The critical period, also known as the duration in which an organ undergoes development, is a stage where development has the potential to become disturbed1. Accordingly, the important aspect of the critical period is the phenomenon of brain plasticity, which is the capability of the brain to undergo the reconstruction of neural pathways on the basis of various experiences. During the critical period, plasticity is at its peak2 and consequently, the neural activity is particularly distinct in the visual cortex development3, which is a portion of the occipital lobe and has a significant role in visual perception1. Subsequently, the visual cortex is an area in which plasticity is particularly evident and the development of ocular dominance plasticity occurs in this area. Ocular dominance plasticity is limited to the critical period and at this stage, closing one eye for a short period of time i.e. monocular deprivation, results in the shifting of ocular dominance towards the eye that is open; this is to maintain neural pathway construction4. The medial (middle) and caudal (near the tail) ganglionic eminences are the location where inhibitory neuron precursors are generated2. The inhibitory neuron precursors release GABA (the inhibitory neurotransmitter) and are significant in making connections to other neurons in which, they receive excitatory signals and undergo inhibitory signalling10. Importantly, the stability of excitatory and inhibitory signalling is vital in the visual system9. The ganglionic eminence of the ventral embryonic forebrain is a structure present in the human brain when it is undergoing the development process5 and ultimately, to test this interpretation, it is suggested that through transplantation of these inhibitory neuron precursors into older animal brains, it is thought that this may achieve ocular dominance plasticity, not just during the critical period but even after the critical period has passed; this means that a novel period of plasticity will be formed. It is thought that this may perhaps assist therapeutically and possibly aid in brain repair2 for damage to the brain; stroke patients, aging, mental illnesses; like schizophrenia and Parkinson's disease9.The main aim of this study is to demonstrate that the transplantation of inhibitory neurons, after being injected as embryonic cells, develop into mature inhibitory neurons and influence ocular dominance plasticity subsequent to the normal critical period2.
Approach of the analysis
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Inhibitory neuron precursors (INP's) were removed from the medial ganglionic eminence (MGE) of the embryonic mouse at embryonic day 13.5-14.5 and underwent transplantation into two sites of the primary visual cortex into two postnatal mice P0-P2 and P9-P11 (shown in figure 1). Subsequent to the injection, the inhibitory neurons scatter and mature into GABA releasing inhibitory neurons. To ensure all aspects were covered, other experiments that involve cells transplanted from the lateral ganglionic eminence (LGE) from a donor at E13.4-14.5 and dead (freeze thawed) MGE cells were also transplanted into the hosts. To find out whether it was the cell age or the host age that was significant in plasticity, the INP's were left in the host mice brains to undergo development for a series of specific days (P0-2 mouse was left for 33-35 days and 43-46 days and P9-P11 mouse was left for 17 days, 25-27 days and 33-35 days). Then for four days, the mice underwent monocular visual deprivation (MD), a technique that consists of blocking any type of visual signals to one specific eye for a short time period. The eye that was blocked was the opposite side to where the transplantation occurred (the right eye). To observe the outcome of transplantation, optical imaging techniques were used on the basis of intrinsic signals to identify the visual response. Immunostaining techniques were used to stain the host cortex and host endogenous neurons and this aided in recognising cortical integration of inhibitory neurons using histological images. Electrophysiology recordings were used to make whole-cell current clamp recordings to see if the transplanted INP's definitely caused inhibition subsequent to being transplanted2.
The mouse as a model organism
Mice were used in this study because the neurons situated in the mouse visual cortex have quite a diverse receptive field and their response to visual stimuli demonstrates similarity to higher (on the evolutionary tree) animals7. In addition, the visual cortex of the mouse is a resourceful model system and due to the introduction of transgenic mouse technology it has been feasible to study plasticity in the visual cortex in greater detail8.
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Medial ganglionic eminences (MGE) of the ventral forebrain containing the inhibitory neuron precursors
Donor at embryonic day 13.5-14.5
Host mouse #1 at postnatal day 0-2
Host mouse #2 at postnatal day 9-11
Injection of inhibitory neurons into two sites of the primary visual cortex using a glass capillary needle
Glass capillary needle
Figure 1- this figure illustrates the transplantation of the embryonic cells, using a glass capillary needle, from the embryonic donor (E13.5-14.5) into the host primary visual cortex of postnatal mice at different ages (adapted from Southwell et al. 2010 supplementary material).
