Dendritic spike

Spike Initiation

Action Potential

Action potentials initiated in the axon normally travel down the axon away from the soma. However, it is also possible for an action potential to travel in the opposite direction, invade the soma, and then travel down the dendrite as a dendritic spike. This retrograde signal provides information to the synapse that the neuron has fired an output. The efficacy of the signal varies among different neuronal types. For example, backward propagation of action potentials is very limited in cerebellar Purkinje cells but is quite prevalent in interneurons of the medium ganglionic layer of the cerebellum-like lobe of some fish.

Synaptic Input

Action potentials may be first generated at the dendrite if stimulated by strong synchronous synaptic inputs. The ability of a dendrite to initiate an action potential is not only highly dependent on synaptic input but also on the number of voltage-gated channels and density of voltage-gated channels present in the membrane.

Spatial Summation

Initiation of a dendritic spike through a single strong synaptic input does not guarantee that the spike will propagate reliably over long distances. If multiple synapses are simultaneously activated, dendritic spikes may be formed through spatial summation. Spatial summation involves the addition of multiple input signals resulting in a larger signal and possibly a dendritic spike. Hippocampal CA1 neurons have been shown to produce reliable dendritic spike propagation through spatial summation of multiple synaptic inputs. In the hippocampus, the CA1 neurons contain two distinctive regions that receive excitatory synaptic inputs: the perforant path (PP) through the apical dendritic tuft (500-750 μm from soma) and the Schaffer-collateral (SC) through the basal and apical dendrites (250-500 μm from soma). Studies show that individual stimulation of either the PP or SC was not sufficient to allow a dendritic spike to initiate an action potential. However, it was shown that when a dendritic spike occurred due to PP stimulations, the presence of a SC stimulation determined whether or not the signal would propagate to the soma.

Spike Propagation

Backward Propagation

Dendritic spikes most commonly propagate backwards from the soma to distal dendritic branches. Backward propagation serves a number of functions in the neuron, and these functions vary based on the type of neuron. In general, backward propagation serves to communicate output information to the postsynaptic membrane. In many neurotransmitter-releasing neurons, backward propagation of dendritic spikes signals the release of neurotransmitters. For example, Mitral cells seem to serve both as projection neurons and as local interneurons. If the axonal output of a mitral cell is shut down by somatic inhibition, local dendritic action potentials cause the mitral cell to release neurotransmitters into the environment. Backward propagation of dendritic spikes has been demonstrated in various neuronal types in the brain but has rarely been studied outside of the brain. Other than neurons in the brain, dendritic spikes have been observed in the neurons of the spinal cord.

Forward Propagation

Forward propagation of dendritic spikes initiates due to synaptic activity, and refers to the transmission of the signal towards the soma. The strength of synaptic stimulation required to generate a dendritic spike varies among neuronal types. Neurons which receive relatively few inputs cannot rely on spatial summation and therefore must rely on stronger synaptic inputs. Some relatively unbranched neurons, such as the globus pallidus neuron, bypass the need of strong synaptic input by increased concentrations of voltage-gated sodium channels at the synapse. Other more branched neurons, such as pyramidal neurons, rely on spatial summation of multiple inputs to generate forward propagating dendritic spikes. Forward propagation is not well understood and much research is devoted to the subject. It is thought by most experts

that this phenomenon does not occur in neurons outside of the brain.

Spike-Timing-Dependent Plasticity

Spike-timing-dependent plasticity (STDP) refers to the functional changes in a neuron and its synapse due to time dependent action potentials. When an action potential reaches the pre-synaptic membrane it opens voltage-gated calcium channels causing an influx of calcium. The influx of calcium releases vesicles filled with neurotransmitters, usually glutamate, into the synaptic cleft. The neurotransmitters bind to receptors on the post-synaptic membrane opening ligand-gated channels causing the membrane to depolarize.

NMDA receptors are found throughout the post-synaptic membrane and act as a coincidence detector. The NMDA detects both glutamate released by pre-synaptic vesicles and depolarization of the post-synaptic membrane. The NMDA receptor exhibits voltage-dependent block by magnesium ions. Depolarization of the post-synaptic membrane (i.e. backward propagating dendritic spike) causes the magnesium ion to be removed from the channel, favoring channel opening. NMDA receptor activation thereby allows calcium influx. Neurons that "fire together wire together" refer to strengthening of synaptic connections through NMDA receptors when glutamate release is coincident with post-synaptic depolarization. This form of wiring is known as long term potentiation. Synaptic connection can also be weakened when the activity of neurons is uncorrelated, also known as long term depression.

The dependence of post-synaptic depolarization in STDP indicates the importance of dendritic spikes. In general, post-synaptic depolarization occurs coincidentally with pre-synaptic activity when a backwards propagating signal reaches the post-synaptic membrane. Dendritic spikes allow backward propagating signals to reach and depolarize the post-synaptic membrane. The strengthening and weakening of synaptic connections is one proposed method of memory formation and learning.

Experimental Methods

Two-Photon Glutamate Uncaging

Two-photon glutamate uncaging, a type of photostimulation, has become the premier tool for studying dendritic spikes due to its high level of precision.

Patch Clamp

Patch clamp recording is used to measure electrical activity in neurons. The technique uses a one micrometer diameter open tip glass micropipette to suction the membrane of a cell. The pipette is filled with ionic solution, and a silver wire is placed in the solution to conduct and amplify electrical signals. The ion solution can be varied and drugs can be delivered through the micropipette to study the effects of current under various conditions. Receptor and voltage-gated channel antagonists are often applied (i.e. nickel used to block NMDA receptors) in order to study the effects of ion channels on dendritic spike initiation. Current injection is often paired with patch clamp recordings in order to observe current modulation due to various experimental factors.

Extracellular Electrophysiology

Tetrode recording methods have also been shown to occasionally allow for observation of dendritic membrane potentials and dendritic action potentials. Interestingly, the chronic recording paradigm that demonstrated this also showed that dendritic voltage properties exhibited egocentric spatial maps comparable to pyramidal neurons. This rare phenomenon may be due to a glial sheath forming around the tetrode tips, creating a high impedance sea, similar to a gigaohm seal in patch recordings, that allows for such small and localized voltage measurement to be made.

Staining and Labeling

Staining and labeling techniques are often used in microscopy to help identify specific structures in a cell. Staining usually involves the use of dyes that are absorbed by various cell structures at different rates. Labeling involves the use of fluorescence to identify specific molecules. Fluorophores, fluorescent molecules, may be directly attached or attached to an antibody in order to detect a specific target. In the case of dendritic spikes, staining and labeling are used to identify and quantify the presence of certain voltage-gated channels. For example, rabbit polyclonal antibodies raised against synthetic peptide sequences have been used to identify the presence of Nav1.2, Nav1.3, and Nav1.6 sodium channels in dendrites of the globus pallidus neuron.

Computational Modeling

Computational modeling of neurons, artificial neural networking, has become a very popular tool in investigating the properties of neuronal signaling. These models are based on biological neural networks. Computational modeling can be used to study single neurons, groups of neurons, or even networks of neurons. This field has generated much interest and serves as a tool for all branches of neuroscience research including dendritic spike initiation.