Cofilin, an actin-severing protein, plays key roles in muscle sarcomere addition and maintenance. Our previous work found that Drosophila cofilin (DmCFL) knockdown in muscle causes progressive deterioration of muscle structure and function and produces features seen in nemaline myopathy caused by cofilin mutations. We hypothesized that disruption of actin cytoskeleton dynamics by DmCFL knockdown would impact other aspects of muscle development, and, thus, conducted an RNA-sequencing analysis that unexpectedly revealed upregulated expression of numerous neuromuscular junction (NMJ) genes. We found that DmCFL is enriched in the muscle postsynaptic compartment and that DmCFL muscle knockdown causes F-actin disorganization in this subcellular domain prior to the sarcomere defects observed later in development. Despite NMJ gene expression changes, we found no significant changes in gross presynaptic Bruchpilot active zones or total postsynaptic glutamate receptor levels. However, DmCFL knockdown resulted in mislocalization of GluRIIA class glutamate receptors in more deteriorated muscles and strongly impaired NMJ transmission strength. These findings expand our understanding of the roles of cofilin in muscle to include NMJ structural development and suggest that NMJ defects may contribute to the pathophysiology of nemaline myopathy.

Cofilin, an actin severing protein, plays critical roles in muscle sarcomere addition and maintenance. Our previous work has shown Drosophila cofilin (DmCFL) knockdown causes progressive deterioration of muscle structure and function and produces features seen in nemaline myopathy (NM) caused by cofilin mutations. We hypothesized that disruption of actin cytoskeleton dynamics by DmCFL knockdown would impact other aspects of muscle development, and, thus, conducted an RNA sequencing analysis which unexpectedly revealed upregulated expression of numerous neuromuscular junction (NMJ) genes. We found that DmCFL is enriched in the muscle postsynaptic compartment and that DmCFL deficiency causes F-actin disorganization in this subcellular domain prior to the sarcomere defects observed later in development. Despite NMJ gene expression changes, we found no significant changes in gross presynaptic Bruchpilot active zones or total postsynaptic glutamate receptor levels. However, DmCFL knockdown results in mislocalization of glutamate receptors containing the GluRIIA subunit in more deteriorated muscles and neurotransmission strength is strongly impaired. These findings expand our understanding of cofilin\'s roles in muscle to include NMJ structural development and suggest that NMJ defects may contribute to NM pathophysiology.

Excitatory synapses in the mammalian cortex are highly diverse, both in terms of their structure and function. However, relationships between synaptic features indicate they are highly coordinated entities. Imaging techniques, that enable physiology at the resolution of individual synapses to be investigated, have allowed the presynaptic activity level of the synapse to be related to postsynaptic function. This approach has revealed that neuronal activity induces the pre- and post-synapse to be functionally correlated and that subsets of synapses are more susceptible to certain forms of synaptic plasticity. As presynaptic function is often examined in isolation from postsynaptic properties, the effect it has on the post-synapse is not fully understood. However, since postsynaptic receptors at excitatory synapses respond to release of glutamate, it follows that they may be differentially regulated depending on the frequency of its release. Therefore, examining postsynaptic properties in the context of presynaptic function may be a useful way to approach a broad range of questions on synaptic physiology. In this review, we focus on how optophysiology tools have been utilized to study relationships between the pre- and the post-synapse. Multiple imaging techniques have revealed correlations in synaptic properties from the submicron to the dendritic level. Optical tools together with advanced imaging techniques are ideally suited to illuminate this area further, due to the spatial resolution and control they allow.

Disruption of sensorimotor gating causes \"flooding\" of irrelevant sensory input and is considered a congenital trait in several neurodevelopmental disorders. Prepulse inhibition of acoustic startle response (PPI) is the operational measurement and has a high translational validity. Pharmacological studies in rodents have linked alterations in serotonin, dopamine and glutamate signalling to PPI disruption. How PPI response is associated with gene expression levels of these receptors is unknown. PPI response was assessed in 39 genetically heterogeneous National Institutes of Health-Heterogeneous Stock (NIH-HS) rats. Animals were classified as high, medium or low PPI. Expression levels of glutamate metabotropic receptor 2 (Grm2), dopamine receptor D2 (Drd2), dopamine receptor D1 (Drd1), serotonin receptor 1A (Htr1a), serotonin receptor 2A (Htr2a) and homer scaffolding protein 1 (Homer1) were investigated in prefrontal cortex (PFC) and striatum (STR). When comparing the two extreme phenotypes, only Drd2 in STR showed increased expression in the low PPI group. A multinomial model fitting all genes and all groups indicated that Grm2 in PFC, and Grm2 and Drd2 in the STR predicted PPI group. This was corroborated by a linear relationship of Grm2 with PPI in PFC, and Drd2 with PPI in STR. An interaction between levels of H3K27 trimethylation, associated with transcriptional repression, and PPI phenotype was observed for Drd2 in STR. Gene set enrichment analysis on a microarray dataset on Lewis rats confirmed enrichment of Drd2 in PFC in relation to PPI. These findings contribute to the understanding of the genetic substrate behind alterations in sensorimotor gating, relevant for its linkage to neurodevelopmental disorders.

