Matrix Metalloproteinase-9 Rapidly Releases and Activates BDNF to Control Structural Synaptic Plasticity

Core Concepts

Matrix metalloproteinase-9 (MMP-9) is rapidly released from dendritic spines upon synaptic stimulation and is essential for the induction and maintenance of structural long-term potentiation (sLTP) by promoting the maturation of brain-derived neurotrophic factor (BDNF) and activation of its receptor TrkB.

Abstract

This study provides insights into the role of matrix metalloproteinase-9 (MMP-9) in the regulation of structural synaptic plasticity. The key findings are: MMP-9 activity is essential for both the induction and maintenance of structural long-term potentiation (sLTP) evoked by glutamate uncaging. Inhibition of MMP-9 or genetic knockout impairs spine volume increases during the transient and sustained phases of sLTP. MMP-9 is rapidly released from dendritic spines within seconds of synaptic stimulation in an NMDAR-dependent and synaptobrevin-dependent manner. This rapid release of MMP-9 coincides with the known fast kinetics of BDNF release and TrkB activation. Inhibition of MMP-9 activity attenuates the activation of the BDNF receptor TrkB during both the transient and sustained phases of sLTP. In a cell-free assay, MMP-9 can directly cleave the precursor form of BDNF (proBDNF) into the mature form (mBDNF), which is known to promote synaptic plasticity through TrkB activation. Together, these results demonstrate that MMP-9 acts as a key regulator of structural synaptic plasticity by rapidly releasing and activating BDNF, leading to the activation of its receptor TrkB. This provides a mechanistic link between MMP-9 and BDNF signaling in the control of synaptic structure and function.

Stats

Spine volume increases during the transient phase (1-3 min) of sLTP were reduced by 35% in the presence of MMP-9 inhibitor compared to control. Spine volume increases during the sustained phase (9-11 min and 15-20 min) of sLTP were reduced by 40-50% in the presence of MMP-9 inhibitor compared to control. Spine volume increases during the transient phase (1-3 min) of sLTP were reduced by 25% in MMP-9 knockout mice compared to wildtype. TrkB activation during the transient (1-3 min) and sustained (9-11 min) phases of sLTP were reduced by 30-40% in the presence of MMP-9 inhibitor compared to control.

Quotes

"MMP-9 activity appears to be important both during the induction and maintenance of sLTP." "Our results showed that MMP-9 can be rapidly released upon stimulation, which further supports the early action of this protease for sLTP induction." "Given that the release kinetics of BDNF and MMP-9 are similar, one could speculate that the effect of MMP-9 inhibition on early TrkB activation can be achieved because both, MMP-9 and BDNF are co-localized and co-released from the same release vesicles."

Key Insights Distilled From

BDNF signaling requires Matrix Metalloproteinase-9 during structural synaptic plasticity

by Legutko,D., ... at www.biorxiv.org 12-09-2023

https://www.biorxiv.org/content/10.1101/2023.12.08.569797v2

Deeper Inquiries

How might the rapid release and action of MMP-9 be regulated at the molecular and cellular level to precisely control the timing and extent of structural synaptic plasticity?

Matrix Metalloproteinase-9 (MMP-9) is tightly regulated at the molecular and cellular levels to ensure precise control over the timing and extent of structural synaptic plasticity. Several mechanisms contribute to this regulation: Transcriptional Regulation: The expression of MMP-9 can be regulated at the transcriptional level by various signaling pathways activated in response to synaptic activity. Transcription factors and signaling molecules can modulate the expression of MMP-9 in a stimulus-dependent manner. Post-Translational Modifications: MMP-9 activity can be regulated by post-translational modifications such as phosphorylation, glycosylation, and proteolytic cleavage. These modifications can alter the enzymatic activity of MMP-9 and its localization within the cell. Subcellular Localization: MMP-9 is known to be localized in dendritic spines under basal conditions, suggesting a role in the regulation of synaptic plasticity. The subcellular localization of MMP-9 can be dynamically regulated in response to synaptic activity to ensure its rapid release and action. Interaction with Regulatory Proteins: MMP-9 activity can be modulated by interactions with endogenous inhibitors such as Tissue Inhibitor of Metalloproteinase-1 (TIMP-1). The balance between MMP-9 and its inhibitors can fine-tune the proteolytic activity of MMP-9 in the synaptic environment. Autocrine and Paracrine Signaling: MMP-9 can act in an autocrine manner by cleaving proBDNF into mature BDNF, which then activates TrkB receptors to promote synaptic plasticity. This autocrine signaling loop ensures rapid and localized effects of MMP-9 on synaptic structure and function. Overall, the regulation of MMP-9 at multiple levels allows for precise control over its release and activity, enabling it to play a critical role in the timing and extent of structural synaptic plasticity.

