Low-threshold spikes

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Low-threshold spikes (LTS) refer to membrane depolarizations by the T-type calcium channel. LTS occur at low, negative, membrane depolarizations. They often follow a membrane hyperpolarization, which can be the result of decreased excitability or increased inhibition. LTS result in the neuron reaching the threshold for an action potential. LTS is a large depolarization due to an increase in Ca2+ conductance, so LTS is mediated by calcium (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 are voltage dependent and are inactivated if the cell's resting membrane potential is more depolarized than −60mV. LTS are deinactivated, or recover from inactivation, if the cell is hyperpolarized and can be activated by depolarizing inputs, such as excitatory postsynaptic potentials (EPSP). [1] LTS were discovered by Rodolfo Llinás and coworkers in the 1980s. [2] [3]

Contents

Physiology

Rhythmicity

Rhythmogenesis 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. [4]

In a somewhat recent finding, cells maintained at a hyperpolarized level have been shown to exhibit intrinsic rhythmicity, resulting in spontaneous oscillatory behavior due to Ca2+ driven depolarizations. As a result, one or more short bursts of spikes occur, followed by hyperpolarization, and then repolarization before the next burst. [5]

LTS kinetics

A study done by Gutierrez et al. examined the kinetics behind low-threshold spikes to better understand their significance towards normal functions of the brain. It has been determined experimentally that four ionic currents contribute to low-threshold spikes, generating three distinct phases after hyperpolarization. Transient outward K+ currents following action potentials can cause hyperpolarization, 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 T-type channels are activated. The other currents primarily affect the activation of the LTS. [6]

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 sensory 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, which results 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 triggers Na+-dependent action potentials and activates high-voltage activated calcium channels. [7]

Low-threshold spikes generate burst firing

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. Low-threshold calcium spikes have been described in neurons from a variety of brain nuclei, including the 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 hypothalamus, dorsal raphe, globus pallidus, striatum, 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. [8]

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. [9]

LTS is mediated by a Ca2+ conductance

When the hyperpolarization 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. [10]

Serotonin inhibition of the low-threshold spike

The striatum, a nucleus in the basal ganglia, contains low-threshold spike interneurons. The basal ganglia serve many functions, which include involuntary motor control, emotions, and cognition. These interneurons produce nitric oxide and are modulated by neurotransmitters, specifically serotonin, released from the brainstem. Serotonin serves to inhibit these interneurons. This was studied using transgenic mice in which nitric oxide interneurons were labeled green using green fluorescent protein (GFP). Serotonin binds to serotonin receptors on the interneuron (5-HT2c), which increases potassium conductance and subsequently decreases the excitability of the neuron. [11]

Research

Much of the research done on LTS 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 to be a useful model species to study. Different variations of current clamp methods, in addition to model simulations have shed light on many aspects of the phenomena.

Recent research has also been conducted on the T-type calcium channel and how modulation of these channels may allow for the treatment of various neurological and psychological disorders such as schizophrenia, dementia, mania, and epilepsy. This is, however, still a new area of research. [12] T-type calcium channels have been known to play a role in the spike-and-wave discharges of absence seizures. Antiepileptic drugs can control absence seizures by inhibiting the T-type calcium channels which prevents low-voltage calcium currents. [13]

Amplitude of the Ca2+ spike

The amplitude of LTS has been shown to directly correlate with the size of 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 predominantly dependent on the level of preceding membrane hyperpolarization and the depolarizing input.

However, it has been demonstrated that the LTS are all-or-none events due to the regenerative nature of the phenomenon. As with the action potentials that follow them, LTS 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. It has also been suggested that the activity of delayed rectifier K+ channels can affect the amplitude of LTS. Burst firing caused by LTS 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. [10]

Latency of the Ca2+ spike

The latency of a LTS is the amount of time between the depolarizing pulse and its 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 the T-type calcium channels.

