Targeting VGLUT Machinery: Implications on mGluR5 Signaling and Behavior

Abstract

Crosstalk between both pre-and post-synaptic components of glutamatergic neurotransmission plays a crucial role in orchestrating a multitude of brain functions including synaptic plasticity and motor planning. Metabotropic glutamate receptor 5 (mGluR5) exhibits a promising therapeutic potential for many neurodevelopmental and neurodegenerative disorders, as the consequence of its modulatory control over diverse neuronal networks required for memory, motor coordination, neuronal survival and differentiation. Given these crucial roles, mGluR5 signaling is under the tight control of glutamate release machinery mediated through vesicular glutamate transporters (VGLUTs) to ultimately dictate glutamatergic output. A particular VGLUT isoform, VGLUT3, exhibits an overlapping, but unique, distribution with mGluR5 and the dynamic crosstalk between mGluR5 and VGLUT3 is key for the function of specific neuronal networks involved in motor coordination, emotions and cognition. Thus, aberrant signaling of the VGLUT3/mGluR5 axis is linked to various pathologies including, but not limited to, Parkinson's disease, anxiety disorders and drug addiction. We argue that a comprehensive profiling of how coordinated VGLUT3/mGluR5 signaling influences overall glutamatergic neurotransmission is warranted. Significance statement: Vesicular glutamate receptor 3 (VGLUT3) machinery orchestrates glutamate release and its distribution overlaps with metabotropic glutamate receptor 5 (mGluR5) in regional brain circuitries including striatum, hippocampus and raphe nucleus. Therefore, VGLUT3/mGluR5 crosstalk can significantly influences both physiological and pathophysiological glutamatergic neurotransmission. Pathological signaling of the VGLUT3/mGluR5 axis is linked to Parkinson's disease, anxiety disorders and drug addiction. However, it is also predicted to contribute to other motor and cognitive disorders.

Glutamic Acid Transporters: Targets for Neuroprotective Therapies in Parkinson’s Disease

“…The expression of VGLUTs is an indicator of the relative synaptic strength of presynaptic glutamatergic innervation in specific brain regions ( Massie et al, 2010 ). Therefore, VGLUTs play an important role in neurodegenerative diseases ( Daniels et al, 2011 ; Steinkellner et al, 2018 ; Ibrahim et al, 2020 ). VGLUT1 is one of the specific markers of glutamatergic neurons.…”

Autoimmune encephalitis with psychiatric features in adults: historical evolution and prospective challenge

“…Later, the spectrum of psychiatric symptoms was expanded to include inattention and anterograde memory impairments (Guevara et al 2018). This variable psychiatric spectrum including memory dysfunction and anxiety might result from mGLUR5 involvement in synaptic transmission and neuromodulatory control over neuronal networks (Ibrahim et al 2020), and in its dysfunction when blocked by mGluR5 antibodies. The novel antibody against the DPPX antigen as a subunit of Kv4.2 potassium channels was proven via immunoprecipitation and mass spectrometry in four patients (Boronat et al 2013) associated with agitation and confusion as psychiatric symptomatology (Fig.…”

The regulatory role of NAAG-mGluR3 signaling on cortical synaptic plasticity after hypoxic ischemia

“…NAAG can also reduce excitotoxicity by affecting Glu binding to the metabolic glutamate receptor (mGluRs). mGluRs includes three subtypes, type I mGluR (mGluR1,5) with postsynaptic localization and known to regulate neuronal excitability, type II (mGluR2,3) and type III mGluR (mGluR4,6,7,8) with presynaptic localization and known to regulate Glu release [ 15 ]. NAAG is released from the postsynapse and competitively binds to type II metabotropic glutamate receptor 3 (mGluR3).…”

“…The use of GCP-II inhibitors such as 2-phosphonomethyl pentanedioic acid (2-PMPA) can increase NAAG levels, thus promoting the neuroprotective effect of NAAG [ 20 , 21 ]. In addition to attenuating neuronal damage caused by Glu over-release, activated NAAG-mGluR3 pathway may maintain Glu homeostasis and regulate postsynaptic responses and plasticity changes across polysynaptic connections in real time [ 15 , 22 ]. Pinheiro et al [ 23 ] demonstrated that activation of presynaptic mGluRs leads to synaptic inhibition and is involved in the long-term and short-term regulation of synaptic plasticity.…”