Roles Of Dopamine Signaling Pathway In Regulating Synaptic Plasticity In Mouse Motor Cortex

DA plays a key role in learning and memory. The main pathological change of PD is dopaminergic neurons death in SNc. And the motor symptoms in patients with PDarerigidity, tremor, bradykinesia, and deficits in motor skill learning later, which mechanism are still unclear. Ml is essential for motor control and the acquisition of motor skills. Neural circuitry remodeling including synaptic plasticity and LTP inducement in motor cortex were proven to be the foundation of motor skill learning.We hypothesized that DA and DA receptors play crucial roles in the regulation of synaptic plasticity in motor cortex and impaired DA signaling would induce the abnormal synaptic dynamics in motor cortex and then the learning and memory deficiencies.To study the effect of DA on synaptic plasticity of M1, we made DA depletion by using MPTP-injected mice, which were classic PD mice model. And then combined with two-photon microscopy imaging through thinned-skull chronic cranial windows, we traced the spine dynamicin M1 layer 5 pyramidal neurons. We amazedly foundthe spine elimination and formation were both enhaced, while extened the MPTP-injected duration from 4 days to 8 days, the spine density decreased gradually. These all show DA depletion will induce abnormal spine plasticity in M1.There are two main dopaminergic pathway can modulate plasticity of primary motor cortex, one is the mesocortical projection arise from the VTA directly to the cortex, the other one is the nigrostriatal projection indirect modulate the cortex through basal ganglia-cortex cholinergic pathway.To directly test these two possibilities, we first used stereotaxic microinjectiontechnique to destroy the local dopaminergic pathway, combinedwith two-photon microscopy imaging through open-skull chronic cranial windows. When we selectively eliminated dopaminergic terminals with 6-OHDA in the area of Ml for testing the mesocortical pathway, the spine elimination and formation were both increased. However, when we eliminated the dopaminergic terminal in the dorsal lateral striatum with 6-OHDA, the spine elimination or formation was no more enhanced. These data suggest that dopamine primarily through local mechanism to promote spine elimination and formation in M1.M1 cortical neurons have both D1 and D2 classes of DA receptors, and what roles the two kinds of DA receptors, which mediate opposite signal pathway in intracellular, play on the plasticity of dendritic spines in M1 is unkown. We imaged the same dendritic spine on Ml repeatedly with D1 or D2 receptor antagonist, and found the spine elimination was elevated in D1 receptor antagonist (SCH23390) injected mice,in stark contrastspine formation was increased in D2 receptor antagonist (Haloperidol) injected mice.It follows that D1 and D2 receptor signaling were responsibleselectively and distinctly regulating structural plasticity in motor cortex.According the dynamic spine plasticity in SCH23390 and Haloperidol-injected mice, and relationship between D1, D2 receptor signaling and synaptic functional plasticity, we suggestedthat D1 receptor antagonist promotes spine elimination for it inhibits LTP and decrease the spine stability, while D2 antagonist promotes spine formation was not correlated with LTP.In summary, we researched roles of DA and DA receptor in regulating spine plasticity in mouse motor cortex with two-photon microscopy imaging through open-skull or thinned-skull chronic cranial windows, and expounded the relationship between spine structural and functional plasticity.