Latency is decreased with an increased depolarizing current, which overruns the outward ohmic current and more quickly depolarizes the membrane. This more quickly activates the exponential growth of the Ca2+ spike. 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 with any larger current. This has led to the hypothesis that burst signaling as a result of LTS with stronger activating inputs is more stable than LTS due to near-threshold activating inputs. [10]

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 in the neurons in the thalamus and how it could relate to Parkinson's disease and the corresponding loss of motor function. Hypo-bradykinesia, as seen in Parkinson's disease, is improved by medial thalamotomy; this suggests that it is caused by interference of thalamic LTS bursts with cortical functions. [14]

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. [15]

Related Research Articles

Action potential Neuron communication by electric impulses

In physiology, an action potential (AP) occurs when the membrane potential of a specific cell location rapidly rises and falls. This depolarization then causes adjacent locations to similarly depolarize. Action potentials occur in several types of animal cells, called excitable cells, which include neurons, muscle cells, endocrine cells and in some plant cells.

Refractory period (physiology) Period of time after an organism performs an action before it is possible to perform again

Refractoriness is the fundamental property of any object of autowave nature not to respond on stimuli, if the object stays in the specific refractory state. In common sense, refractory period is the characteristic recovery time, a period that is associated with the motion of the image point on the left branch of the isocline .

An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential. IPSP were first investigated in motorneurons by David P. C. Lloyd, John Eccles and Rodolfo Llinás in the 1950s and 1960s. The opposite of an inhibitory postsynaptic potential is an excitatory postsynaptic potential (EPSP), which is a synaptic potential that makes a postsynaptic neuron more likely to generate an action potential. IPSPs can take place at all chemical synapses, which use the secretion of neurotransmitters to create cell to cell signalling. Inhibitory presynaptic neurons release neurotransmitters that then bind to the postsynaptic receptors; this induces a change in the permeability of the postsynaptic neuronal membrane to particular ions. An electric current that changes the postsynaptic membrane potential to create a more negative postsynaptic potential is generated, i.e. the postsynaptic membrane potential becomes more negative than the resting membrane potential, and this is called hyperpolarisation. To generate an action potential, the postsynaptic membrane must depolarize—the membrane potential must reach a voltage threshold more positive than the resting membrane potential. Therefore, hyperpolarisation of the postsynaptic membrane makes it less likely for depolarisation to sufficiently occur to generate an action potential in the postsynaptic neurone.

Membrane potential Type of physical quantity

Membrane potential is the difference in electric potential between the interior and the exterior of a biological cell. That is, there is a difference in the energy required for electric charges to move from the internal to exterior cellular environments and vice versa, as long as there is no acquisition of kinetic energy or the production of radiation. The concentration gradients of the charges directly determine this energy requirement. For the exterior of the cell, typical values of membrane potential, normally given in units of millivolts and denoted as mV, range from –80 mV to –40 mV.

Threshold potential

In electrophysiology, the threshold potential is the critical level to which a membrane potential must be depolarized to initiate an action potential. In neuroscience, threshold potentials are necessary to regulate and propagate signaling in both the central nervous system (CNS) and the peripheral nervous system (PNS).

End-plate potential

End plate potentials (EPPs) are the voltages which cause depolarization of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance. When an action potential reaches the axon terminal of a motor neuron, vesicles carrying neurotransmitters are exocytosed and the contents are released into the neuromuscular junction. These neurotransmitters bind to receptors on the postsynaptic membrane and lead to its depolarization. In the absence of an action potential, acetylcholine vesicles spontaneously leak into the neuromuscular junction and cause very small depolarizations in the postsynaptic membrane. This small response (~0.4mV) is called a miniature end plate potential (MEPP) and is generated by one acetylcholine-containing vesicle. It represents the smallest possible depolarization which can be induced in a muscle.

