entail updating, expanding, and reformatting the current Wikipedia page for Low-threshold spikes. This is a group project and as such each group member will be responsible for researching and writing the new article. We will meet throughout the semester to accomplish this.

The following is a representation of what our proposed page will look like.

T-type calcium channel
The T-type calcium channel is found in neurons throughout the brain. These channels produce particularly large currents in thalamic, septal, and sesnory neurons. Due to their activation near the resting membrane potential, as well as their fast recovery from inactivation, they are able to generate low-threshold spikes. Low threshold spikes result in a burst of action potentials.

T-type channels play a secondary pacemaker role in neurons that have resting membrane potential between -90 and -70 mV as they have an important role in the genesis of burst firing. An excitatory postsynaptic potential (EPSP) opens the channels, thus generating a LTS. The LTS activates Na+-dependent action potentials and high-voltage activated calcium channels.

History
Evidence for low-threshold calcium current was first described in neurons of the inferior olivary nucleus (1981). This nucleus generates synchronous rhythmic activity which under certain conditions is manifested as a tremor.

Physiology
Low-threshold spikes refer to a phenomenon that occurs in neurons as a result of a certain membrane hyperpolarization. This hyperpolarization can be the result of decreased excitability or increased inhibition. This hyperpolarization results in a deactivation of the calcium channels and the result which results in "spike bursts".

Rhythmogenesis
Rythmogenesis in a neuron is due to an instability associated with the resting potential. Such instability can be attributed to properties of low-threshold calcium currents. The current is activated at around -60 mV making it able to generate a low-threshold spike at or near the resting potential.

A somewhat recent finding is the presence of intrinsic rhythmicity. This occurs when the cells are maintained at a hyperpolarized level. This results in spontaneous oscillatory behavior as a result of Ca2+ driven depolarizations. This results in single or short bursts of spikes, then hyperpolarization and then repolarization before the next burst.

LTS Kinetics
LTS is a large depolarization due to an increase in Ca2+ conductance, so LTS is mediated by Ca2+ conductance. The spike is typically crowned by a burst of two to seven action potentials, which is known as a Low-threshold burst. LTS is voltage dependent and is inactivated if the cell's resting membrane potential is more depolarized than -60mV; LTS is deinactivated if the cell is hyperpolarized and can be activated by depolarization such as from an excitatory postsynaptic potential (EPSP).

It has been determined experimentally that five ionic currents contribute to low-threshold spikes, generating three distinct phases after hyperpolariztion. Transient outward K+ currents following an action potential can cause hyperpolariztion, allowing for low-threshold spikes. An initial ohmic leakage current composed of K+ and Na+ ions characterizes the first phase. This is followed by a hyperpolarization-activated “sag” current that contributes to slowly depolarizing the membrane potential. An inward Ca2+ current through T-type calcium channels is the last phase, and the main current responsible for the large transient depolarization. This overrides the other currents once the T-type channels are activated. Other currents primarily affect the activation of the LTS.

Low-threshold spikes generate burst firing
Low-threshold calcium spikes (LTS) have been described in neurons from a variety of brain nuclei, including: inferior olive, thalamic relay, medial pontine reticular formation, lateral habenula, septum, deep cerebellar nuclei, CA1-CA3 of the hippocampus, association cortex, paraventricular and preoptic nuclei of the hypothalmus, dorsal raphe, globus pallidus, and subthalamic nucleus.

Thalamic relay cells show two types of responses. One response mode is a relay or tonic mode, in which the cell is depolarized and LTS are inactivated. This leads to tonic firing of action potentials. The second response is a burst mode, in which the cell is hyperpolarized and typically responds with LTS and their associated bursts of action potentials.

In general, LTS cannot be triggered by depolarization of the neuron from the resting membrane potential. LTS is observed after a hyperpolarizing pulse is delivered to the neuronal cell, which is called "deinactivation" and is a result of channels recovering from inactivation.

LTS are often triggered after an inhibitory postsynaptic potential (IPSP) due to the fast recovery of T-type calcium channels during the IPSP and their opening as there is a return to resting membrane potential.

