Forebrain Deletion of αGDI in Adult Mice Worsens the Pre-Synaptic Deficit at Cortico-Lateral Amygdala Synaptic Connections

The GDI1 gene encodes αGDI, which retrieves inactive GDP-bound RAB from membranes to form a cytosolic pool awaiting vesicular release. Mutations in GDI1 are responsible for X-linked Intellectual Disability. Characterization of the Gdi1-null mice has revealed alterations in the total number and distribution of hippocampal and cortical synaptic vesicles, hippocampal short-term synaptic plasticity and specific short-term memory deficits in adult mice, which are possibly caused by alterations of different synaptic vesicle recycling pathways controlled by several RAB GTPases. However, interpretation of these studies is complicated by the complete ablation of Gdi1 in all cells in the brain throughout development. In this study, we generated conditionally gene-targeted mice in which the knockout of Gdi1 is restricted to the forebrain, hippocampus, cortex and amygdala and occurs only during postnatal development. Adult mutant mice reproduce the short-term memory deficit previously reported in Gdi1-null mice. Surprisingly, the delayed ablation of Gdi1 worsens the pre-synaptic phenotype at cortico-amygdala synaptic connections compared to Gdi1-null mice. These results suggest a pivotal role of αGDI via specific RAB GTPases acting specifically in forebrain regions at the pre-synaptic sites involved in memory formation

Dynamic interplay between thalamic activity and Cajal-Retzius cells regulates the wiring of cortical layer 1

Cortical wiring relies on guidepost cells and activity-dependent processes that are thought to act sequentially. Here, we show that the construction of layer 1 (L1), a main site of top-down integration, is regulated by crosstalk between transient Cajal-Retzius cells (CRc) and spontaneous activity of the thalamus, a main driver of bottom-up information. While activity was known to regulate CRc migration and elimination, we found that prenatal spontaneous thalamic activity and NMDA receptors selectively control CRc early density, without affecting their demise. CRc density, in turn, regulates the distribution of upper layer interneurons and excitatory synapses, thereby drastically impairing the apical dendrite activity of output pyramidal neurons. In contrast, postnatal sensory-evoked activity had a limited impact on L1 and selectively perturbed basal dendrites synaptogenesis. Collectively, our study highlights a remarkable interplay between thalamic activity and CRc in L1 functional wiring, with major implications for our understanding of cortical development.We thank the IBENS Imaging Facility (France BioImaging, supported by ANR-10-INBS-04, ANR-10-LABX-54 MEMO LIFE, and ANR-11-IDEX-000-02 PSL∗ Research University, “Investments for the Future”). This work was supported by grants from the Spanish Ministry of Science, Innovation, and Universities (PGC2018-096631-B-I00) and the European Research Council (ERC-2014-CoG-647012) to G.L.-B. N.C. received funding from the Marie Skłodowska-Curie individual fellowship under the European Union’s Horizon 2020 research and innovation program (AXO-MATH, grant agreement no. 798326). F.G. received funding from the Agence Nationale de la Recherche (SyTune, ANR-21-CE37-0010), the European Research Council under the European Union’s Horizon 2020 research and innovation program (NEUROGOAL, grant agreement no.677878), the Region Nouvelle-Aquitaine, and the University of Bordeaux. The Garel laboratory is supported by INSERM, CNRS, ANR-15-CE16-0003, ANR-19-CE16-0017-02, Investissements d’Avenir implemented by ANR-10-LABX-54 MEMO LIFE, ANR-11-IDEX-0001-02 PSL∗ Research University, and the European Research Council (ERC-2013-CoG-616080, NImO). I.G. is a recipient of a fellowship from the French Ministry of Research and postdoctoral funding from Labex MemoLife, and S.G. is part of the Ecole des Neurosciences de Paris Ile-de-France network.Peer reviewe

Pre and Post Synaptic NMDA Effects Targeting Purkinje Cells in the Mouse Cerebellar Cortex

