Abstract
Calcium through NMDA receptors (NMDARs) is necessary for the long-term potentiation (LTP) of synaptic strength; however, NMDARs differ in several properties that can influence the amount of calcium influx into the spine. These properties, such as sensitivity to magnesium block and conductance decay kinetics, change the receptor's response to spike timing dependent plasticity (STDP) protocols, and thereby shape synaptic integration and information processing. This study investigates the role of GluN2 subunit differences on spine calcium concentration during several STDP protocols in a model of a striatal medium spiny projection neuron (MSPN). The multi-compartment, multi-channel model exhibits firing frequency, spike width, and latency to first spike similar to current clamp data from mouse dorsal striatum MSPN. We find that NMDAR-mediated calcium is dependent on GluN2 subunit type, action potential timing, duration of somatic depolarization, and number of action potentials. Furthermore, the model demonstrates that in MSPNs, GluN2A and GluN2B control which STDP intervals allow for substantial calcium elevation in spines. The model predicts that blocking GluN2B subunits would modulate the range of intervals that cause long term potentiation. We confirmed this prediction experimentally, demonstrating that blocking GluN2B in the striatum, narrows the range of STDP intervals that cause long term potentiation. This ability of the GluN2 subunit to modulate the shape of the STDP curve could underlie the role that GluN2 subunits play in learning and development.
Highlights
The striatum is the main input structure of the basal ganglia, which is necessary for proper motor function and habit formation
The NMDA receptor is sensitive to the timing of neuronal activity, allowing calcium influx only when glutamate release and a postsynaptic depolarization coincide temporally
Our experiments manipulating the dominate subunit in brain slices show that the subunit effect on calcium influx predicted by our computational model is mirrored by a change in the amount of potentiation that occurs in our experimental preparation
Summary
The striatum is the main input structure of the basal ganglia, which is necessary for proper motor function and habit formation. The medium spiny projection neurons (MSPNs), which comprise ,95% of striatal neurons, undergo changes in synaptic strength during the learning of a motor task [1]. This synaptic plasticity is thought to be the cellular basis of motor learning and habit formation, and it is disrupted in animal models of Parkinson’s Disease [2] and Huntington’s Disease [3]. The sources of calcium are quite diverse, and depend on brain region and direction of plasticity. The source of spine calcium that contributes to long-term potentiation (LTP) is the NMDA receptor (NMDAR) in the hippocampus [6], cortex [7], and striatum [8]
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