The peak of ocular dominance plasticity is during the fourth week following birth and this is when cortical inhibitory neurons are approximately 33-35 days old. During this time, monocular visual deprivation causes a shift of the neural response from the closed eye to the open eye. During the critical period (postnatal day 28), mice that didn't undergo any transplantation underwent optical imaging and were found to have a higher response to the contralateral eye (mean ODI=0.22), however; when they underwent 4 days of monocular deprivation of the same eye (contralateral eye) the response indicated a shift of neuronal response to the ipsilateral eye (mean ODI=0.00) table 1 shows ocular dominance index (ODI) representation2.
Quantification summary:the balance of cortical responses towards both eyes using optical imaging:
Table 1- The ODI is the quantification of the cortical response to the eyes of the host mice. Optical imaging maps regions in the cortical layer and the main benefit of this is that it is not an invasive technique11. Data adapted from Southwell et al. 2010
Ocular dominance index (ODI)
The aim of the transplantation of INP's was to identify whether there would be any difference in visual response to the monocular deprivation following the phase of the critical period. Table 2 shows the results after the INP's were left in the host mice brains for a series of specific days. The P0-2 host mouse was studied following 33-35 and 43-46 days after transplantation (DAT) and the P9-11 mouse was studied after 17, 25-27 and 33-35 (DAT). The results below show the outcome2.
Table 2- this table displays the results from the plasticity investigations. Inhibitory neuron transplantation caused plasticity when the host mice were 33-35 days old. However, no plasticity was produced when the inhibitory neurons were 25-27 or 43-46 days old. A strong shift signifies plasticity. (Data adapted from Southwell et al. 2010)
MD caused a shift from the closed (deprived) eye to the non-deprived eye (open). This is the control.
(14-18 days after Critical period)
MD caused a strong shift
MD caused a weak shift
(5-9 days after Critical period)
MD caused a strong shift
MD caused a weak shift
Transplantation of inhibitory neurons had no effect on the normal MD effect as in the control.
LGE cells used rather than MGE cells - MD gave no effect.
Transplantation of inhibitory neuron precursors into host P9-P11 mice caused an increase in ocular dominance plasticity 33-35 DAT when studied at P42-46. The transplantation into P0-P2 host mice did not cause an increase in ocular dominance plasticity at 43-46 DAT (shown in table 2); therefore further experiments were performed on the P0-2 mouse where the results show that there was a strong effect 33-35 DAT in the P0-2 mice and a weak effect 25-27 DAT in the P9-11 host mice; this showed the cell age was significant in plasticity. This gave reason to believe that the transplantation of INP's caused plasticity when they were 33-35 days old but not when 25-27 or 43-46 days old. This indicates that transplantation of INP's caused plasticity after the critical period and further experiments went on to see if plasticity was adjusted when transplanted with INP's at P28 (peak of critical period) and the results show that the response was the same as the untreated mice2. The INP's transplanted from the lateral ganglionic eminence into the P9-11 host mice showed no effect on plasticity and after 33-35 DAT. The dead (freeze-thawed) MGE INP's also showed no effect on plasticity either and this indicates that only the INP's that are alive have an effect in plasticity following the MD experiments2.
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Figure 2- This figure shows the data displayed in table 2; however, the ocular dominance index is displayed here and it is more clear to see the results after the INP's were left to develop in the host mice primary visual cortex for a set of series of specific days. The biggest effect produced by monocular deprivation is 33-35 DAT the statistics in the paper show the significance (Mann-Whitney).
Monocular deprivation had the biggest effect on the visual response in the P9-11 hosts when the cells were 33-35 days old. The ocular dominance shift was the largest; signifying that the MD is causing a shift from the covered (deprived) eye where the visual response is shifting to the non-deprived eye (open eye); this has the highest evidence of OD plasticity. As mentioned initially, the peak of OD plasticity is when the cortical inhibitory neurons are about 33-35 days old; subsequently, 33-35 DAT in the P0-2 host mice showed the highest plasticity effect. The data proves this: P0-2 ODI=0.04±0.05 and P9-11=0.05±0.06, respectively2.
