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Non-linear synaptic integration on dendrites of striatal medium-spiny neuron : a computational study

Published in 2016 by Kai Du
This paper was not found in any repository; the policy of its publisher is unknown or unclear.
This paper was not found in any repository; the policy of its publisher is unknown or unclear.

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Abstract

Striatum is the main input nucleus of basal ganglia. Medium-spiny neurons (MSNs), the principal neurons of the striatum, receive convergent excitatory inputs from cortex and thalamus, thus “gate” the information flow to the basal ganglia. The activity of MSNs is further modulated by massive inhibition from their neighboring MSNs as well as from GABAergic interneurons. At corticostriatal synapses in MSNs, a potent and reliable spike timing-dependent plasticity (STDP) can be found. It has been suggested this plasticity follows an “anti-Hebbian” learning rule: pre-synaptic signals preceding post-synaptic action potentials (‘pre-post’ paring) induces LTD while post-synaptic action potentials preceding pre-synaptic signals (‘postpre’ paring) leads to LTP. The long-term potentiation (LTP) relies on NMDAR-mediated calcium influx, while the long-term depression relies on L-type calcium channels and endocannabinoid (eCB) dependent signaling pathways. The sign ofSTDP rule at the corticostriatal synapses appears to be influenced by the presence of GABAergic inputs. In addition to the role of synaptic interactions for modulating and controlling plasticity, synaptic interactions can also give rise to “dendritic plateaus” were found in MSNs. Clustered activation ofspines at distal dendrites, within a short temporal window, can evoke a long-lasting plateau potential in MSNs. It is generally assumed that this supra-linear integration could promote spiking in MSNs, however, it has not been clear how dendritic plateaus are controlled by excitatory and inhibitory inputs in MSNs. In this thesis, using biophysically detailed models of MSNs, we explored: (1) the possible mechanisms of GABA in STDP formation, (2) the roles of different NMDAR subunits in STDP formation, and (3) how dendritic plateaus affect the integration of excitatory and inhibitory inputs in MSNs. We found that in brain slices the GABA tightly controlled the polarity of STDP in MSNs, while blocking GABA could reverse the STDP rule from anti-Hebbian learning to Hebbian. Surprisingly, the model predicted that GABA depolarizes the dendrites during the STDP protocols and such depolarizing effects further change the balance between NMDA-mediated calcium and the calcium influx from L-type calcium channels. In “pre-post” parings, the GABA strength pushes the balance towards L-type calcium, thus promoting LTD formation. In contrast, during “post-pre” parings, the presence of GABA pushes the balance more towards NMDAR-mediated calcium, thus favoring LTP formation. Next, we identified the role of NMDAR subunits in LTP formation. The model predicted that the GluN2B subunit could broaden the timing window of LTP. We confirmed the prediction with experiments. At last, we investigated the functional importance of dendritic plateaus in MSNs. The model predicted that dendritic plateaus could enhance neuron-wide integration of excitatory inputs and promote spiking. In contrast, the impact of dendritic inhibition depends on a particular “spatiotemporal” window: the efficacy of dendritic inhibition could be dramatically increased if it is positioned close to the plateau initiation zone and activated within a specific timing window. Intriguingly, the model predicted that such branch-specific inhibition is not due to shutting of GABAARs, but relies on the Magnesium (Mg2+) block of NMDARs. We verified the mechanism with two-photon uncaging of glutamate and single-photon uncaging of GABA. To conclude, we found GABA tightly controlled the direction of STDP in MSNs through depolarizing effects and could effectively suppress the dendritic plateau in MSNs through an NMDAR Mg2+ block dependent mechanism.