Summation (neurophysiology)

The nervous system first began to be encompassed within the scope of general physiological studies in the late 1800s, when Charles Sherrington began to test neurons' electrical properties. His main contributions to neurophysiology involved the study of the knee-jerk reflex and the inferences he made between the two reciprocal forces of excitation and inhibition. He postulated that the site where this modulatory response occurs is the intercellular space of a unidirectional pathway of neural circuits. He first introduced the possible role of evolution and neural inhibition with his suggestion that “higher centers of the brain inhibit the excitatory functions of the lower centers”.[1]

Much of today's knowledge of chemical synaptic transmission was gleaned from experiments analyzing the effects of acetylcholine release at neuromuscular junctions, also called end plates. The pioneers in this area included Bernard Katz and Alan Hodgkin, who used the squid giant axon as an experimental model for the study of the nervous system. The relatively large size of the neurons allowed the use of finely-tipped electrodes to monitor the electrophysiological changes that fluctuate across the membrane. In 1941 Katz's implementation of microelectrodes in the gastrocnemius sciatic nerve of frogs’ legs illuminated the field. It soon became generalized that the end-plate potential (EPP) alone is what triggers the muscle action potential, which is manifested through contractions of the frog legs.[3]

One of Katz's seminal findings, in studies carried out with Paul Fatt in 1951, was that spontaneous changes in the potential of muscle-cell membrane occur even without the stimulation of the presynaptic motor neuron. These spikes in potential are similar to action potentials except that they are much smaller, typically less than 1 mV; they were thus called miniature end plate potentials (MEPPs). In 1954, the introduction of the first electron microscopic images of postsynaptic terminals revealed that these MEPPs were created by synaptic vesicles carrying neurotransmitters. The sporadic nature of the release of quantal amounts of neurotransmitter led to the "vesicle hypothesis" of Katz and del Castillo, which attributes quantization of transmitter release to its association with synaptic vesicles.[3] This also indicated to Katz that action potential generation can be triggered by the summation of these individual units, each equivalent to an MEPP.[4]

A diagram of temporal summation.

At any given moment, a neuron may receive postsynaptic potentials from thousands of other neurons. Whether threshold is reached, and an action potential generated, depends upon the spatial (i.e. from multiple neurons) and temporal (from a single neuron) summation of all inputs at that moment. It is traditionally thought that the closer a synapse is to the neuron's cell body, the greater its influence on the final summation. This is because postsynaptic potentials travel through dendrites which contain a low concentration of voltage-gated ion channels.[5] Therefore, the postsynaptic potential attenuates by the time it reaches the neuron cell body. The neuron cell body acts as a computer by integrating (adding or summing up) the incoming potentials. The net potential is then transmitted to the axon hillock, where the action potential is initiated. Another factor that should be considered is the summation of excitatory and inhibitory synaptic inputs. The spatial summation of an inhibitory input will nullify an excitatory input. This widely observed effect is called inhibitory 'shunting' of EPSPs.[5]

Neurotransmitters bind to receptors which open or close ion channels in the postsynaptic cell creating postsynaptic potentials (PSPs). These potentials alter the chances of an action potential occurring in a postsynaptic neuron. PSPs are deemed excitatory if they increase the probability that an action potential will occur, and inhibitory if they decrease the chances.[4]

As long as the membrane potential is below threshold for firing impulses, the membrane potential can summate inputs. That is, if the neurotransmitter at one synapse causes a small depolarization, a simultaneous release of transmitter at another synapse located elsewhere on the same cell body will summate to cause a larger depolarization. This is called spatial summation and is complemented by temporal summation, wherein successive releases of transmitter from one synapse will cause progressive polarization change as long as the presynaptic changes occur faster than the decay rate of the membrane potential changes in the postsynaptic neuron.[4] Neurotransmitter effects last several times longer than presynaptic impulses, and thereby allow summation of effect. Thus, the EPSP differs from action potentials in a fundamental way: it summates inputs and expresses a graded response, as opposed to the all-or-none response of impulse discharge.[10]

At the same time that a given postsynaptic neuron is receiving and summating excitatory neurotransmitter, it may also be receiving conflicting messages that are telling it to shut down firing. These inhibitory influences (IPSPs) are mediated by inhibitory neurotransmitter systems that cause postsynaptic membranes to hyperpolarize.[11] Such effects are generally attributed to the opening of selective ion channels that allow either intracellular potassium to leave the postsynaptic cell or to allow extracellular chloride to enter. In either case, the net effect is to add to the intracellular negativity and move the membrane potential farther away from the threshold for generating impulses.[8][10]

When EPSPs and IPSPs are generated simultaneously in the same cell, the output response will be determined by the relative strengths of the excitatory and inhibitory inputs. Output instructions are thus determined by this algebraic processing of information. Because the discharge threshold across a synapse is a function of the presynaptic volleys that act upon it, and because a given neuron may receive branches from many axons, the passage of impulses in a network of such synapses can be highly varied.[12] The versatility of the synapse arises from its ability to modify information by algebraically summing input signals. The subsequent change in stimulation threshold of the postsynaptic membrane can be enhanced or inhibited, depending on the transmitter chemical involved and the ion permeabilities. Thus the synapse acts as a decision point at which information converges, and it is modified by algebraic processing of EPSPs and IPSPs. In addition to the IPSP inhibitory mechanism, there is a presynaptic kind of inhibition that involves either a hyperpolarization on the inhibited axon or a persistent depolarization; whether it is the former or the latter depends on the specific neurons involved.[6]

The microelectrodes used by Katz and his contemporaries pale in comparison to the technologically advanced recording techniques available today. Spatial summation began to receive a lot of research attention when techniques were developed that allowed the simultaneous recording of multiple loci on a dendritic tree. A lot of experiments involve the use of sensory neurons, especially optical neurons, because they are constantly incorporating a ranging frequency of both inhibitory and excitatory inputs. Modern studies of neural summation focus on the attenuation of postsynaptic potentials on the dendrites and the cell body of a neuron.[1] These interactions are said to be nonlinear, because the response is less than the sum of the individual responses. Sometimes this can be due to a phenomenon caused by inhibition called shunting, which is the decreased conductance of excitatory postsynaptic potentials.[8]

Shunting inhibition is exhibited in the work of Michael Ariel and Naoki Kogo, who experimented with whole cell recording on the turtle basal optic nucleus. Their work showed that spatial summation of excitatory and inhibitory postsynaptic potentials caused attenuation of the excitatory response during the inhibitory response most of the time. They also noted a temporary augmentation of the excitatory response occurring after the attenuation. As a control they tested for attenuation when voltage-sensitive channels were activated by a hyperpolarization current. They concluded that attenuation is not caused by hyperpolarization but by an opening of synaptic receptor channels causing conductance variations.[13]

• Shunting
• Length constant
• Long-Term Potentiation
• Neurotransmission