MMP-1 overexpression selectively alters inhibition in D1 spiny projection neurons in the mouse nucleus accumbens core

Abstract

Protease activated receptor-1 (PAR-1) and its ligand, matrix metalloproteinase-1 (MMP-1), are altered in several neurodegenerative diseases. PAR-1/MMP-1 signaling impacts neuronal activity in various brain regions, but their role in regulating synaptic physiology in the ventral striatum, which is implicated in motor function, is unknown. The ventral striatum contains two populations of GABAergic spiny projection neurons, D1 and D2 SPNs, which differ with respect to both synaptic inputs and projection targets. To evaluate the role of MMP-1/PAR-1 signaling in the regulation of ventral striatal synaptic function, we performed whole-cell recordings (WCR) from D1 and D2 SPNs in control mice, mice that overexpress MMP-1 (MMP-1OE), and MMP-1OE mice lacking PAR-1 (MMP-1OE/PAR-1KO). WCRs from MMP1-OE mice revealed an increase in spontaneous inhibitory post-synaptic current (sIPSC), miniature IPSC, and miniature excitatory PSC frequency in D1 SPNs but not D2 SPNs. This alteration may be partially PAR-1 dependent, as it was not present in MMP-1OE/PAR-1KO mice. Morphological reconstruction of D1 SPNs revealed increased dendritic complexity in the MMP-1OE, but not MMP-1OE/PAR-1KO mice. Moreover, MMP-1OE mice exhibited blunted locomotor responses to amphetamine, a phenotype also observed in MMP-1OE/PAR-1KO mice. Our data suggest PAR-1 dependent and independent MMP-1 signaling may lead to alterations in striatal neuronal function.

Extracellular Metalloproteinases in the Plasticity of Excitatory and Inhibitory Synapses

“…The involvement of PAR1 in GABAergic plasticity was described in cultured hippocampal neurons [183], in which it induced suppression of synaptic inhibition through the stimulation of endocannabinoid synthesis. Furthermore, studies performed in mice globally overexpressing MMP1 showed that MMP1-induced activation of PAR1 gives rise to increased frequency of inhibitory synaptic currents in the striatum [184]. In addition, activation of astrocytic PAR1 increased the activity of the calcium-activated anion channel Bestrophin-1, which is responsible for releasing GABA from astrocytes, thereby regulating GABAergic tonic inhibition in neurons [185].…”

Matrix metalloproteinase-3 in brain physiology and neurodegeneration

“…In recent years, numerous studies described the crucial role played by MMPs-dependent ECM proteolysis in physiological processes such as synaptic plasticity, learning and memory. 12,13 Nonetheless, abnormal expression, localization and activity of MMPs could have a detrimental impact on brain functioning, 6,14,15 and, in physiological conditions, MMPs activity is kept under strict control at both the transcriptional and cellular levels by controlling the synthesis, release, activation, inhibition, and degradation.…”