The 100 billion neurones in the human brain need to effectively communicate with one another. This is achieved through a meeting point called a synapse, which is essentially a gap between two neurones where neurotransmitters are released.
Synapses mediate one of the most essential and fascinating features of the brain: its ability to change. The flow of information in the brain is regulated by the formation of new synapses, the elimination of redundant or old synapses well as changes in the strength of already existing synapses. Collectively, this gives rise to a phenomenon called synaptic plasticity.
In this article, we will explore the core principles and types of synaptic plasticity. We will have a closer look at long-term potentiation (LTP) and long-term depression (LTD) and their molecular mechanisms. Finally, we will examine how the activity of synapses can be disrupted in the disease processes.
The variability in the level of communication between two neurones is akin to the variation in speech volume, the “strength” of the synapse is variable and may be altered over the short or the long term.
This variation in synaptic strength is one of the forms of synaptic plasticity and it primarily depends on the levels of activity between two neurones (activity-dependent process).
Duration of Synaptic Plasticity
Synaptic plasticity can be classified according to the duration in changes to the synaptic strength into:
- Short-term synaptic plasticity – a change lasting from milliseconds to several minutes, with a prompt return to normal.
This type of synaptic plasticity is believed to play an important role in transient changes in behavioural states or short-lasting forms of memory. It is mostly triggered by short bursts of presynaptic activity. Examples of short-term plasticity include paired-pulse depression and paired-pulse facilitation.
- Long-term synaptic plasticity – describes strength-modifying processes happening for a few minutes, days or even years.
The major examples of this type of plasticity include long-term potentiation (LTP) and long-term depression (LTD).
Long-Term Synaptic Plasticity
Long-Term Potentiation (LTP)
LTP and LTD are the most widely researched types of activity-dependent long-lasting synaptic plasticity. They are induced by differential patterns of synaptic activity. Hence, some patterns of synaptic activity result in a long-lasting increase in synaptic strength – LTP, whereas other patterns of synaptic activity will produce a long-term reduction in the synaptic strength known as LTD.
LTP has been detected throughout the brain, including in the cerebral cortex, amygdala and cerebellum. But it was for the first time described in the hippocampus. This ultimately means that the pre-synaptic neurone can evoke a greater post-synaptic response when stimulated.
LTP has a few key features:
- It requires strong activity in both presynaptic and postsynaptic neurones i.e. neurones which ‘fire together wire together’.
- LTP is synapse-specific. It is restricted to the synapse between two activated neurones rather than to all synapses on a particular neurone.
Mechanisms of Long-Term Potentiation
Induction of LTP requires activation of glutamate NMDA receptors (NMDARs). At the resting membrane potential, NMDARs are blocked by magnesium ions and only become permeable to sodium, potassium and calcium ions upon post-synaptic depolarization (mediated by glutamate AMPA receptors(AMPARs)). An increase in post-synaptic calcium concentration initiates the molecular processes necessary for LTP.
The pivotal role of NMDARs activation in LTP reflects the activity-dependent nature of synaptic plasticity. NMDARs can be only activated upon simultaneous pre-synaptic release of glutamate and postsynaptic depolarization mediated by AMPARs. This can be only achieved at high levels of synaptic activity.
As NMDARs require two processes: the presynaptic release of glutamate and postsynaptic depolarization to co-occur for their activation, they are often referred to as a ‘coincidence detectors’.
LTP has two main phases:
- Early Phase – An influx of calcium activates calcium calmodulin-dependent kinase II (CaMKII), which phosphorylates AMPARs. Phosphorylation of these receptors increases their permeability to sodium and potassium ions, increasing the excitability of the postsynaptic neurone. Furthermore, additional AMPARs are inserted into the post-synaptic membrane from a cytoplasmic pool.
- Late Phase – Increased activity of CaMKII, stimulates activation of other kinases responsible for the regulation of gene expression, such as extracellular signal-regulated kinase (ERK). The subsequent changes in gene transcription and translation lead to the increased synthesis of new AMPARs, which can be then inserted into the post-synaptic membrane. These genomic changes continue for hours to days.
Both phases ultimately ensure that the pre-synaptic neurone can evoke a greater post-synaptic response when stimulated.
Long-Term Depression (LTD)
Similarly to LTP, LTD was also described for the first time in the hippocampus. However, it is initiated by prolonged (10-15 minutes) low-frequency stimulation. This particular pattern of stimulation creates depressed synaptic strength (reflected by a reduction in the size of excitatory postsynaptic potentials (EPSPs)), which may last for several hours.
Importantly, LTD can erase the increase in EPSP size due to LTP and vice versa. Hence, LTP and LTD can reversibly affect the synaptic strength guided by the patterns of synaptic activity.
Mechanisms of Long-Term Depression
Molecularly, LTD is also initiated due to a calcium influx via NMDARs. However, in contrast to a large and fast increase in calcium concentration, which drives LTP, LTD is promoted by a small and slow rise in calcium concentrations.
Clinical Relevance – Fragile X syndrome
Fragile X syndrome (FXS) is an X-linked inherited neuropsychological disease caused by a deficiency in mental retardant protein fragile X (FMRP). Individuals with FXS experience mild-to-moderate intellectual disability, often co-occurring with attention deficit hyperactivity disorder (ADHD), social anxiety and autism.
FMRP is an mRNA binding protein which transports newly synthesised proteins out of the cell nucleus and to the neuronal synapses. Hence, its deficiency may lead to the subsequent abnormalities in the function of synapses, including impaired neuroplasticity.
To further explore the pathophysiology of Fragile X syndrome (FXS) scientists created the FMR1 knockout mice i.e. mice which are also unable to produce FMRP. These mice showed deficits in synaptic plasticity including abnormal long-term potentiation (LTP) and long-term depression (LTD).
Additionally, dysregulation of synapses has been observed on histology where a greater density of immature long and thin dendritic spines of neurons have been observed. Hence, abnormal synaptic plasticity is likely to lead to intellectual disability and a range of other neuropsychological diseases.