**7. References**

290 Neuroscience – Dealing with Frontiers

recruitment, possibly as part of a process that has directed the homeostasis described above toward repair. The failure of our attempts to facilitate this recruitment using 1-EBIO or quinpirole in the present study might be due to depletion of the population of recruitable cells by this spontaneous recovery. It also indicates the rate of replenishment of the recruitable population (i.e. neurogenesis) is not very high, since not enough were generated within the timeframe of our experiments (4-17 weeks) to significantly impact the TH+ population. This would fit with the consensus in the literature that the rate of adult midbrain neurogenesis is not very high (Shan et al. 2006, Zhao *et al.* 2003) or zero (Aponso *et al.* 2008, Chen *et al.* 2005, Cooper & Isacson 2004, Frielingsdorf *et al.* 2004, Lie *et al.* 2002, Peng *et al.* 2008, Yoshimi *et al.* 2005). This point brings us to another caveat of the present experiments, which is the very rapid depletion of SNc DA neurons by 6-OHDA injection may not be the best PD model in which to study activity-dependent DA phenotype recruitment. Perhaps a model in which the rate of degeneration is much slower, which better mimics the situation in PD, would provide enough time for the recruitable population

In summary, our working model is: (1) The nigrostriatal DA pathway is under homeostatic control to maintain a constant level of striatal DA signaling; (2) This is achieved at the level of individual SNc cells via activity- and Ca2+-dependent alterations in DA (TH) gene expression; (3) It is also achieved at the level of D2 DA receptor-mediated striatonigral feedback circuitry (the indirect pathway) leading to changes in the number of SNc DA cells; (4) A population of relatively mature NeuN+ but TH- cells located in and immediately surrounding SNc is available to be rapidly recruited into and out of the DA population; (5) This recruitable population of cells can be rapidly depleted (i.e. recruited into the DA population) in response to perturbations of the system (e.g. altered SNc neuronal activity, nigrostriatal DA signaling, or 6-OHDA), but is only slowly replenished by neurogenesis. The implication of this homeostasis for nigrostriatal DA cell-replacement therapies is that any manipulation designed to increase the number of SNc DA cells is likely to be offset by a homeostatic response. The effects of infusing D2 agonists into the striatum suggest that striatal DA signaling may be a factor. Thus in PD or its models the effect of homeostatic control may be difficult to predict. On the other hand, pharmaceuticals that increase SNc DA cells in normal mice fail to do so in 6-OHDA-lesioned rodents, possibly because the population of recruitable cells is also extensively depleted. Thus, researchers looking to help develop cell-replacement therapies to treat the motor symptoms of PD should consider the effects their interventions might have on nigrostriatal DA homeostasis because: (1) homeostatic responses may be confounding interpretation of the effects of their interventions; and (2) homeostatic responses may need to be addressed also, as part of an

overall strategy to increase cell-based nigrostriatal DA transmission.

Future work should therefore aim to better understand these homeostatic responses by: (1) identifying downstream signaling pathways mediating activity- and Ca2+-dependent changes in DA gene expression; (2) identifying mechanisms of SNc DA phenotype recruitment; (3) identifying the phenotype of recruitable cells; (4) characterizing the ontogenesis of newborn SNc neurons; and (5) investigating mechanisms regulating the rate

of cells to be sustained.

**5. Conclusion** 


Activity-Dependent Regulation of the Dopamine

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**13** 

*India* 

M. Mayadevi\*, G.M. Archana\*,

*Molecular Neurobiology Division,* 

Ramya R. Prabhu\* and R.V. Omkumar†

 *Rajiv Gandhi Centre for Biotechnology, Thycaud, Kerala,* 

**Molecular Mechanisms in Synaptic Plasticity** 

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

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

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

**1. Introduction** 

plasticity.

 \*

 Equal contribution † Corresponding Author

the molecular basis of learning and memory.

