Synaptic plasticity

Synaptic plasticity is thought to be one of the mechanisms underlying learning and memory. It exists in many forms, ranging from changes of property in a single synapse to large-scale modifications of synaptic strengths, also including formation or pruning of synaptic connections (Figure 1.4). Synaptic plasticities are normally categorized as short-term and long-term. While short-term synaptic plasticity leads to transient changes in synaptic functions (lasting from milliseconds to minutes) that regulate the moment-to-moment information flow through the circuits, long-term synaptic plasticity leads to persistent changes in synaptic strengths (lasting from hours to the lifetime of the synapse) that adaptively alter synaptic function in response to activities and computational demands (Collingridge, Peineau, Howland, & Wang, 2010; Granger &

Nicoll, 2014; Zucker & Regehr, 2002).

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Figure 1.4. Different forms of synaptic plasticity.

Short-term plasticity can be further divided into presynaptic and postsynaptic plasticities. In the presynaptic forms of short-term plasticity, there can be depression (hundreds of milliseconds to seconds), facilitation (hundreds of milliseconds to seconds), as well as augmentation and post-tetanic potentiation (PTP) (tens of seconds to minutes) (Fioravante & Regehr, 2011) (Figure 1.5).

Presynaptic depression can be observed at many synapses when stimulated repetitively at short time intervals. Several factors can account for the reduced synaptic strength, including depletion of the readily releasable pool, inactivation of release sites, and decreased presynaptic calcium influx.

Presynaptic facilitation is often found at synapses with a low initial release probability (e.g. mossy fiber synapses), and repeated stimulation at short time intervals can lead to a transient increase in release probability of these synapses. Increased presynaptic residual calcium level, saturation of endogenous calcium buffers, and facilitation of calcium currents are considered to be contributing to this phenomenon (Fioravante & Regehr, 2011). At Mf-CA3 synapses, this type of plasticity are often registered with two protocols: paired-pulse (PP) or even longer train protocol with repetitive stimulation at short intervals, and frequency facilitation (FF) protocol with increasing stimulation frequency from basal (0.1Hz) to moderate (1-3 Hz) (Gundlfinger, Breustedt, Sullivan, & Schmitz, 2010; Nicoll & Schmitz, 2005; Salin, Scanziani, Malenka, & Nicoll, 1996). Post-tetanic potentiation (PTP) and augmentation is another form of short-term plasticity noticed at Mf synapses, which means enhancement in

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Figure 1.5. Presynaptic mechanisms of use-dependent short-term plasticity.

Schematic illustrations of different mechanisms for use-dependent short-term plasticity:

A. depression, B. facilitation, C. post-tetanic potentiation (PTP) and augmentation.

RRP: readily releasable pool of vesicles; Cares: residual calcium. Adapted from (Fioravante & Regehr, 2011)

synaptic strength following sustained, high-frequency synaptic activation (Vyleta, Borges-Merjane, & Jonas, 2016).

Other forms of short-term plasticity involving both pre- and postsynaptic elements and retrograde messengers have been reported, such as endocannabinoids mediated depolarization-induced suppression of inhibition (DSI) (Regehr et al., 2009; Wilson &

Nicoll, 2002), and depolarization-induced potentiation of excitation (DPE) at the Mf synapses (Carta, Lanore, et al., 2014).

On the other hand, long-term plasticity also exists in various forms, including but

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not limited to: NMDA-dependent LTP, presynaptic LTP, NMDA-dependent LTD, mGluR-dependent LTD, eCB-LTD, which were nicely reviewed by Kauer & Malenka (Kauer & Malenka, 2007) (Figure 1.6). Interestingly, albeit the presence of functional NMDA receptors (Weisskopf & Nicoll, 1995), a form of presynaptic NMDA-independent LTP is characterized at Mf-CA3 synapses, which is quite different from the canonical NMDA-dependent LTP found in other regions of the brain (Harris &

Cotman, 1986).

In addition, other forms of plasticity such as homeostatic plasticity (up- or down-scaling of excitability), metaplasticity (plasticity of synaptic plasticity), structural plasticity like formation or deletion of synapses are also actively regulating neuronal network activities (Fernandes & Carvalho, 2016; Holtmaat, Randall, & Cane, 2013;

Hulme, Jones, & Abraham, 2013).

Figure 1.6. Well-described forms of LTP and LTD.

Highly simplified diagrams of the induction and expression of synaptic plasticity observed in the rodent brain. A. NMDAR-dependent LTP is dependent on postsynaptic NMDAR activation and calcium/CaMKII signaling pathway for its initiation. The voltage-dependent relief of the magnesium block of the NMDAR allows the synapse

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to detect coincident presynaptic release of glutamate and postsynaptic depolarization, leading to AMPAR insertion into the postsynaptic membrane. B. Presynaptic LTP has been best characterized at hippocampal Mf–CA3 synapses. Repetitive synaptic activity leads to the entry of presynaptic Ca2+, which activates a Ca2+-sensitive adenylate cyclase (AC) leading to a rise in cAMP and the activation of cyclic AMP-dependent protein kinase A (PKA). This in turn modifies the functions of Rab3a and RIM1α leading to a long-lasting increase in glutamate release. C. NMDAR-dependent LTD is triggered by Ca2+ entry through postsynaptic NMDAR channels, leading to increases in the activity of the protein phosphatases calcineurin and protein phosphatase 1 (PP1).

The primary expression mechanism involves internalization of postsynaptic AMPARs and a downregulation of NMDARs by an unknown mechanism. D. mGluR-dependent LTD has been best characterized at cerebellar parallel fibre–purkinje cell synapses and hippocampal synapses. Activation of postsynaptic mGluR1/5 triggers the internalization of postsynaptic AMPARs, a process that under some conditions appears to require protein synthesis. E. Endocannabinoid-LTD is the most recently discovered form of LTD. Either mGluR1/5 activation, leading to activation of phospholipase C (PLC) or an increase of intracellular Ca2+ (or both), in the postsynaptic neuron initiates the synthesis of an endocannabinoid (eCB). The eCB is subsequently released from the postsynaptic neuron, travels retrogradely to bind to presynaptic cannabinoid 1 receptors (CB1R), and this prolonged activation of CB1Rs depresses neurotransmitter release via unknown mechanisms. Adapted from (Kauer & Malenka, 2007).