Summary
In the BGS of control mice, a single and brief stimulation of the STN in the continuous presence of a GABAA antagonist generates similar long lasting excitations in GP, EP and SNr neurons. These excitations consist of a monosynaptic EPSC of small amplitude and short duration followed by a long-lasting barrage of asynchronous, polysynaptic, AMPA-mediated EPSCs superimposed on a slow NMDA current. These polysynaptic EPSCs depend on the intensity of STN stimulation and on the presence of the STN in the BGS, and generate long lasting bursts of spikes (for several hundreds of milliseconds) in GP, EP and SNr neurons.
In the BGS of dopamine-depleted mice, the same STN stimulation generates compound EPSCs in GP and SNr neurons. However, this response has a much lower threshold of activation (2-3 times lower), and may reverberate several times and be spontaneously generated.
In order to understand the mechanisms at the level of the STN, we studied the response of STN neurons either to STN stimulation or stimulation of its glutamatergic afferent fibres running in the internal capsule. In control BGS the response of STN neurons consists of a monosynaptic EPSC of short duration and small amplitude mediated by AMPA receptors only. But in dopamine-depleted BGS this EPSC is dramatically increased in amplitude and duration. This complex EPSC may reverberate several times in response to a single STN stimulation and can be spontaneously generated. Similar results were obtained in three dopamine-depleted preparations: BGS from 6-hydroxydopamine-treated mice, BGS from reserpinized mice and BGS incubated with D1-like antagonists.
We propose that a glutamatergic network present within the STN is under the strict negative control of dopamine D1-like receptors. Relieved from dopaminergic inhibition, it can spontaneously generate bursts of EPSCs that activate depolarizing voltage-dependent currents of STN neurons. This system greatly amplifies the response to incoming excitation by generating bursts of spikes that will in turn generate bursts of spikes in GP, EP, and SNr neurons.
From a functional point of view, we propose:
- Under control conditions, the STN-evoked long lasting excitation of the GABAergic basal ganglia output neurons (EP/SNr) represents the global NoGo signal that inhibits thalamo-motor cortical programs until another program is triggered. This signal is likely terminated by the recurrent GP-STN GABAergic pathway.
- In dopamine-depleted conditions spontaneous bursts of EPSCs in STN neurons may underlie the spontaneous bursting state present in neurons of the extrastriatal network (STN, GP, EP, SNr). This bursting state of the STN could be maintained by incoming excitations from cortical, thalamic or PPN neuronal afferents to the STN and synchronized by the GABAergic GP-STN connection.