Dissociation of functional and structural plasticity of dendritic spines during NMDAR and mGluR-dependent long-term synaptic depression in wild-type and fragile X model mice

Abstract

Many neurodevelopmental disorders are characterized by impaired functional synaptic plasticity and abnormal dendritic spine morphology, but little is known about how these are related. Previous work in the Fmr1-/y mouse model of fragile X (FX) suggests that increased constitutive dendritic protein synthesis yields exaggerated mGluR5-dependent long-term synaptic depression (LTD) in area CA1 of the hippocampus, but an effect on spine structural plasticity remains to be determined. In the current study, we used simultaneous electrophysiology and time-lapse two photon imaging to examine how spines change their structure during LTD induced by activation of mGluRs or NMDA receptors (NMDARs), and how this plasticity is altered in Fmr1-/y mice. We were surprised to find that mGluR activation causes LTD and AMPA receptor internalization, but no spine shrinkage in either wildtype or Fmr1-/y mice. In contrast, NMDAR activation caused spine shrinkage as well as LTD in both genotypes. Spine shrinkage was initiated by non-ionotropic (metabotropic) signaling through NMDARs, and in wild-type mice this structural plasticity required activation of mTORC1 and new protein synthesis. In striking contrast, NMDA-induced spine plasticity in Fmr1-/y mice was no longer dependent on acute activation of mTORC1 or de novo protein synthesis. These findings reveal that the structural consequences of mGluR and metabotropic NMDAR activation differ, and that a brake on spine structural plasticity, normally provided by mTORC1 regulation of protein synthesis, is absent in FX. Increased constitutive protein synthesis in FX appears to modify functional and structural plasticity induced through different glutamate receptors.

Non-ionotropic NMDA receptor signaling gates bidirectional structural plasticity of dendritic spines

“…Ion-flow-independent NMDAR signaling has been implicated by many independent studies in spine shrinkage and synaptic weakening ( Aow et al, 2015 ; Birnbaum et al, 2015 ; Carter and Jahr, 2016 ; Nabavi et al, 2013 ; Stein et al, 2015 , 2020 ; Thomazeau et al, 2020 ; Wong and Gray, 2018 ). Here, we made the unexpected discovery that this non-ionotropic NMDAR signaling pathway is also required for spine growth during synaptic strengthening.…”

“…Recent studies have demonstrated that LTD ( Carter and Jahr, 2016 ; Nabavi et al, 2013 ; Wong and Gray, 2018 ) and dendritic spine shrinkage ( Birnbaum et al, 2015 ; Stein et al, 2015 ; Thomazeau et al, 2020 ) can occur independent of ion flux through the NMDAR. These findings have supported a model in which glutamate binding leads to conformational changes in the NMDAR that drive spine shrinkage and synaptic weakening.…”

Non-ionotropic NMDA receptor signaling gates bidirectional structural plasticity of dendritic spines

“…Ion flow-independent NMDAR signaling has been implicated by many independent studies in spine shrinkage and synaptic weakening (Nabavi et al, 2013;Aow et al, 2015;Birnbaum et al, 2015;Stein et al, 2015;Carter and Jahr, 2016;Wong and Gray, 2018;Stein et al, 2020;Thomazeau et al, 2020). Here, we made the unexpected discovery that this non-ionotropic NMDAR signaling pathway is also required for spine growth during synaptic strengthening.…”

“…Recent studies have demonstrated that LTD (Nabavi et al, 2013;Carter and Jahr, 2016;Wong and Gray, 2018) and dendritic spine shrinkage (Birnbaum et al, 2015;Stein et al, 2015;Thomazeau et al, 2020) can occur independent of ion flux through the NMDA receptor. These findings have supported a model in which glutamate binding leads to conformational changes in the NMDAR that drive spine shrinkage and synaptic weakening.…”

NMDA receptors in axons: there's no coincidence

“…Dysregulated glutamate signalling and impaired synapse development have been proposed to contribute to neurodevelopmental and psychiatric disorders. Mutations in NMDAR subunits have been linked to pathogenesis of autism spectrum disorders (ASD), intellectual disability, epilepsy, anxiety, depression and schizophrenia (Endele et al 2010;Hamdan et al 2011;Tarabeux et al 2011;O'Roak et al 2012). Changes in glutamate signalling and aberrant NMDAR expression and function have been observed in the brains of individuals with ASD (Blatt et al 2001;Purcell et al 2001) and in different mouse models of ASD (Etherton et al 2011;Eadie et al 2012;Sceniak et al 2016).…”