There is a strong correlation between LTS amplitude and the number of action potentials that result from a LTS. There is much more depolarization of T channels near the dendritic location of activated receptors than at the soma. The activation of either metabotropic glutamate or muscarinic receptors results in a hyperpolarizing shift in the relationship between LTS amplitude and the initial potential of the membrane. This affects the maximum LTS amplitude. This means that there is a dependency between the LTS amplitude and voltage, and therefore the resulting number of action potentials generated.

LTS is mediated by a Ca2+ conductance
When the hypolarization of the membrane in these interneurons is maintained at a certain level calcium conductance is reduced, if not completely inactivated. This results in the membrane polarization not being in the right range for single spikes and hence "bursts" result. The LTS therefore is dependent upon the conductance of calcium.

Serotonin Inhibition of the Low-threshold spike
Low-threshold spike interneurons make up the striatum. The striatum is a nucleus in the basal ganglia which is located in the forebrain. The basal ganglia serves many functions some of which include involuntary motor control, emotions, and cognition. These interneurons produce nitric-oxide and they are modulated by neurotransmitters, specifically serotonin, released from the brainstem. Seratonin serves to inhibit these interneurons. This was studied using transgenic mice in which these nitric oxide interneurons were labeled green using green fluorescent protein (GFP). Serotonin binds to a serotonin receptor on the interneuron (5-HT2c) and this increases potassium conductance therefore decreasing the excitability of the neuron.

Research
Much of the research done on Low-Threshold Spikes has examined cells of a cat’s lateral geniculate nucleus. All thalamic relay cells experience these specific voltage-dependent calcium currents and the cat has proven a useful model species for study. Different variations of current clamp methods, in addition to model simulations have shed light on many aspects of the phenomena.

Amplitude of the Ca2+ spike
The amplitude of LTS’s have been shown to directly correlate with the size of it, the transient Ca2+ current that underlies the LTS in certain neuronal cells. They are triggered by a combination of a hyperpolarized membrane, or de-inactivation of Ca2+ channels, and a suprathreshold depolarizing input. The amplitude of the Ca2+ spike is therefore only dependent on the level of preceding membrane hyperpolarization, and the depolarizing input.

However, it has been demonstrated that the LTS’s are all-or-none events due to the regenerative nature of It, and along with the action potentials that follow them, vary little in amplitude or shape at different holding potentials. This dictates that suprathreshold depolarizing inputs do not affect the amplitude, and only factor into the initial activation of the LTS. The amount of de-inactivation determines the conductance of Ca2+ channels and is the main factor that contributes to the amplitude of LTS’s. It has also been shown that the activity of delayed rectifier K+ channels can affect the amplitude of LTS’s.

Burst firing caused by LTS’s are therefore thought to be used as on/off signaling as opposed to tonic firing which is graded and more responsive to the intensity of depolarizing inputs.

Latency of the Ca2+ spike
The latency of a LTS is the amount of time between the depolarizing pulse and it’s peak. It has been shown that unlike amplitude, it is directly affected by the size of the initial depolarizing current. This is derived from the interaction between the initial, outward ohmic response, which is the leakage K+ ions out of the cell in response to change in membrane potential, and the voltage dependent-gating of It.

Latency is decreased with an increased depolarizing current, which overruns the outward ohmic current and quicker depolarizes the membrane. This quicker activates the exponential growth of It. This reduction occurs more sharply with depolarizing currents closer to the threshold and more gradually as current injections are increased beyond threshold. Latency cannot be further reduced beyond a certain depolarizing current, and becomes nearly uniform any greater current.

This has lead to the hypothesis that burst signaling as a result of LTS’s with stronger activating inputs are more stable than LTS’s as a result of near-threshold activating inputs.

Parkinson's Disease
The thalamus is responsible for relaying sensory and motor signals to the cerebral cortex. Therefore, much research has been conducted on low-threshold spikes (LTS) in the neurons in the thalamus and how it could relate to Parkinson's disease and the corresponding loss of motor function.

LTS have been found to occur in the human lateral thalamus during sleep; however, they fade as soon as the patient is awakened. Abnormal LTS bursting activities that have been noted in awake parkinsonian patients suggests a relation between the clinical condition and this neuronal activity.

Division of Workload
We will meet weekly to discuss and research these areas that we have outlined. We will assign equal work to each member of the group to do further outside research on a particular topic and to add those findings to the page.