MMP-1 Overexpression Selectively Alters Inhibition in D1 Spiny Projection Neurons in the Nucleus Accumbens and Disrupts Amphetamine Induced Locomotion

Abstract

Protease activated receptor-1 (PAR-1) and its ligand, matrix metalloproteinase-1 (MMP-1), are altered in several neurodegenerative diseases. PAR-1 and MMP-1 signaling impact neuronal excitation and inhibition in various brain regions, but their role in regulating synaptic physiology in the ventral striatum (nucleus accumbens, NuAcc), which has recently been implicated in motor function, is unknown. The NuAcc contains two populations of GABAergic spiny projection neurons (SPNs), those that express the dopamine D1 receptor and those that express the dopamine D2 receptor. D1 and D2 SPNs differ with respect to both synaptic inputs and projection targets. In addition, data outlined in this thesis revealed differential electrophysiological properties. D2 SPNs in the NuAcc core display decreased rheobase, increased excitability, increased rectification, and increased tonic current compared to D1 SPNs. To evaluate the role of MMP-1/PAR-1 signaling in the regulation of ventral striatal synaptic function, I performed whole-cell recordings (WCRs) from D1 and D2 SPNs in control mice, mice that overexpress MMP-1 (MMP-1OE), and MMP-1OE mice that lack PAR-1 (MMP-1OE/PAR-1KO).

WCRs from MMP1-OE mice revealed a selective increase in spontaneous inhibitory post-synaptic current (sIPSC), miniature IPSC (mIPSC), and miniature excitatory PSC (mEPSC) frequency in D1 SPNs but not D2 SPNs as compared to control mice. This enhanced IPSC frequency may be at least partially PAR-1 dependent, as it was not present in the MMP-1OE/PAR-1KO mice. Average IPSC amplitudes, decay times, and rise times did not differ across genotypes. D1 and D2 SPNs in the MMP-1OE mice exhibit increased dendritic complexity and decreased excitability, but D1 SPNs also display increased inward rectification. D2 SPNs of the MMP-1OE/PAR-1KO also displayed increased dendritic complexity, decreased excitability, and increased inward rectification. D1 SPNs of the MMP-1OE/PAR-1KO mice did not display altered dendritic complexity or excitability but their input resistance, time constant, and inward rectification were increased. Moreover, MMP-1OE mice exhibited a blunted locomotor response to amphetamine, a phenotype also observed in MMP-1OE/PAR-1KO mice, implicating a non-PAR-1 mediated MMP-1 mechanism. The data presented in this thesis suggest PAR-1 dependent and independent MMP-1 signaling may lead to alterations in striatal neuronal inhibition, electrophysiological properties, and SPN morphology with a motor behavior correlate.