SYNAPSES: SYNAPTIC STRENGTH and LONG TERM POTENTIATION
In some synapses, such as dendritic spine synapses, or synapses concerned with nociceptive transmission in the dorsal horn, the size of the EPSP increases following bursts of activity (long-term potentiation, LTP), or decreases after a period of inactivity (long-term depression, LTD).
In the CNS there are a number of ways in which the size of the EPSP generated at a synapse can be changed. Here are some :
changing the amount of transmitter released by a synaptic bouton, e.g. by pre-synaptic inhibition
altering the number of post-synaptic receptors, e.g. by trafficking of receptors between the membrane and internal stores
recruiting more powerful types of post-synaptic receptor, e.g. by depolarisation to a threshold level that allows NMDA receptors to carry larger currents into the neurone
activating signalling cascades within the post-synaptic cell that produce longer-term changes in synaptic strength e.g by activating enzymes or G-proteins that regulate the expression of receptors.
In the CNS, there are also specialised synapses
between axon terminals (axo-axonic synapses), and
axonal terminals on the dendrites of cortical pyramidal cells, cerebellar Purkinje cells, and striatal medium spiny cells, which are the site of dendritic spine synapses, that allow local regulation of synaptic strength.
Dendritic Spine Synapses can alter the size of the EPSP by changing the number of glutamatergic receptors in the post-synaptic membrane; this is achieved using two ionotropic receptors and two groups of metabotropic receptors. Synaptic strength is increased following repetitive activity of the synapse, and decreased by the absence of activity. The glutamatergic ionotropic and metabotropic receptors will be described separately.
Key Words: Long-term potentiation, Long-term Depression, Pre-synaptic Inhibition; Trafficking of receptors; Glutamatergic ionotropic and metabotropic receptors.
What is Long-Term Potentiation (LTP) ?
Image source: Purves: Neuroscience ncbi.nih.gov
Long Term Potentiation. The images show the sizes of the EPSPs in a cell in the hippocampal cortex. Two pathways are being stimulated, but Pathway 1 is stimulated repeatedly for a short period around time zero. It can be seen that the size of the EPSP increases about threefold and gradually declines over the following hour. However, pathways 2 that is not tetanised, shows no changes in the size of its EPSPs
Long Term Potentiation (LTP)
Repetition aids learning. Repeated inputs to a synapse can stengthen the function of a synapse, and the effects of repeated inputs are prolonged. This is known as Long Term Potentiation (LTP) and is seen by many as the neuronal basis of learning.
LTP is an increase in the response of a synapse following repeated stimulation, an effect that can last for hours or days or longer.
The diagram opposite shows the increase in the size of the EPSP in a pathway that has been repetitively stimulated; not that the changes considerably outlast the period of high frequency stimulation.
LTP has been studied at glutamatergic synapses in the hippocampus, and the phenomenon depends on activation of the NMDA receptor. Blocking the NMDA receptor interferes with LTP and learning and memory.
The effects of increasing numbers of AMPA receptors in the post-synaptic membrane
Image source: asiaforest.org
This diagram illustrates the effects of raised intracelluar calcium concentration, that causes AMPA receptors to be moved from intracellular stores into the post-synaptic membrane. Thi is part of the mechanism of long-term potentiation: the increase in the size of the EPSP is partly due to the increased numbers of post-synaptic AMPA receptors, trafficked form internal stores of the receptor..
Glutamatergic transmission and synaptic strength
Image source: www.slideshare.net This diagram illustrates the role of NMDA receptors in calcium entry to a dendritic spine synapse: additional AMPA receptors are added to the post-synaptic membrane and in addition there is the generation of sigmal, possibly the gas, nitric oxide (NO), that acts pre-synapticaly to enhance glutamate release.
More information about the relationships between the four glutamate receptors are covered in the tutorials on ionotropic and metabotropic receptors
Longer term changes in CNS synapses.
Image source: dialogues-cns.com
Neurotransmission via a G protein-coupled receptor (GPCR): binding of the neurotransmitter to the receptor initiates a cascade of intracellular events that drive the activity of the neuron or cell. The G-protein complex, consisting of subunits α, β, and γ, serves as the machinery that transduces the extracellular signal to various effectors at the intracellular side of the plasma membrane, to the enzymes adenylyl cyclase or phospholipase. These enzymes catalyze the synthesis of second messengers, such as cyclic adenosine monophosphate (cAMP) and diacylglycerol, which regulate gene transcription in the nucleus. Transcripts (mRNA) are later translated into protein. Calcium ions released from intracellular stores and other second messengers activate protein kinases and phosphatases. This leads to phosphorylation and/or dephosphorylation of many intracellular proteins as well as ion channels that are located in the plasma membrane of the cell. Phosphorylation/dephosphorylation induces opening and closing of these channels and this modulates the electrical activity of the neuron. These dynamic cellular processes are accelerated during stress when neurotransmitter concentrations are elevated. (from dialogues-cns.com)
Longer term Synaptic events
The rapid responses of central post-synaptic neurones are due to summation of EPSPs and IPSPs; however, some post-synaptic neurones have, in addition, mechanisms that alter their sensitivity, the efficacy or duration of the response to synaptic inputs.
These changes occur because glutamate and GABA can also activate receptors that initiate the release of second messengers within the neurone. Second messengers include calcium ion concentration, and internal second messengers, such as cyclic AMP, IP3 or DAG, that activate certain enzymes or signalling cascades.
Membrane G-proteins, are an very important component of the route by which longer term changes can be effected. These occur in neurones that express NMDA and the metabotropic receptors which can alter the duration and sensitivity to incoming glutamatergic signals.
GABA B Receptors
Gamma Amino Butyric Acid (GABA) caused inhibition of neurones through two mechanisms. GABAA is an intotropic receptor and GABAB is an metabotropic receptor. The latter has delayed and longer acting actions as a result of the activation of intracellular cascades, and these longer lasting actions occur in neurones that possess the GABAB receptor.