Intracranial graft of bioresorbable polymer scaffolds loaded with human Dental Pulp Stem Cells in stab wound murine injury model.

The prevalence of central nervous system (CNS) dysfunction as a result of disease or trauma remains a clinically unsolved problem which is raising increased awareness in our aging society. Human Dental Pulp Stem Cells (hDPSCs) are excellent candidates to be used in tissue engineering and regenerative therapies of the CNS due to their neural differentiation ability and lack of tumorigenicity. Accordingly, they have been successfully used in animal models of spinal cord injury, stroke and peripheral neuropathies.

The DDHD2-STXBP1 interaction mediates long-term memory via generation of saturated free fatty acids.

The phospholipid and free fatty acid (FFA) composition of neuronal membranes plays a crucial role in learning and memory, but the mechanisms through which neuronal activity affects the brain's lipid landscape remain largely unexplored. The levels of saturated FFAs, particularly of myristic acid (C14:0), strongly increase during neuronal stimulation and memory acquisition, suggesting the involvement of phospholipase A1 (PLA1) activity in synaptic plasticity. Here, we show that genetic ablation of the PLA1 isoform DDHD2 in mice dramatically reduces saturated FFA responses to memory acquisition across the brain.

CA3 hippocampal synaptic plasticity supports ripple physiology during memory consolidation.

The consolidation of recent memories depends on memory replays, also called ripples, generated within the hippocampus during slow-wave sleep, and whose inactivation leads to memory impairment. For now, the mobilisation, localisation and importance of synaptic plasticity events associated to ripples are largely unknown. To tackle this question, we used cell surface AMPAR immobilisation to block post-synaptic LTP within the hippocampal region of male mice during a spatial memory task, and show that: 1- hippocampal synaptic plasticity is engaged during consolidation, but is dispensable during encoding or retrieval.

Axo-axonic cells in neuropsychiatric disorders: a systematic review.

Imbalance between excitation and inhibition in the cerebral cortex is one of the main theories in neuropsychiatric disorder pathophysiology. Cortical inhibition is finely regulated by a variety of highly specialized GABAergic interneuron types, which are thought to organize neural network activities. Among interneurons, axo-axonic cells are unique in making synapses with the axon initial segment of pyramidal neurons.

High-resolution imaging and manipulation of endogenous AMPA receptor surface mobility during synaptic plasticity and learning.

Regulation of synaptic neurotransmitter receptor content is a fundamental mechanism for tuning synaptic efficacy during experience-dependent plasticity and behavioral adaptation. However, experimental approaches to track and modify receptor movements in integrated experimental systems are limited. Exploiting AMPA-type glutamate receptors (AMPARs) as a model, we generated a knock-in mouse expressing the biotin acceptor peptide (AP) tag on the GluA2 extracellular N-terminal.

Missense mutation of Fmr1 results in impaired AMPAR-mediated plasticity and socio-cognitive deficits in mice.

Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the best-described monogenic cause of autism. CGG-repeat expansion in the FMR1 gene leads to FMR1 silencing, loss-of-expression of the Fragile X Mental Retardation Protein (FMRP), and is a common cause of FXS. Missense mutations in the FMR1 gene were also identified in FXS patients, including the recurrent FMRP-R138Q mutation.

The integration of Gaussian noise by long-range amygdala inputs in frontal circuit promotes fear learning in mice.

Survival depends on the ability of animals to select the appropriate behavior in response to threat and safety sensory cues. However, the synaptic and circuit mechanisms by which the brain learns to encode accurate predictors of threat and safety remain largely unexplored. Here, we show that frontal association cortex (FrA) pyramidal neurons of mice integrate auditory cues and basolateral amygdala (BLA) inputs non-linearly in a NMDAR-dependent manner.

A proline-rich motif on VGLUT1 reduces synaptic vesicle super-pool and spontaneous release frequency.

Glutamate secretion at excitatory synapses is tightly regulated to allow for the precise tuning of synaptic strength. Vesicular Glutamate Transporters (VGLUT) accumulate glutamate into synaptic vesicles (SV) and thereby regulate quantal size. Further, the number of release sites and the release probability of SVs maybe regulated by the organization of active-zone proteins and SV clusters.

The next generation of approaches to investigate the link between synaptic plasticity and learning.

Activity-dependent synaptic plasticity has since long been proposed to represent the subcellular substrate of learning and memory, one of the most important behavioral processes through which we adapt to our environment. Despite the undisputed importance of synaptic plasticity for brain function, its exact contribution to learning processes in the context of cellular and connectivity modifications remains obscure. Causally bridging synaptic and behavioral modifications indeed remains limited by the available tools to measure and control synaptic strength and plasticity in vivo under behaviorally relevant conditions.

Synapsin I Controls Synaptic Maturation of Long-Range Projections in the Lateral Amygdala in a Targeted Selective Fashion.

The amygdala, and more precisely its lateral nucleus, is thought to attribute emotional valence to external stimuli by generating long-term plasticity changes at long-range projections to principal cells. Aversive experience has also been shown to modify pre- and post-synaptic markers in the amygdala, suggesting their possible role in the structural organization of adult amygdala networks. Here, we focused on how the maturation of cortical and thalamic long-range projections occurs on principal neurons and interneurons in the lateral amygdala (LA).

Modulation of AMPA receptor surface diffusion restores hippocampal plasticity and memory in Huntington's disease models.

