**Molecular Mechanisms in Synaptic Plasticity**

M. Mayadevi\*, G.M. Archana\*, Ramya R. Prabhu\* and R.V. Omkumar†

*Molecular Neurobiology Division, Rajiv Gandhi Centre for Biotechnology, Thycaud, Kerala, India* 

#### **1. Introduction**

294 Neuroscience – Dealing with Frontiers

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Brain is a sophisticated information processing and storage system with capabilities unmatched by any manmade computers. Neurons, the primary building blocks of the brain are structurally and functionally specialized to do these functions. The neuronal membrane is equipped with several types of ion channel and ion pump proteins which enable it to conduct nerve impulses in the form of electrochemical signals called action potentials. The highly branched structure of the neuron with dendrites and axons helps in not only transmitting these signals but also in information processing by integrating multiple inputs. Storage of information, on the other hand, happens by permanent changes in the brain consequent to activity that will serve the function of recording information input. This remarkable property of the brain is known as plasticity and brings about changes in the structures and functions of the brain in response to internal and external stimuli. Plasticity can be defined as the ability of neural circuitry to undergo modifications consequent to experience and thereby modify future thought, behaviour and feeling. Neuronal activity can modify the behaviour of neural circuits by one of the three mechanisms : (a) by modifying the strength or efficacy of synaptic transmission at pre-existing synapses, (b) by eliciting the growth of new synaptic connections or the pruning away of existing ones, or (c) by modulating the excitability of individual neurons (Malenka, 2002). It is now reasonably well established that synapses are the primary sites of information storage, enabled by synaptic plasticity.

Synaptic plasticity is the cellular phenomenon by which synapses can undergo permanent changes in their properties consequent to specific patterns of activity. Since synaptic activity represents incoming information into the brain, the consequent permanent changes in synapses are thought to serve as the engram or record of the information. Hence mechanisms underlying synaptic plasticity events have attracted considerable attention as the molecular basis of learning and memory.

Synaptic plasticity was first proposed as a cellular mechanism for memory by Donald Hebb in 1949. According to Hebb's postulate, repeated communication between two neurons via

<sup>\*</sup> Equal contribution

<sup>†</sup> Corresponding Author

Molecular Mechanisms in Synaptic Plasticity 297

Several observations from a variety of species indicate that synaptic plasticity and memory are correlative. Behavioural and *in vitro* studies suggest that activity-induced synaptic modulations, such as LTP, play a role in information storage in the brain. This idea has been proposed as the "synaptic plasticity and memory (SPM) hypothesis" (Martin et al., 2000), and has been a major driving force behind the study of synaptic plasticity. Synaptic plasticity includes both short-term changes in the strength or efficacy of neurotransmission as well as longer-term changes in the structure of synapses (Kandel, 2001). Experimental models of changes in synaptic strength or effectiveness in response to repeated electrical stimulation are thought to mimic physiological plasticity at the neuronal level. The efficacy of synaptic transmission could increase as in LTP or it could decrease as in LTD as a result of plasticity. These modifications in synaptic strength, both positive and negative, distributed across millions of connections among neurons, are believed to form the physical

Hippocampal LTP became a favourite model for the study of learning and memory due to the following reasons. First, there is compelling evidence from studies in rodents and higher primates, including humans, that the hippocampus is a critical component of the neural system involved in various forms of long-term memory. Second, several properties of LTP make it an attractive cellular mechanism for information storage. Like memories, LTP can be generated rapidly and is prolonged and strengthened with repetition. It is also input specific in that it is elicited at the synapses activated by afferent activity and not at adjacent synapses

LTP is an activity-dependent, persistent enhancement of synaptic strength. LTP mainly occurs at glutamatergic synapses and is often measured in terms of the magnitude of excitatory post synaptic potential (EPSP) enhancement at a given time-point after induction. This measurement is influenced by the initial magnitude of potentiation and the decay rate of the potentiation and are independently regulated. Generally longer-lasting forms of plasticity are observed following repetitive or tetanic stimulation of synapses with prolonged (approximately 200-millisecond to 5-second) trains of stimuli applied at high

LTP is formed by a series of distinguishable mechanisms. LTP can be divided into two temporally distinct phases such as early and late phases. Early LTP (E-LTP) lasts for about 1- 3 hrs and requires modification of existing proteins and their trafficking at synapses but not *de novo* protein synthesis (Bliss & Collingridge, 1993; Malenka & Bear, 2004). This short lasting form of LTP can be induced by a weak, high frequency tetanus (single train of 100 pulses at 100 Hz). Late LTP (L-LTP) requires the synthesis of RNA, new proteins and protein kinase activity especially cyclic adenosine 3', 5'-monophosphate (cAMP)–dependent protein kinase or protein kinase A (PKA) (Frey et al., 1993; Huang and Kandel, 1994; Nguyen et al., 1994), which lasts for up to 8-10 hrs *in vitro* and weeks *in vivo*. L-LTP can be induced by repeated strong high frequency stimulation such as multiple trains of 100 pulses

at 100 Hz and is necessary for structural modification of synapses (Lu et al., 2007).

and biochemical substrates for learning and memory.

on the same postsynaptic cell (Malenka, 2002).

**3. Long term potentiation** 

frequencies (10 to 200 Hz).

**3.1 Phases of LTP** 

synaptic transmission can cause an enhancement in the efficacy of transmission between those neurons, brought about by biochemical changes at the synapses. Accordingly Hebbian conditioning needs both presynaptic and postsynaptic activity for its induction. This was followed by a search for instances where synaptic efficacy is altered. The discovery of Long term potentiation (LTP) by Bliss and Lomo in 1973 (Bliss & Lomo, 1973) was the first demonstration of synaptic plasticity. LTP had all the characteristics necessary for a mechanism responsible for learning and memory and thus gained acceptance as a cellular correlate or cellular model system for learning and memory. Moreover, the cellular system with reduced complexity compared to the animal models was more amenable for interrogations at the molecular level. LTP thus became an essential component of a paradigm in which initial insights on molecular mechanisms are provided by experiments involving LTP which could then be validated in higher animal models.

In addition to the fundamental interest of how learning and memory are performed by brain, the study of synaptic plasticity is also attractive as it could lead to practical applications. The principles governing the workings of the molecular machineries involved in synaptic plasticity could be useful in the design of manmade memory devices. In the case of many CNS disorders, early aberrations at the molecular level are likely to involve synaptic plasticity mechanisms since the initial clinical symptoms very often involve cognitive impairments such as deficits in learning and memory. These mechanisms could be possible targets for early therapeutic intervention, provided they drive further molecular processes leading to the pathology of such diseases. Understanding of the mechanisms of synaptic plasticity would be of great therapeutic value in such instances.

A major challenge in understanding the molecular mechanisms of synaptic plasticity has been the diversity in the underlying mechanisms in different parts of the brain. The current article has reviewed the literature on molecular mechanisms that are involved in the induction and maintenance of different forms synaptic plasticity, mainly LTP and long term depression (LTD) and has attempted to simplify the scenario by extracting general features possessed by these mechanisms. Impairments in synaptic plasticity that could occur in disease conditions have also been touched upon.