Experiments were undertaken to see the migration of the transplanted INP's in the host mouse visual cortex by immunostaining techniques and it was shown that all the MGE-derived cells that were transplanted 17-46 DAT had the structures comparable to fully grown mature cortical inhibitory neurons. Some developed into glia and others developed into functional subtypes of proteins. The electrophysiology recordings showed that the transplanted INP's were involved in making many synaptic connections albeit, weak ones.
Success and significance of the article
The authors propose that the transplantation of inhibitory neuron precursors do result in ocular dominance plasticity subsequent to the critical period in an older brain. Transplanting the embryonic cells, which later develop into inhibitory neurons that encompass an influence on the development of the brain, cause plasticity in older host brain; however, the study indicates that the consequence of transplantation causes ocular dominance plasticity to take place 33-35 DAT and when mice are aged P42-46 this is the age when the transplanted inhibitory neurons have matured to the normal critical period of connectivity12; in addition, any period greater or fewer than this has an extremely small insignificant effect. During the critical period, when ocular dominance plasticity occurs, any disruption to the inhibitory neuron synthesis could cause a delay in the plasticity. Giving benzodiazepines or other drugs that increase inhibitory circuit formation during the critical period, cause premature plasticity12; however, when the host is aged P42-46 - direct alteration of inhibition by pharmacological substances does not cause plasticity2.
Questions that arise next ask why the transplanted cells cause a production of weak inhibitory synapses, which causes a rearrangement of the cortical circuitry in the host visual cortex2. It is thought that a developmental program controls the critical period and the advantage of this finding helps in assisting brain repair especially in mental disorders such as schizophrenia, where the cortical inhibitory neurons have a development classified as abnormal. This has been displayed in mice, where the abnormal inhibitory neuron development and function has the outcome of irregular behaviour, resembling those seen in schizophrenic patients10.
Future research the paper gave rise to:
Transplantation of inhibitory neuron precursors act as a possible therapeutic aid in treating Epilepsy
Another experiment was proposed, where by inhibitory neuron precursors were obtained from the MGE and transplanted into the striatum of a host rat, whom had Parkinson's disease. Inhibitory neuron precursors were transplanted into the striatum of the rat and the reason why the INP's were taken from the MGE was because it was evident that this specific location had large amounts of GABA-releasing inhibitory neurons and the unique ability of the INP's to migrate, happens on a large scale-basis. Accordingly, the majority of the transplanted GABA-releasing precursors differentiate into different proteins, but only small amounts are enough to help in the improvement of the behaviour and motor abilities in Parkinson's disease. When the inhibitory neuron precursors are injected into the striatum and later mature, they spread and incorporate in the striatum, aiding in therapeutic effects for Parkinson's patients13.
Transplantation of inhibitory neuron precursors act as a possible therapeutic aid in treating Parkinson's Disease
Epilepsy is considered a magnification of electrical excitability in the central nervous system and a feature of this disorder is the seizures, which are high frequency firing of neurons. Since glutamate (excitatory neurotransmitter) is very high in epileptic patients, a target for controlling epilepsy is through increasing the effects of GABA (inhibitory neurotransmitter) since patients with epilepsy tend to have loss if inhibitory neurons in their brain15. The medial ganglionic eminence (MGE) of an embryo is an important location for obtaining inhibitory neuron precursor cells14. Since inhibitory neurons release GABA, it was found that the injection of INP's into a mouse host brain caused a reduction in the time and frequency of seizures; accordingly, this is thought to be an alternative way for epileptic patients to control this disorder as drugs can often cause various side-effects. Electroencephalography (EEG) was used to monitor the electrical activity after the inhibitory neuron precursor transplantation15. GABA inhibition is useful in controlling high levels of excitation commonly observed in epileptic patients; never the less, transplantation is useful when grafted cells cause the disease symptoms to improve15.
Future studies might encompass more about the actual alterations that the INP's transplantation cause and in the future, the exact types of connections may be studied in more detail. Future research might include studies on the time scale that the ocular dominance plasticity occurs for and what kind of effects may go wrong after transplantation16. In the future, this type of transplantation may potentially treat damage to brain circuitry therapeutically in humans instead of model organisms that were used to test this inspiration out on.
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