Neuroplasticity

Synaptic plasticity can occur at either the presynaptic or postsynaptic terminal. Modifications to the presynaptic terminal affect the release of neurotransmitters. As the action potential invades the presynaptic terminal, it activates voltage-gated calcium channels that conduct calcium ions into the presynaptic terminal. This rise in intracellular calcium triggers the exocytosis of vesicles (fusion with the plasma membrane) and thus the release of neurotransmitters. Each presynaptic terminal contains between 200 and 500 vesicles, though only a small proportion of these are ready to be released at any time. Vesicles in the presynaptic terminal Figure 1 The synapse: Neurons maintain thousands of synapses. In this synapse schematic, the axon of neuron 1 (N1) contributes the presynaptic terminal and the postsynaptic terminal is contained on a specialization of the dendrite of neuron 2 (N2), called a synaptic spine. When an action potential is propagated down the axon of N1, the presynaptic terminal depolarizes through the activation of voltage-gated calcium channels. The rise in calcium in the presynaptic terminal will trigger the fusion of synaptic vesicles with presyaptic membrane, resulting in the release of neurotransmitters into the synaptic cleft. The neurotransmitters will bind to specific receptors located on the postsynaptic membrane that will lead to a change in the membrane potential in the dendrite that is conducted toward the cell body of N2. Synaptic plasticity, or the change in the strength of this synapse, can result from molecular changes at either the pre- or postsynaptic terminal (see text). SOURCE: Author move through a specific release cycle, including vesicle storage, priming for release, release, vesicle reformation, and reloading with neurotransmitter.

Factors that alter the presynapse resulting in either modification of the calcium channel conductance or modification of the vesicle cycle will yield changes in synaptic strength. One such factor is the cyclic nucleotide cAMP. An increase in cAMP presynaptically can enhance transmitter release by activating protein kinase A (PKA). PKA activation induces a decrease in a specific potassium channel conductance called a delayed rectifier current. Decreased delayed rectifier conductance will increase the calcium entry into the presynaptic terminal by increasing the duration of the action potential. In addition, a rise in cAMP can activate vesicular release from presynaptic terminals that were previously dormant. Such terminals are present, but do not release neurotransmitters in response to an action potential prior to a rise in cAMP. A morphologically distinct synapse that is physiologically dormant has been termed a silent synapse and can be the result of deficient presynaptic release, or a deficiency of transmitter receptors expressed postsynaptically.

The postsynaptic terminal can also be modified to produce changes in synaptic efficacy. Signaling molecules in the postsynaptic compartment such as protein kinase A (PKA) and the alpha subunit of calcium/calmodulin-dependent kinase II (α-CaMKII) are thought to play major roles in synaptic plasticity. For example, when a mouse is genetically altered to express a version of α-CaMKII incapable of activation, LTP and learning are disrupted. While α-CaMKII can directly phosphorylate neurotransmitter receptors leading to an increase in conductance, it is likely to play additional roles in synaptic plasticity as well. Neurotransmitter receptors can cycle in and out of the postsynaptic membrane (in a process not unlike the presynaptic vesicles), and α-CaMKII phosphorylation of an as yet unidentified substrate could lead to the rapid insertion of more receptors. This would result in LTP of an active synapse and the unsilencing of a synapse that was not previously expressing these receptors in its membrane. As stated above, there is substantial evidence implicating long-lasting changes in synaptic strength with the formation of memory. It should be noted that synapses do not act in isolation. The neural circuits to which they belong are a result of the many thousands of synapses contained therein. Although the cellular coding of information may be encoded at synapses, memory itself is likely dependent upon the circuit(s) in which they are contained.