Rashmi Venkatesh
Neuropharmacology EssayWhen discussing synaptic plasticity, the majority of research is concentrated on addressing long-term depression and long-term potentiation1. The broad problem that Turrigiano et al1 serve to answer is to provide more information on an understudied aspect of synaptic plasticity: the mechanisms that underlie the strength of a neuron1. In doing so, they introduce the activity dependent relationship of synaptic plasticity1. The experiments conducted rely on two observations concerning mEPSCs (miniature excitatory postsynaptic potential): chronic blockade of cortical activity will increase mEPSC amplitude without influencing kinetics1 and blocking GABA inhibition over a 48-hour period will initially raise firing rates but will eventually return firing rates to control level1. These observations give way to the concept of ‘synaptic scaling’, a mechanism that counteracts the destabilization of Hebbian modification1 as well as acting as a protective measure against firing saturation for developmental neurons1.
The first experiment conducted by Turrigiano et al1 utilizes postnatal cortical pyramidal neurons of rats to determine if AMPA mediated currents are scaled based on neuronal activity1. Here the authors make use of small molecules comes into play. The experiment makes use of the neurotoxin tetrodotoxin (TTX)1 and bicuculine (GABA antagonist)1, which were used for two separate growth cultures (citation). The control mEPSC amplitude was 13.6 +/- 0.7 pA1. These two cultures confirmed the two key observations mentioned earlier: TTX blocked firing but produced a large increase in mEPSC amplitude (192 +/- 16%)1 while bicuculine’s blockade of GABA inhibition decreased mEPSC amplitude (70+/- 4%)1. Through this experiment, authors were able to conclude that the amplitude of AMPA mediated currents is dependent on changes in activity1, thus confirming the relationship of synaptic plasticity as a function of activity. The authors were also able to rule out the influence of NMDA signaling on mEPSC amplitudes. A culture was grown with the NMDA antagonist AP51 (another small compound), and no change in firing rates1, area1 or mEPSC1 was observed. These results further affirm the effect of activity blockade on synaptic plasticity and how, unlike certain types of LTD and LTP, synaptic strength regulation as a result of activity blockade is not a product of NMDA signaling1.
Turrigiano et al1 also sought to verify another aspect of their observations: that activity blockade does not influence mEPSC kinetics. When the average mEPSC waveforms were scaled and graphed, no difference was observed in the kinetics of the unscaled (average) or the scaled average1 . In addition, this new form of synaptic plasticity also differs from LTP in that there were no significant differences in mEPSC frequency1 observed. These results are concurrent with other studies that conducted similar experiments. Benson and Cohen2 were able to prove that neural activity was not needed for the isolation of synaptic terminals2. Both studies mentioned explain that changing neuronal activity has little impact on the placement of synapses1,2.
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With regards to synaptic scaling, as mentioned earlier, one of this mechanism’s functions is to prevent against the saturation of firing rates and maintain the firing rates at control/normal level. In order to validate this ‘homeostatic’ mechanism, Turrigiano et al1 grew cultures with bicuculine1 and recorded firing rates1. In line with the key observation, firing rates initially rose (0.4 +/- 0.1 to 1.1 +/- 0.2 Hz)1, and after 48 hours, the firing rates were significantly reduced (0.24 +/- 0.06 Hz)1. Through this experiment, the authors were able to conclude that there is indeed a homeostatic regulation to firing rates1, in which increased levels are brought back down to normal1. Conversely, the use of tetrodotoxin instead of bicuculine saw increased activity levels3, even after the TTX had been removed. Turrigiano et al1 propose that this bidirectional regulation1,3 of mEPSCs is a factor that leads to the firing rates being controlled through a homeostatic mechanism. The role of the small molecule glutamate also was important in further clarifying the mechanism. In comparison to TTX, when glutamate was given to pyramidal neurons, no variations in amplitude1 was seen. These results imply that glutamate uptake or removal does not significantly influence mEPSC amplitude1, and that changes in amplitude are more attributed to postsynaptic changes1, particularly in receptor number and function1. The synaptic receptors thus are involved in the regulation of firing rates1.