Impaired hippocampal synaptic plasticity contributes to cognitive impairment in Huntington's disease (HD). However, the molecular basis of such synaptic plasticity defects is not fully understood. Combining live-cell nanoparticle tracking and super-resolution imaging, we show that AMPAR surface diffusion, a key player in synaptic plasticity, is disturbed in various rodent models of HD.

Protein Kinase A Deregulation in the Medial Prefrontal Cortex Impairs Working Memory in Murine Oligophrenin-1 Deficiency.

Classical and systems genetics have identified wide networks of genes associated with cognitive and neurodevelopmental diseases. In parallel to deciphering the role of each of these genes in neuronal or synaptic function, evaluating the response of neuronal and molecular networks to gene loss of function could reveal some pathophysiological mechanisms potentially accessible to nongenetic therapies. Loss of function of the Rho-GAP oligophrenin-1 is associated with cognitive impairments in both human and mouse.

Profiling olfactory stem cells from living patients identifies miRNAs relevant for autism pathophysiology.

Background: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders caused by the interaction between genetic vulnerability and environmental factors. MicroRNAs (miRNAs) are key posttranscriptional regulators involved in multiple aspects of brain development and function. Previous studies have investigated miRNAs expression in ASD using non-neural cells like lymphoblastoid cell lines (LCL) or postmortem tissues.

Conditional depletion of intellectual disability and Parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration.

ATP6AP2, an essential accessory component of the vacuolar H+ ATPase (V-ATPase), has been associated with intellectual disability (ID) and Parkinsonism. ATP6AP2 has been implicated in several signalling pathways; however, little is known regarding its role in the nervous system. To decipher its function in behaviour and cognition, we generated and characterized conditional knockdowns of ATP6AP2 in the nervous system of Drosophila and mouse models.

Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis.

Mutations in interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene have been associated with non-syndromic intellectual disability (ID) and autism spectrum disorder. This protein interacts with synaptic partners like PSD-95 and PTPδ, regulating the formation and function of excitatory synapses. The aim of this work was to characterize the synaptic consequences of three IL1RAPL1 mutations, two novel causing the deletion of exon 6 (Δex6) and one point mutation (C31R), identified in patients with ID.

The hippocampo-amygdala control of contextual fear expression is affected in a model of intellectual disability.

The process of learning mainly depends on the ability to store new information, while the ability to retrieve this information and express appropriate behaviors are also crucial for the adaptation of individuals to environmental cues. Thereby, all three components contribute to the cognitive fitness of an individual. While a lack of behavioral adaptation is a recurrent trait of intellectually disabled patients, discriminating between memory formation, memory retrieval or behavioral expression deficits is not easy to establish.

Coronin 1 regulates cognition and behavior through modulation of cAMP/protein kinase A signaling.

Cognitive and behavioral disorders are thought to be a result of neuronal dysfunction, but the underlying molecular defects remain largely unknown. An important signaling pathway involved in the regulation of neuronal function is the cyclic AMP/Protein kinase A pathway. We here show an essential role for coronin 1, which is encoded in a genomic region associated with neurobehavioral dysfunction, in the modulation of cyclic AMP/PKA signaling.

The Coffin-Lowry syndrome-associated protein RSK2 regulates neurite outgrowth through phosphorylation of phospholipase D1 (PLD1) and synthesis of phosphatidic acid.

More than 80 human X-linked genes have been associated with mental retardation and deficits in learning and memory. However, most of the identified mutations induce limited morphological alterations in brain organization and the molecular bases underlying neuronal clinical features remain elusive. We show here that neurons cultured from mice lacking ribosomal S6 kinase 2 (Rsk2), a model for the Coffin-Lowry syndrome (CLS), exhibit a significant delay in growth in a similar way to that shown by neurons cultured from phospholipase D1 (Pld1) knock-out mice.

Lack of the presynaptic RhoGAP protein oligophrenin1 leads to cognitive disabilities through dysregulation of the cAMP/PKA signalling pathway.

Loss-of-function mutations in the gene encoding for the RhoGAP protein of oligophrenin-1 (OPHN1) lead to cognitive disabilities (CDs) in humans, yet the underlying mechanisms are not known. Here, we show that in mice constitutive lack of Ophn1 is associated with dysregulation of the cyclic adenosine monophosphate/phosphate kinase A (cAMP/PKA) signalling pathway in a brain-area-specific manner. Consistent with a key role of cAMP/PKA signalling in regulating presynaptic function and plasticity, we found that PKA-dependent presynaptic plasticity was completely abolished in affected brain regions, including hippocampus and amygdala.

Target-specific vulnerability of excitatory synapses leads to deficits in associative memory in a model of intellectual disorder.

Intellectual disorders (IDs) have been regularly associated with morphological and functional deficits at glutamatergic synapses in both humans and rodents. How these synaptic deficits may lead to the variety of learning and memory deficits defining ID is still unknown. Here we studied the functional and behavioral consequences of the ID gene il1rapl1 deficiency in mice and reported that il1rapl1 constitutive deletion alters cued fear memory formation.

In vivo evidence that TRAF4 is required for central nervous system myelin homeostasis.

Tumor Necrosis Factor Receptor-Associated Factors (TRAFs) are major signal transducers for the TNF and interleukin-1/Toll-like receptor superfamilies. However, TRAF4 does not fit the paradigm of TRAF function in immune and inflammatory responses. Its physiological and molecular functions remain poorly understood.