Inhibition of the Interaction Between Group I Metabotropic Glutamate Receptors and PDZ-Domain Proteins Prevents Hippocampal Long-Term Depression, but Not Long-Term Potentiation.

Sergey Neyman,Kara E O’Connell,Denise Manahan-Vaughan,Kumlesh K Dev,Karl-Heinz Braunewell

doi:10.3389/fnsyn.2019.00013

Sergey Neyman, Kara E O’Connell + Show 3 more

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https://doi.org/10.3389/fnsyn.2019.00013

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Abstract

The group I metabotropic glutamate (mGlu) receptor subtypes, mGlu1 and mGlu5, strongly regulate hippocampal synaptic plasticity. Both harbor PSD-95/discs-large/ZO-1 (PDZ) motifs at their extreme carboxyl terminals, which allow interaction with the PDZ domain of Tamalin, regulate the cell surface expression of group I mGlu receptors, and may modulate their coupling to signaling proteins. We investigated the functional role of this interaction in hippocampal long-term depression (LTD). Acute intracerebral treatment of adult rats with a cell-permeable PDZ-blocking peptide (pep-mGluR-STL), designed to competitively inhibit the interaction between Tamalin and group 1 mGlu receptors, prevented expression of LTD in the hippocampal CA1 region without affecting long-term potentiation (LTP) or basal synaptic transmission. Pep-mGluR-STL prevented facilitation by the group I mGlu receptor agonist, (S)-3,5-Dihydroxyphenylglycine (DHPG), and the mGlu5 agonist, (R,S)-2-chloro-5-Hydroxyphenylglycine (CHPG), of short-term depression (STD) into LTD, suggesting that Tamalin preferentially acts by mediating signaling through mGlu5. These data support that Tamalin is essential for the persistent expression of LTD and that it subserves the effective signaling of group 1 mGlu receptors.

Highlights

Metabotropic glutamate receptors are widely distributed throughout the CNS, and play a crucial role in glutamate-mediated neurotransmission and synaptic plasticity events
To clarify whether the pep-mGluR-STL effects were mediated by a change in group I metabotropic glutamate (mGlu) receptor contributions to long-term depression (LTD), we examined its effects on the late component of LTD that is supported by activation of group I receptors (Figure 4)
LTD in the CA1 region requires protein synthesis (Manahan-Vaughan et al, 2000), whereas in the dentate gyrus it does not (Pöschel and Manahan-Vaughan, 2007). These findings suggest that a number of mechanistically distinct forms of LTD are expressed in the hippocampus, and what is striking, in this regard, is that all forms of LTD that have been identified to date are regulated in a differentiated way by group I mGlu receptors (Huber et al, 2001; Volk et al, 2006; Naie et al, 2007; Neyman and Manahan-Vaughan, 2008; Mukherjee and Manahan-Vaughan, 2013; Hagena and Manahan-Vaughan, 2015)

Summary

Introduction

Metabotropic glutamate (mGlu) receptors are widely distributed throughout the CNS, and play a crucial role in glutamate-mediated neurotransmission and synaptic plasticity events. The persistence of hippocampal synaptic plasticity and memory is strongly regulated by group I mGlu receptors (mGlu and mGlu5; Cohen and Abraham, 1996; Manahan-Vaughan, 1997; Cohen et al, 1998; Balschun et al, 1999; Naie and Manahan-Vaughan, 2004, 2005; Mukherjee and Manahan-Vaughan, 2013). The blockade of group I mGlu receptors using pharmacological antagonists prevents hippocampus-based spatial memory, impairs late-LTP (Balschun et al, 1999; Naie and Manahan-Vaughan, 2004, 2005; Hagena and Manahan-Vaughan, 2015) and inhibits hippocampal LTD (Manahan-Vaughan, 1997; Popkirov and Manahan-Vaughan, 2011; Goh and Manahan-Vaughan, 2013a; Hagena and Manahan-Vaughan, 2015)

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