Finally, the authors attempt to further define synaptic scaling. Turrigiano et al (1998) plotted control amplitudes versus bicuculline and TTX amplitudes1, and the resulting slopes (2.73 for TTX and 0.66 for bicuculline)1 when scaled multiplicatively1, were near superimposable1 over the control distributions1. The authors introduce the concept of multiplicative scaling into the research field, and they assert that this mechanism allows for a neuron’s ability to regulate firing rates as a result of excitation1.
Having discussed the various experiments conducted, the authors of Activity-dependent scaling of quantal amplitude in neocortical neurons main contributions to the field of neuroscience are presenting a type of synaptic plasticity that influences all a neuron’s synaptic input though alterations in neuronal activity1. They also introduced the homeostatic nature of synaptic plasticity, through the utilization of glutaminergic synapses. The use of small molecules like TTX and bicuculline were utilized for culture growth and compounds like AMPA and NMDA were also used in order to prove the relationship between activity and synaptic plasticity. Concerning their overall impact on the field, the discovery of homeostatic control of synaptic plasticity, sparked further research into that topic. The homeostatic regulation was further expanded to include scaling of vesicular transporters, VGLUT1 and VGLUT24 . The reciprocal4 regulation of these receptors’ activity is proposed as being feedback regulators4 for synaptic transmission. More recently, and with regards to the medical field, this idea of homeostatic regulation has been hypothesized to be linked to the development of Alzheimer’s Disease5. In their research published, Styr and Slutsky5 propose a hypothesis in which the early stages of Alzheimer’s disease could be due to the instability of neuronal circuits5 which a result of the disruption in homeostatic control5 of synaptic plasticity are. In addition, the research by Turrigiano et al1 led others to expand on possibilities suggested by the authors. At the end of the article, the authors remark that synaptic scaling could possibly lead to competition among synapses as they contend for strong inputs1. Further research on this synaptic competition has been made as researchers have proposed a mathematical model6 explaining this mechanism. This model also proceeds to reaffirm the concept of multiplicative scaling and how competition of synapses produces this mechanism1,5.
The authors in the last few paragraphs of the article propose a couple of possibilities that could reasonably occur based off what they have discovered through their experiments, but do not provide any proof to these potentials. For example, while the authors have proven that it is postsynaptic changes that are the key factor upon activity-based regulation of mEPSC amplitudes, they also allude to possible presynaptic changes as well1. This could be a direction that further research could expand upon and seek to verify. Another thread the authors leave hanging includes the possible link between circuit formation1 and a neuron’s ability to modulate excitatory input1. Considering the importance of establishing neural networks to developing neurons, this seems like the logical next step to follow up from Turrigiano et al work1.
References
1. Turrigiano GG, Leslie KR, Desai NS, Rutherford LC, Nelson SB. Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature. 1998;391(6670):892-896. doi: 10.1038/36103.
2. Benson DL, Cohen PA. Activity-independent segregation of excitatory and inhibitory synaptic terminals in cultured hippocampal neurons. J Neurosci. 1996;16(20):6424. http://www.jneurosci.org/content/16/20/6424.abstract. Accessed November 22, 2018.
3. Ramakers GJA, Corner MA, Habets, A. M. M. C. Development in the absence of spontaneous bioelectric activity results in increased stereotyped burst firing in cultures of dissociated cerebral cortex. Experimental Brain Research. 1990;79(1):157-166. doi: 10.1007/BF00228885.
4. De Gois S, Schafer MK, Defamie N, et al. Homeostatic scaling of vesicular glutamate and GABA transporter expression in rat neocortical circuits. J Neurosci. 2005;25(31):7121-7133. doi: 25/31/7121.
5. Styr, Slutsky. Imbalance between firing homeostasis and synaptic plasticity drives early-phase Alzheimer’s disease. Nature Neuroscience. 2018:463-473. doi:10.1038/s41593-018-0080-x.
6. Triesch J, Vo AD, Hafner AS. Competition for synaptic building blocks shapes synaptic plasticity. Elife. 2018;7:e37836. Published 2018 Sep 17. doi:10.7554/eLife.37836.
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