The ability of the brain to adapt and reorganize in response to external stimuli was first introduced as an idea in 1890 by William James in his “Principles of Psychology,” while the term “neural plasticity” was subsequently proposed by the Polish neuroscientist Jerzy Konoski. Contrary to the consensus of the 20th century, newer findings suggest that most brain functional areas are not immutable after childhood and thus, a degree of plasticity is retained throughout life. It is thought that this capability entails constant remodeling of the synapse network configuration, fine-tuning of the properties of individual synapses, as well as neurogenesis.1,2 In the clinical world, an attempt to maximize the benefits of this plasticity after nervous system injury is made through intensive rehabilitation. The yielding results are variable, depending on the extent of the initial insult, the age, the affected area, the comorbidities of the patient etc. In general though, they are far from perfect, as certain functional areas in the brain are less amenable to reorganization after a specific “critical period” of maximal plasticity, usually present in younger ages.
In mice, there is a similar critical period for ocular dominance plasticity, during which monocular visual deprivation shifts neuronal responses in the binocular visual cortex away from the deprived eye and toward the non-deprived eye. This critical period coincides with the development of intra-cortical inhibitory synaptic transmission and corresponds to the fourth postnatal week, when the inhibitory neurons are ∼33 to 35 days old.3 Pharmacologic augmentation or reduction of this inhibitory synaptic transmission during or before the critical period results in analogous effects in plasticity, causing precocious onset or inhibition respectively. The same pharmacologic manipulations after this period, however, prove largely ineffective.4,5 A group of investigators from the University of California-San Francisco, elegantly managed to regenerate an ocular plasticity period in adult mice, through the transplantation of cortical inhibitory neurons and published their results in the Science magazine in February 2010.6 Notably the reconstitution of plasticity was achieved at time-points when pharmacologic interventions were ineffective. The group observed that transplanted inhibitory neurons, by receiving excitatory synapses and making inhibitory synapses onto host cortical neurons, promote plasticity when they reach a cellular age equivalent to that of endogenous inhibitory neurons during the normal critical period (33–35 days). Based on these findings, they concluded that ocular dominance plasticity is regulated by the execution of a maturational program, intrinsic to inhibitory neurons.
More specifically, inhibitory neurons, tagged with fluorescent dyes from the medial ganglionic eminence (MGE) of the embryonic ventral forebrain, were transplanted into sites flanking the host primary visual cortex. By studying the morphologies, molecular phenotypes, spatial distributions, and densities of transplanted cells, the investigators observed that the transplanted cells had migrated into all layers of the host visual cortex and developed morphologies of mature inhibitory neurons. A series of elegant experiments involved the transplantation of MGE inhibitory neurons in host mice and evaluation of the shift in visual cortex dominance after monocular visual deprivation (MD). Hosts of different ages were transplanted, treated with MD at different time-points after transplantation, and evaluated for a shift in visual cortex dominance. Through these experiments it was concluded that the cellular age of the transplanted inhibitory neurons, rather than the age of the host at transplantation, was crucial for the induction of plasticity. This age was found to be 33 to 35 days, corresponding to the cellular age of the intrinsic inhibitory neurons during the critical period. Less or more than 33 to 35 days after transplantation, MD yielded less than half the shift in the visual cortex dominance. Furthermore, it was concluded that the induced plasticity period after transplantation was an isolated phenomenon, not dependent by, and not affecting the normal critical plasticity period in the fourth postnatal week. Variations in transplanted cell densities and spatial distributions could not account for why the transplant-induced plasticity peaked 33 to 35 days after transplantation, again pointing to the cellular age as the main determinant.
Next, the investigators studied the actual effects of the transplanted neurons by making whole-cell current-clamp recordings, from transplanted and host neurons. Compared to the host inhibitory neurons, transplanted neurons had individually weaker synaptic contacts but much more numerous. Based on these results, the investigators speculated that the transplanted inhibitory neurons have the ability to reorganize the cortical circuitry, by introducing a new set of inhibitory synapses, rather than simply augmenting the strength of the endogenous, mature inhibitory connections.
The group from UCSF has provided very exciting as well as promising data. Anyone who deals with the neural tissue and its “lack of forgiveness” to injury will of course find the idea of translating the concept of inducible plasticity into a powerful clinical tool very appealing. The use of intensive rehabilitation, in conjunction with the multiplying effect of an induced receptiveness, is expected as a ground-breaking landmark in clinical neurosciences. The use of inhibitory neuron transplantation for this induction will definitely raise many technical, as well as ethical difficulties, and it remains to be seen whether it is indeed an answer. Studies such as the current one, nonetheless, continue to make leaps toward what was formerly considered impossible and open new doors to brain repair therapeutics.
FIGURE. A, visual re...Image Tools
JEONG EUN KIM
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