Chu HY, Atherton JF, Wokosin D, Surmeier DJ, Bevan MD. Heterosynaptic regulation of external globus pallidus inputs to the subthalamic nucleus by the motor cortex. Neuron. 2015;85:364–376. doi: 10.1016/j.neuron.2014.12.022
Recent reports have emphasized that parkinsonism is associated with striatal1,2 and extrastriatal nondopaminergic plasticity. As an important example, a paper by Fan et al.3 demonstrated a strengthening of the gamma-aminobutyric acid (GABA)ergic pallidosubthalamic connection, which may be relevant for the development of abnormal burst discharges and oscillatory activity in the subthalamic nucleus (STN) in dopamine-depleted rodents.
The new report by Chu et al. shows that this phenomenon may result from increased activity at glutamatergic corticosubthalamic projections, mediated via activation of N-methyl-d-aspartate (NMDA) receptors. This “heterosynaptic” long-term potentiation (hLTP) of pallidosubthalamic synapses occurred together with long-term potentiation (LTP) of the corticosubthalamic pathway. Furthermore, they found that hLTP involved increased postsynaptic GABA-A receptor expression in STN and an increase in presynaptic active zones in GABAergic pallidosubthalamic terminals, perhaps triggered by retrograde nitric oxide signaling. Finally, knockdown of subthalamic NMDA receptors prevented the previously observed plasticity at pallidosubthalamic synapses in parkinsonian animals, suggesting that hLTP is, in fact, responsible for it.
The newly described heterosynaptic regulation may be a homeostatic mechanism, by which excitatory glutamatergic drive of STN neurons along the corticosubthalamic pathway triggers GABAergic inhibition along pallidosubthalamic inputs. Normally, the extent of hLTP would be modest, because cortical and pallidal STN inputs are not synchronized and frequently shunt each other. In the parkinsonian state, it may become more pronounced, because pallidal and cortical inputs to STN show greater temporal separation, allowing hLTP and LTP to develop. This is not a runaway feed-forward process, however: in Chu et al.’s experiments, hLTP quickly reached a functional ceiling in dopamine-depleted animals. Furthermore, parkinsonism (in primates) is associated with a loss of cortical terminals in STN,4 which may limit the development of LTP/hLTP.
If NMDA-receptor–dependent hLTP in STN is indeed responsible for some of the pathological firing patterns in the parkinsonian state, therapies that specifically target these receptors may warrant renewed exploration.
Footnotes
Relevant conflicts of interest/financial disclosures: Nothing to report. Author roles may be found in the online version of this article.
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