What other extracellular matrix proteins or cell adhesion molecules might be targeted by MMP-9 to influence synaptic structure and function beyond the BDNF-TrkB pathway?

In addition to the BDNF-TrkB pathway, Matrix Metalloproteinase-9 (MMP-9) can target other extracellular matrix proteins and cell adhesion molecules to influence synaptic structure and function. Some of the key targets of MMP-9 in the synaptic environment include: ICAM-5: Intercellular Adhesion Molecule-5 is a cell adhesion molecule that has been shown to be cleaved by MMP-9. ICAM-5 is involved in dendritic spine morphogenesis and synaptic plasticity, and its cleavage by MMP-9 can modulate synaptic structure. β-Dystroglycan: MMP-9 has been reported to cleave β-Dystroglycan, a component of the dystrophin-associated glycoprotein complex that plays a role in synaptic stability and function. Cleavage of β-Dystroglycan by MMP-9 can impact synaptic integrity and plasticity. Nectin-3: Nectin-3 is a cell adhesion molecule involved in synaptic development and plasticity. MMP-9 has been shown to cleave Nectin-3, affecting its function in synaptic adhesion and signaling. CD44: CD44 is a cell surface glycoprotein that interacts with extracellular matrix components and is involved in synaptic plasticity. MMP-9 can cleave CD44, influencing its role in cell adhesion and signaling at the synapse. Neuroligin-1: Neuroligin-1 is a cell adhesion molecule that mediates trans-synaptic signaling and is essential for synapse formation and function. MMP-9 has been shown to cleave Neuroligin-1, impacting synaptic connectivity and plasticity. By targeting these extracellular matrix proteins and cell adhesion molecules, MMP-9 can modulate synaptic structure and function beyond the BDNF-TrkB pathway, contributing to the regulation of synaptic plasticity and neuronal connectivity.

Could the dysregulation of the MMP-9-BDNF signaling axis contribute to the pathogenesis of neurological or psychiatric disorders characterized by aberrant synaptic plasticity?

Dysregulation of the MMP-9-BDNF signaling axis could indeed contribute to the pathogenesis of neurological or psychiatric disorders characterized by aberrant synaptic plasticity. Here are some ways in which this dysregulation could impact the development and progression of such disorders: Altered Synaptic Plasticity: MMP-9 plays a crucial role in regulating structural synaptic plasticity through the cleavage of proBDNF into mature BDNF. Dysregulation of MMP-9 activity could disrupt the balance between proBDNF and mature BDNF, leading to aberrant synaptic plasticity and impaired neuronal connectivity. Neurodevelopmental Disorders: Conditions such as autism spectrum disorders (ASD) and intellectual disabilities are associated with disruptions in synaptic plasticity. Dysregulation of the MMP-9-BDNF axis could contribute to the synaptic abnormalities observed in these disorders, affecting learning, memory, and social behavior. Neurodegenerative Diseases: Neurodegenerative diseases like Alzheimer's and Parkinson's are characterized by synaptic dysfunction and cognitive decline. Alterations in MMP-9 activity and BDNF processing could exacerbate synaptic damage and neuronal loss, contributing to the progression of these disorders. Mood Disorders: Conditions like depression and anxiety are linked to changes in synaptic plasticity and neurotrophic signaling. Dysregulation of the MMP-9-BDNF axis could impact mood regulation pathways, leading to mood disturbances and affective disorders. Schizophrenia: Schizophrenia is associated with abnormalities in synaptic connectivity and plasticity. Disruption of the MMP-9-BDNF signaling axis could contribute to the synaptic deficits observed in schizophrenia, potentially influencing cognitive and perceptual disturbances. Overall, dysregulation of the MMP-9-BDNF signaling axis has the potential to disrupt normal synaptic function and contribute to the pathogenesis of various neurological and psychiatric disorders characterized by aberrant synaptic plasticity. Understanding and targeting this signaling axis may offer new therapeutic strategies for these conditions.