Repolarization

In neuroscience, repolarization refers to the change in membrane potential that returns it to a negative value just after the depolarization phase of an action potential which has changed the membrane potential to a positive value. The repolarization phase usually returns the membrane potential back to the resting membrane potential. The efflux of potassium (K+) ions results in the falling phase of an action potential. The ions pass through the selectivity filter of the K+ channel pore.

Visual phototransduction Sensory transduction of the visual system

Visual phototransduction is the sensory transduction of the visual system. It is a process by which light is converted into electrical signals in the rod cells, cone cells and photosensitive ganglion cells of the retina of the eye. This cycle was elucidated by George Wald (1906–1997) for which he received the Nobel Prize in 1967. It is so called "Wald's Visual Cycle" after him.

Pre-Bötzinger complex

The pre-Bötzinger complex (preBötC) is a cluster of interneurons in the ventral respiratory group of the medulla of the brainstem. This complex has been proven to be essential for the generation of the respiratory rhythm in mammals. The exact mechanism of the rhythm generation and transmission to motor nuclei remains controversial and the topic of much research.

T-type calcium channels are low voltage activated calcium channels that become inactivated during cell membrane hyperpolarization but then open to depolarization. The entry of calcium into various cells has many different physiological responses associated with it. Within cardiac muscle cell and smooth muscle cells voltage-gated calcium channel activation initiates contraction directly by allowing the cytosolic concentration to increase. Not only are T-type calcium channels known to be present within cardiac and smooth muscle, but they also are present in many neuronal cells within the central nervous system. Different experimental studies within the 1970s allowed for the distinction of T-type calcium channels from the already well-known L-type calcium channels. The new T-type channels were much different from the L-type calcium channels due to their ability to be activated by more negative membrane potentials, had small single channel conductance, and also were unresponsive to calcium antagonist drugs that were present. These distinct calcium channels are generally located within the brain, peripheral nervous system, heart, smooth muscle, bone, and endocrine system.

The P-type calcium channel is a type of voltage-dependent calcium channel. Similar to many other high-voltage-gated calcium channels, the α1 subunit determines most of the channel's properties. The 'P' signifies cerebellar Purkinje cells, referring to the channel's initial site of discovery. P-type calcium channels play a similar role to the N-type calcium channel in neurotransmitter release at the presynaptic terminal and in neuronal integration in many neuronal types.

Synaptic gating

Synaptic gating is the ability of neural circuits to gate inputs by either suppressing or facilitating specific synaptic activity. Selective inhibition of certain synapses has been studied thoroughly, and recent studies have supported the existence of permissively gated synaptic transmission. In general, synaptic gating involves a mechanism of central control over neuronal output. It includes a sort of gatekeeper neuron, which has the ability to influence transmission of information to selected targets independently of the parts of the synapse upon which it exerts its action.

Neural backpropagation is the phenomenon in which, after the action potential of a neuron creates a voltage spike down the axon, another impulse is generated from the soma and propagates towards the apical portions of the dendritic arbor or dendrites. In addition to active backpropagation of the action potential, there is also passive electrotonic spread. While there is ample evidence to prove the existence of backpropagating action potentials, the function of such action potentials and the extent to which they invade the most distal dendrites remain highly controversial.

Subthreshold membrane potential oscillations

Subthreshold membrane potential oscillations are membrane oscillations that do not directly trigger an action potential since they do not reach the necessary threshold for firing. However, they may facilitate sensory signal processing.

Recurrent thalamo-cortical resonance is an observed phenomenon of oscillatory neural activity between the thalamus and various cortical regions of the brain. It is proposed by Rodolfo Llinas and others as a theory for the integration of sensory information into the whole of perception in the brain. Thalamocortical oscillation is proposed to be a mechanism of synchronization between different cortical regions of the brain, a process known as temporal binding. This is possible through the existence of thalamocortical networks, groupings of thalamic and cortical cells that exhibit oscillatory properties.

Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are integral membrane proteins that serve as nonselective voltage-gated cation channels in the plasma membranes of heart and brain cells. HCN channels are sometimes referred to as pacemaker channels because they help to generate rhythmic activity within groups of heart and brain cells. HCN channels are activated by membrane hyperpolarization, are permeable to Na+ and K+, and are constitutively open at voltages near the resting membrane potential. HCN channels are encoded by four genes and are widely expressed throughout the heart and the central nervous system.

Spike-and-wave

Spike-and-wave is a pattern of the electroencephalogram (EEG) typically observed during epileptic seizures. A spike-and-wave discharge is a regular, symmetrical, generalized EEG pattern seen particularly during absence epilepsy, also known as ‘petit mal’ epilepsy. The basic mechanisms underlying these patterns are complex and involve part of the cerebral cortex, the thalamocortical network, and intrinsic neuronal mechanisms.

Dendritic spike

In neurophysiology, a dendritic spike refers to an action potential generated in the dendrite of a neuron. Dendrites are branched extensions of a neuron. They receive electrical signals emitted from projecting neurons and transfer these signals to the cell body, or soma. Dendritic signaling has traditionally been viewed as a passive mode of electrical signaling. Unlike its axon counterpart which can generate signals through action potentials, dendrites were believed to only have the ability to propagate electrical signals by physical means: changes in conductance, length, cross sectional area, etc. However, the existence of dendritic spikes was proposed and demonstrated by W. Alden Spencer, Eric Kandel, Rodolfo Llinás and coworkers in the 1960s and a large body of evidence now makes it clear that dendrites are active neuronal structures. Dendrites contain voltage-gated ion channels giving them the ability to generate action potentials. Dendritic spikes have been recorded in numerous types of neurons in the brain and are thought to have great implications in neuronal communication, memory, and learning. They are one of the major factors in long-term potentiation.

A depolarizing prepulse (DPP) is an electrical stimulus that causes the potential difference measured across a neuronal membrane to become more positive or less negative, and precedes another electrical stimulus. DPPs may be of either the voltage or current stimulus variety and have been used to inhibit neural activity, selectively excite neurons, and increase the pain threshold associated with electrocutaneous stimulation.

A paroxysmal depolarizing shift (PDS) or depolarizing shift is a hallmark of cellular manifestation of epilepsy. Little is known about the initiation, propagation and termination of PDS. Previously, electrophysiological studies have provided the evidence that there is a Ca2+ mediated depolarization, which causes voltage gated Na+ channels to open, resulting in action potentials. This depolarization is followed by a period of hyperpolarization mediated by Ca2+-dependent K+ channels or GABA-activated Cl− influx.. In general, synaptic PDS could be initiated by EPSPs, and the plateau potential of the PDS is maintained by a combination of synaptic potentials (EPSPs, IPSPs) and ionic conductances (persistent sodium current and high-threshold calcium current) and the post-PDS hyperpolarization is governed by multiple potassium currents, activated by calcium or sodium entry, as well as by leak current. The next cycle of depolarization is initiated by both synaptic drive and the hyperpolarization-activated IH current.