N-methyl-D-aspartate (NMDA) receptors are associated with many forms of synaptic plasticity. Their expression level and subunit composition undergo developmental changes in several brain regions. In the mouse cerebellum, beside a developmental switch between NR2B and NR2A/C subunits in granule cells, functional postsynaptic NMDA receptors are seen in Purkinje cells of neonate and adult but not juvenile rat and mice. A presynaptic effect of NMDA on GABA release by cerebellar interneurons was identified recently. Nevertheless whereas NMDA receptor subunits are detected on parallel fiber terminals, a presynaptic effect of NMDA on spontaneous release of glutamate has not been demonstrated. Using mouse cerebellar cultures and patch-clamp recordings we show that NMDA facilitates glutamate release onto Purkinje cells in young cultures via a presynaptic mechanism, whereas NMDA activates extrasynaptic receptors in Purkinje cells recorded in old cultures. The presynaptic effect of NMDA on glutamate release is also observed in Purkinje cells recorded in acute slices prepared from juvenile but not from adult mice and requires a specific protocol of NMDA application

Synaptic Maturation at Cortical Projections to the Lateral Amygdala in a Mouse Model of Rett Syndrome

Rett syndrome (RTT) is a neuro-developmental disorder caused by loss of function of Mecp2 - methyl-CpG-binding protein 2 - an epigenetic factor controlling DNA transcription. In mice, removal of Mecp2 in the forebrain recapitulates most of behavioral deficits found in global Mecp2 deficient mice, including amygdala-related hyper-anxiety and lack of social interaction, pointing a role of Mecp2 in emotional learning. Yet very little is known about the establishment and maintenance of synaptic function in the adult amygdala and the role of Mecp2 in these processes. Here, we performed a longitudinal examination of synaptic properties at excitatory projections to principal cells of the lateral nucleus of the amygdala (LA) in Mecp2 mutant mice and their wild-type littermates. We first show that during animal life, Cortico-LA projections switch from a tonic to a phasic mode, whereas Thalamo-LA synapses are phasic at all ages. In parallel, we observed a specific elimination of Cortico-LA synapses and a decrease in their ability of generating presynaptic long term potentiation. In absence of Mecp2, both synaptic maturation and synaptic elimination were exaggerated albeit still specific to cortical projections. Surprisingly, associative LTP was unaffected at Mecp2 deficient synapses suggesting that synaptic maintenance rather than activity-dependent synaptic learning may be causal in RTT physiopathology. Finally, because the timing of synaptic evolution was preserved, we propose that some of the developmental effects of Mecp2 may be exerted within an endogenous program and restricted to synapses which maturate during animal life

Can NMDA Spikes Dictate Computations of Local Networks and Behavior?

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Synapses Let Loose for a Change: Inhibitory Synapse Pruning throughout Experience-Dependent Cortical Plasticity

In this issue of Neuron, Chen et al. (2012) and van Versendaal et al. (2012) used fluorescently tagged gephyrin to track inhibitory synapses in the mouse visual cortex in vivo. Their studies show that visual experience-dependent plasticity is associated with clustered and location-specific pruning of inhibitory synapses

Spike-Timing-Dependent Potentiation of Sensory Surround in the Somatosensory Cortex Is Facilitated by Deprivation-Mediated Disinhibition

Functional maps in the cerebral cortex reorganize in response to changes in experience, but the synaptic underpinnings remain uncertain. Here, we demonstrate that layer (L) 2/3 pyramidal cell synapses in mouse barrel cortex can be potentiated upon pairing of whisker-evoked postsynaptic potentials (PSPs) with action potentials (APs). This spike-timing-dependent long-term potentiation (STD-LTP) was only effective for PSPs evoked by deflections of a whisker in the neuron's receptive field center, and not its surround. Trimming of all except two whiskers rapidly opened the possibility to drive STD-LTP by the spared surround whisker. This facilitated STD-LTP was associated with a strong decrease in the surrounding whisker-evoked inhibitory conductance and partially occluded picrotoxin-mediated LTP facilitation. Taken together, our data demonstrate that sensory deprivation-mediated disinhibition facilitates STD-LTP from the sensory surround, which may promote correlation- and experience-dependent expansion of receptive fields

X-linked mental retardation: focus on synaptic function and plasticity

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