Inhibition within the CNS can be either postsynaptic or pre synaptic. Examples of the neuronal connections that can mediate presynaptic inhibition and postsynaptic inhibition are compared in Figure 1. Postsynaptic inhibition during the course of an IPSP is called direct inhibition because it is not a consequence of previous discharges of the postsynaptic neuron. There are various forms of indirect inhibition, which is inhibition due to the effects of previous postsynaptic neuron discharge. For example, the postsynaptic cell can be refractory to excitation because it has just fired and is in its refractory period. During after-hyperpolarization it is also less excitable. In spinal neurons, especially after repeated firing, this after hyperpolarization may be large and prolonged.
Fig1. Comparison of neuronal connections that can produce presynaptic and postsynaptic inhibition. A) Presynaptic inhibition is a process mediated by neurons whose terminals are on excitatory nerve endings, forming axoaxonal synapses and reducing transmitter release form the excitatory neuron. B) Postsynaptic inhibition occurs when an inhibitory transmitter such as GABA is released from the nerve terminals of an inhibitory interneuron (dark) that synapses on a postsynaptic neuron.
POSTSYNAPTIC INHIBITION
Postsynaptic inhibition occurs when an inhibitory transmitter such as glycine or GABA is released from a presynaptic nerve terminal onto the postsynaptic neuron to induce an IPSP in the postsynaptic neuron (Figure 1B). Various pathways in the nervous system are known to mediate postsynaptic inhibition, and one illustrative example is presented here. Afferent fibers from the muscle spindles (stretch receptors) in skeletal muscle project directly to the spinal motor neurons of the motor units supplying the same muscle (Figure 2). Impulses in this afferent fiber cause an EPSP and, with summation, propagated action potentials in the postsynaptic motor neurons. At the same time, an IPSP is produced in motor neurons supplying the antagonistic muscle, which has an inhibitory interneuron interposed between the afferent fiber and the motor neuron. Therefore, activity in the afferent fibers from the muscle spindles excites the motor neurons supplying the muscle from which the impulses come, and inhibits the motor neurons sup plying its antagonists (reciprocal innervation).
Fig2. Excitatory and inhibitory synaptic connections mediating the stretch reflex provide an example of typical circuits within the CNS. A) The stretch receptor sensory neuron of the quadriceps muscle makes an excitatory connection with the extensor motor neuron of the same muscle and an inhibitory interneuron projecting to flexor motor neurons supplying the antagonistic hamstring muscle. B) Experimental setup to study excitation and inhibition of the extensor motor neuron. Top panel shows two approaches to elicit an excitatory (depolarizing) postsynaptic potential or EPSP in the extensor motor neuron–electrical stimulation of the whole Ia afferent nerve using extracellular electrodes and intracellular current passing through an electrode inserted into the cell body of a sensory neuron. Bottom panel shows that current passing through an inhibitory interneuron elicits an inhibitory (hyperpolarizing) postsynaptic potential or IPSP in the flexor motor neuron. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. New York, NY: McGraw-Hill; 2000.)
PRESYNAPTIC INHIBITION & FACILITATION
Presynaptic inhibition is a process mediated by neurons whose terminals are on excitatory endings, forming axoaxonal syn apses (Figures 3 and 1A). Three mechanisms of presynaptic inhibition have been described. First, activation of the presynaptic receptors increases Cl– conductance, and this has been shown to decrease the size of the action potentials reaching the excitatory ending (Figure 4). This in turn reduces Ca2+ entry and consequently the amount of excitatory transmitter released. Voltage-gated K+ channels are also opened, and the resulting K+ efflux also causes a decrease in Ca2+ influx. Finally, there is evidence for direct inhibition of transmitter release independent of Ca2+ influx into the excitatory ending.
Fig3. Axodendritic, axoaxonal, and axosomatic synapses. Many presynaptic neurons terminate on dendritic spines, as shown at the top, but some also end directly on the shafts of dendrites. Note the presence of clear and granulated synaptic vesicles in endings and clustering of clear vesicles at active zones.
Fig4. Effects of presynaptic inhibition and facilitation on the action potential and the Ca2+ current in the presynaptic neuron and the EPSP in the postsynaptic neuron. In each case, the solid lines are the controls and the dashed lines the records obtained during inhibition or facilitation. Presynaptic inhibition occurs when activation of presynaptic receptors increases Cl– conductance, which decreases the size of the action potential. This reduces Ca2+ entry and thus the amount of excitatory transmitter released. Presynaptic facilitation is produced when the action potential is prolonged and the Ca2+ channels are open for a longer duration. (Reproduced with permission from Kandel ER, Schwartz JH, Jessell TM [editors]: Principles of Neural Science, 4th ed. New York, NY: McGraw-Hill; 2000.)
The first transmitter shown to produce presynaptic inhibition was GABA. Acting via GABAA receptors, GABA increases Cl– conductance. GABAB receptors are also present in the spinal cord and appear to mediate presynaptic inhibition via a G-protein that produces an increase in K+ conductance. Baclofen, a GABAB agonist, is effective in the treatment of the spasticity of spinal cord injury and multiple sclerosis, particularly when administered intrathecally via an implanted pump. Other transmitters also mediate presynaptic inhibition by G-protein–mediated effects on Ca2+ channels and K+ channels.
Conversely, presynaptic facilitation is produced when the action potential is prolonged (Figure 4) and the Ca2+ channels are open for a longer period. The molecular events responsible for the production of presynaptic facilitation mediated by serotonin in the sea snail Aplysia have been worked out in detail. Serotonin released at an axoaxonal ending increases intraneuronal cyclic adenosine monophosphate (cAMP) levels, and the resulting phosphorylation of one group of K+ channels closes the channels, slowing repolarization and prolonging the action potential.
ORGANIZATION OF INHIBITORY SYSTEMS
Presynaptic inhibition and postsynaptic inhibition are usually produced by stimulation of certain systems converging on a given postsynaptic neuron. Neurons may also inhibit themselves in a negative feedback manner (negative feedback inhibition). For instance, a spinal motor neuron emits a recur rent collateral that synapses with an inhibitory interneuron, which then terminates on the cell body of the spinal neuron and other spinal motor neurons (Figure 5). This particular inhibitory neuron is sometimes called a Renshaw cell after its discoverer. Impulses generated in the motor neuron activate the inhibitory interneuron to secrete the inhibitory neu rotransmitter glycine, and this reduces or stops the discharge of the motor neuron. Similar inhibition via recurrent collaterals is seen in the cerebral cortex and limbic system. Presynaptic inhibition due to descending pathways that terminate on afferent pathways in the dorsal horn may be involved in the gating of pain transmission.
Fig5. Negative feedback inhibition of a spinal motor neuron via an inhibitory interneuron. The axon of a spinal motor neuron has a recurrent collateral that synapses on an inhibitory interneuron that terminates on the cell body of the same and other motor neurons. The inhibitory interneuron is called a Renshaw cell and its neurotransmitter is glycine.
Another type of inhibition is seen in the cerebellum. In this part of the brain, stimulation of basket cells produces IPSPs in the Purkinje cells. However, the basket cells and the Purkinje cells are excited by the same parallel-fiber excitatory input. This arrangement, which has been called feed-forward inhibition, presumably limits the duration of the excitation produced by any given afferent volley.