References

  1. ↑ Beatty, J. A.; Sullivan, M. A.; Morikawa, H.; Wilson, C. J. (2012). "Complex autonomous firing patterns of striatal low-threshold spike interneurons". Journal of Neurophysiology. 108 (3): 771–81. doi:10.1152/jn.00283.2012. PMC   3424086 . PMID   22572945.
  2. ↑ Llinás, R.; Yarom, Y. (June 1981). "Electrophysiology of mammalian inferior olivary neurones in vitro. Different types of voltage-dependent ionic conductances". The Journal of Physiology. 315: 549–567. doi:10.1113/jphysiol.1981.sp013763. ISSN   0022-3751. PMC   1249398 . PMID   6273544.
  3. ↑ Llinás, R.; Yarom, Y. (June 1981). "Properties and distribution of ionic conductances generating electroresponsiveness of mammalian inferior olivary neurones in vitro". The Journal of Physiology. 315: 569–584. doi:10.1113/jphysiol.1981.sp013764. ISSN   0022-3751. PMC   1249399 . PMID   7310722.
  4. ↑ Gutnick, MJ; Yarom, Y (1989). "Low threshold calcium spikes, intrinsic neuronal oscillation and rhythm generation in the CNS". Journal of Neuroscience Methods. 28 (1–2): 93–9. doi:10.1016/0165-0270(89)90014-9. PMID   2657227.
  5. ↑ Llinas, R. R.; Steriade, M (2006). "Bursting of Thalamic Neurons and States of Vigilance". Journal of Neurophysiology. 95 (6): 3297–308. doi:10.1152/jn.00166.2006. PMID   16554502.
  6. ↑ Gutierrez, Carolina; Cox, Charles L.; Rinzel, John; Sherman, S. Murray (February 1, 2001). "Dynamics of Low-Threshold Spike Activation in Relay Neurons of the Cat Lateral Geniculate Nucleus". The Journal of Neuroscience. 21 (3): 1022–32. doi:10.1523/jneurosci.21-03-01022.2001. PMC   6762305 . PMID   11157087.
  7. ↑ Perez-Reyes, Edward (2003). "Molecular Physiology of Low-Voltage-Activated T-type Calcium Channels". Physiological Reviews. 83 (1): 117–61. doi:10.1152/physrev.00018.2002. PMID   12506128.
  8. ↑ Lu, SM; Guido, W; Sherman, SM (Dec 1992). "Effects of membrane voltage on receptive field properties of lateral geniculate neurons in the cat: contributions of the low-threshold Ca2+ conductance". Journal of Neurophysiology. 68 (6): 2185–98. doi:10.1152/jn.1992.68.6.2185. PMID   1337104.
  9. ↑ Zhan, XJ; Cox, CL; Sherman, SM (2000). "Dendritic depolarization efficiently attenuates low-threshold calcium spikes in thalamic relay cells". The Journal of Neuroscience. 20 (10): 3909–14. doi:10.1523/JNEUROSCI.20-10-03909.2000. PMC   6772701 . PMID   10804230.
  10. 1 2 3 Zhan, XJ; Cox, CL; Rinzel, J; Sherman, SM (1999). "Current clamp and modeling studies of low-threshold calcium spikes in cells of the cat's lateral geniculate nucleus". Journal of Neurophysiology. 81 (5): 2360–73. doi:10.1152/jn.1999.81.5.2360. PMID   10322072.
  11. ↑ Cains, Sarah; Blomeley, Craig P.; Bracci, Enrico (2012). "Serotonin inhibits low-threshold spike interneurons in the striatum". The Journal of Physiology. 590 (10): 2241–52. doi:10.1113/jphysiol.2011.219469. PMC   3424750 . PMID   22495583.
  12. ↑ Siwek, Magdalena; Henseler, Christina; Broich, Karl; Papazoglou, Anna; Weiergräber, Marco (2012). "Voltage-Gated Ca2+ Channel Mediated Ca2+ Influx in Epileptogenesis". In Islam, Md. Shahidul (ed.). Calcium Signaling. Advances in Experimental Medicine and Biology. Vol. 740. pp. 1219–47. doi:10.1007/978-94-007-2888-2_55. ISBN   978-94-007-2887-5. PMID   22453990.
  13. ↑ Ochoa, J; Willise, R (2012). "Antiepileptic Drugs". Medscape Reference.
  14. ↑ Jeanmonod, D.; Magnin, M.; Morel, A. (1996). "Low-threshold calcium spike bursts in the human thalamus". Brain. 119 (2): 363–75. doi: 10.1093/brain/119.2.363 . PMID   8800933.
  15. ↑ Magnin, M; Morel, A; Jeanmonod, D (2000). "Single-unit analysis of the pallidum, thalamus and subthalamic nucleus in parkinsonian patients". Neuroscience. 96 (3): 549–64. doi:10.1016/S0306-4522(99)00583-7. PMID   10717435.
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