**3. Long term potentiation**

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 frequencies (10 to 200 Hz).

#### **3.1 Phases of LTP**

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).

Molecular Mechanisms in Synaptic Plasticity 299

another afferent on the same cell, then the weakly stimulated afferent also exhibits LTP (Levy & Steward, 1979). This property is called as associativity. This property makes LTP an attractive mechanism for associating two pieces of information being conveyed by different

LTP can also be generated by weaker stimulation of a crucial number of presynaptic fibres to achieve a threshold stimulation to activate a postsynaptic neuron to induce LTP. This property is called cooperativity because different presynaptic fibres are cooperatively

In addition to the above mentioned three characteristics, persistence can also be included as a fourth characteristic. LTP is persistent, lasting from several minutes to many months as

The cellular and molecular mechanisms of LTP induction are comprised of many events such as covalent modification of pre-existing proteins, the activation of cellular programs for gene expression and increased protein synthesis. The regulatory events move from the synapse to the nucleus and then back to the synapse in the course of LTP

LTP induction experiments have mostly been done in hippocampal excitatory synapses. The hippocampus is divided into three distinctive regions composed of three distinctive kinds of cells. The dentate gyrus (DG), which is composed of granule cells and the CA3 and CA1 regions, which are composed of pyramidal cells having different properties. These regions are connected by well defined pathways through which signals traverse the hippocampus. The perforant fibre pathway (pp) from the entorhinal cortex forms excitatory connections with the granule cells of the DG. The granule cells give rise to axons that form the mossy fibre pathway (mf), which connects with the pyramidal cells in area CA3 of the hippocampus. The pyramidal cells of the CA3 region project to the pyramidal cells in CA1

LTP is widely studied in the CA1 region of the hippocampus (Bliss and Collingridge, 1993; Reymann and Frey, 2007). The establishment of LTP in the CA1 region requires both presynaptic activity and large postsynaptic depolarization. The original stimulus protocol used by Bliss and Lomo in the anesthetized rabbit ranged from 10 to 100 Hz (Bliss & Lomo, 1973). Since that time, a variety of LTP induction protocols from different research groups have emerged in the literature. Most involve trains of high-frequency stimulation (tetanization) that are delivered to presynaptic axons. The tetanization typically lasts several

The induction of LTP requires an influx of calcium into the postsynaptic neuron that can be

either through NMDAR dependent or NMDAR-independent mechanisms.

sets of afferents that synapse on the same postsynaptic cell (Malenka, 2003).

**3.3.3 Cooperativity** 

eliciting LTP.

induction.

**3.3.4 Persistence** 

long as the memory persists.

**3.4 Molecular mechanisms of LTP** 

by means of the Schaffer collateral pathway (Fig. 1).

seconds and is delivered at frequencies of 25 to 400 Hz.

### **3.2 Types of LTP**

Even though plasticity events can be distinguished as either LTP or LTD, a huge variation in forms of LTP has also been observed. Several factors contribute to these different types of LTP. LTP varies with the type of molecular pathway involved in its induction as can be seen in the case of LTP in hippocampal CA1 region which is either N-methyl-D-aspartate receptor (NMDAR) dependent or independent. Different regions of brain show different forms of LTP. The age of the organism also contributes to the variation in LTP. LTP in neonatal (<9 postnatal days) rodent hippocampal CA1 region is different from that in mature animals (Yasuda et al., 2003). Based on the pre and postsynaptic activity patterns required for induction, LTP can be classified as Hebbian, Non-Hebbian, anti-Hebbian and neo-Hebbian. Hebbian LTP requires both pre and post synaptic activity at the same time for its induction (Hebb, 1949). Non-Hebbian LTP requires activation of either pre or post synaptic compartment and does not need simultaneous depolarization of pre- and postsynaptic cells; an example of this occurs in the mossy fibre hippocampal pathway. Anti-Hebbian LTP can be formed by a conjunction of presynaptic depolarization and postsynaptic hyperpolarization (Lamsa et al., 2007). This can be induced in several classes of interneurons in strata oriens and pyramidale by high or low frequency stimulation patterns applied to axon collaterals of local pyramidal neurons, as long as the postsynaptic membrane potential is kept negative to the action potential threshold (Kullmann & Lamsa, 2008). In addition to these three forms of LTP, neo-Hebbian LTP has been described recently which is related with the late phase of LTP induced by an NMDAR dependent process (Lisman et al., 2011). This form of LTP not only depends on the two factors of the Hebbian condition (glutamate release and postsynaptic depolarization), but also on a third factor, dopamine release. Dopamine will enhance the protein synthesis within the dendrites of hippocampal neurons (Smith, 2005).

Analyses of LTP decay rates and biochemical mechanisms have revealed three different forms of LTP (LTP-1, 2 and 3) in the hippocampus. LTP-1, induced by a single train of conditioning stimulation, is short lasting (2–3 h *in vitro*) and is dependent on post-translational modifications of existing synaptic proteins. LTP-2, induced by several repetitions of a conditioning train, is an intermediate form of LTP that depends on protein synthesis but not transcription of new mRNA. Finally, LTP-3, induced by multiple, spaced repetitions of conditioning stimulation, is very durable (perhaps even permanent in some cases, e.g. Abraham et al.*,* 2002) and requires gene transcription and translation (Raymond, 2008).

#### **3.3 Properties of LTP**

Three key properties of LTP were elucidated in the 1970s and early 1980s. All of these can be explained using NMDA receptor dependent LTP mechanisms.

#### **3.3.1 Input specificity**

LTP can be generated only in those synapses which had undergone activation and not in adjacent synapses. But this is not valid for closely located synapses.

#### **3.3.2 Associativity**

One of the interesting properties of LTP mechanism is its associativity. If a weak non-LTP inducing stimulation in one afferent is paired with a strong LTP inducing stimulation in another afferent on the same cell, then the weakly stimulated afferent also exhibits LTP (Levy & Steward, 1979). This property is called as associativity. This property makes LTP an attractive mechanism for associating two pieces of information being conveyed by different sets of afferents that synapse on the same postsynaptic cell (Malenka, 2003).
