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Abstract

The long-lasting deterioration of motor output in Parkinson’s disease (PD) is thought to arise from the degeneration of midbrain dopamine neurons and the subsequent loss of dopamine signaling in the striatum. While much is already known about dopaminergic modulation of striatal activity, few studies have directly linked aberrant synaptic plasticity to PD motor symptoms. Here, I examine the striatal synaptic plasticity mechanisms that contribute to parkinsonian motor behaviors. To establish a technique for examining plasticity ex vivo, I first characterize an in vitro optogenetic long-term depression (LTD) protocol that induces postsynaptic corticostriatal depression in D2 dopamine receptor (D2R)-expressing medium spiny neurons (MSNs). Unlike previously reported forms of striatal LTD, this light-mediated LTD is cannabinoid type 1 receptor (CB1R)-independent and does not alter presynaptic glutamate release. Moreover, I show that it does not require the activation of N-methyl-D-aspartate (NMDA) receptors or metabotropic glutamate receptor 5 (mGluR5). Previous studies from our laboratory have suggested that the loss of dopamine signaling in the striatum may lead to motor decline through aberrant plasticity at corticostriatal synapses in the D2R-expressing indirect pathway. To test this, I use optogenetics and whole-cell recordings to assess changes in corticostriatal plasticity in mice that underwent motor training with a pharmacological D2R blockade. I demonstrate that this treatment results in enhanced ex vivo corticostriatal LTD in D2R-expressing MSNs, suggesting that long-term potentiation (LTP) had previously occurred at these synapses in vivo. I also show that co-administration of an A2A adenosine receptor (A2AR) antagonist is sufficient to prevent induction of aberrant corticostriatal potentiation, revealing a potential mechanism for caffeine’s protective effects in PD. Finally, I demonstrate that direct in vivo corticostriatal stimulation in mice with D2R blockade leads to a lasting impairment in rotarod performance following stimulation. Together, these results implicate aberrant corticostriatal plasticity in the development of parkinsonian motor symptoms and provide support for therapeutic strategies that target altered plasticity in PD and other neuropsychiatric disorders.

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