Opioid administration in preclinical models induces long-lasting adaptations in reward and habit circuitry. The latest research demonstrates that in the nucleus accumbens, opioid-induced excitatory synaptic plasticity involves presynaptic and postsynaptic elements as well as adjacent astroglial processes and the perisynaptic extracellular matrix. We outline opioid-induced modifications within each component of the tetrapartite synapse and provide a neurobiological perspective on how these adaptations converge to produce addiction-related behaviors in rodent models. By incorporating changes observed at each of the excitatory synaptic compartments into a unified framework of opioid-induced glutamate dysregulation, we highlight new avenues for restoring synaptic homeostasis that might limit opioid craving and relapse vulnerability.

Precise neuronal wiring is critical for the function of the nervous system and is ultimately determined at the level of individual synapses. Neurons integrate various intrinsic and extrinsic cues to form synapses onto their correct targets in a stereotyped manner. In the past decades, the nervous system of nematode (Caenorhabditis elegans) has provided the genetic platform to reveal the genetic and molecular mechanisms of synapse formation and specificity. In this review, we will summarize the recent discoveries in synapse formation and specificity in C. elegans.

Neurons undergo dynamic processes of constitutive AMPA-type glutamate receptor (AMPAR) trafficking, such as the insertion and internalization of AMPARs by exocytosis and endocytosis, while stably maintaining synaptic efficacy. Studies using advanced imaging techniques have suggested that the frequency of these constitutive trafficking processes, as well as the number of AMPARs that are involved in a particular event highly fluctuate. In addition, mechanisms that trigger some forms of synaptic plasticity have been shown to include not only these processes but also additional fluctuating processes, such as the sorting of AMPARs to late endosomes (LEs). Thus, the regulation of postsynaptic AMPARs by the endosomal trafficking system appears to have superficially conflicting properties between the stability or organized control of plasticity and highly fluctuating or stochastic processes. However, it is not clear how the endosomal trafficking system reconciles and utilizes such conflicting properties. Although deterministic models have been effective to describe the stable maintenance of synaptic AMPAR numbers by constitutive recycling, as well as the involvement of endosomal trafficking in synaptic plasticity, they do not take stochasticity into account. In this study, we introduced the stochasticity into the model of each crucial machinery of the endosomal trafficking system. The specific questions we solved by our improved model are whether stability is accomplished even with a combination of fluctuating processes, and how overall variability occurs while controlling long-term synaptic depression (LTD). Our new stochastic model indeed demonstrated the stable regulation of postsynaptic AMPAR numbers at the basal state and during LTD maintenance, despite fast fluctuations in AMPAR numbers as well as high variability in the time course and amounts of LTD. In addition, our analysis suggested that the high variability arising from this stochasticity is beneficial for reproducing the relatively constant timing of LE sorting for LTD. We therefore propose that the coexistence of stability and stochasticity in the endosomal trafficking system is suitable for stable synaptic transmission and the reliable induction of synaptic plasticity, with variable properties that have been observed experimentally.

Since the first observation that described a patient with a mutation in IL1RAPL1 gene associated with intellectual disability in 1999, the function of IL1RAPL1 has been extensively studied by a number of laboratories. In this review, we summarize all the major data describing the synaptic and neuronal functions of IL1RAPL1 and recapitulate most of the genetic deletion identified in humans and associated to intellectual disability (ID) and autism spectrum disorders (ASD). All the data clearly demonstrate that IL1RAPL1 is a synaptic adhesion molecule localized at the postsynaptic membrane. Mutations in IL1RAPL1 gene cause either the absence of the protein or the production of a dysfunctional protein. More recently it has been demonstrated that IL1RAPL1 regulated dendrite formation and mediates the activity of IL-1β on dendrite morphology. All these data will possibly contribute to identifying therapies for patients carrying mutations in IL1RAPL1 gene.

Long-term potentiation (LTP) of excitatory synaptic strength, which has long been considered a synaptic correlate for learning and memory, requires a fast recruitment of additional α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors (AMPARs) to the postsynaptic sites. As cell biological concepts have been applied to the field and genetic manipulation and microscopic imaging technologies have been advanced, visualization of the trafficking of AMPARs to synapses for LTP has been investigated intensively over the last decade. Recycling endosomes have been reported as intracellular storage organelles to supply AMPARs for LTP through the endocytic recycling pathway. In addition, exocytic domains in the spine plasma membrane, where AMPARs are inserted from the intracellular compartment, and nanodomains, where diffusing AMPARs are trapped and immobilized inside synapses for LTP, have been described. Furthermore, cell surface lateral diffusion of AMPARs from extrasynaptic to synaptic sites has been reported as a key step for AMPAR location to the synaptic sites for LTP. This review article will discuss recent findings and views on the reservoir(s) of AMPARs and their trafficking for LTP expression by focusing on the exocytosis and lateral diffusion of AMPARs, and provide some future directions that need to be addressed in the field of LTP.

Dendritic spines are small actin-rich protrusions from neuronal dendrites that form the postsynaptic part of most excitatory synapses. Changes in the shape and size of dendritic spines correlate with the functional changes in excitatory synapses and are heavily dependent on the remodeling of the underlying actin cytoskeleton. Recent evidence implicates synapses at dendritic spines as important substrates of pathogenesis in neuropsychiatric disorders, including autism spectrum disorder (ASD). Although synaptic perturbations are not the only alterations relevant for these diseases, understanding the molecular underpinnings of the spine and synapse pathology may provide insight into their etiologies and could reveal new drug targets. In this review, we will discuss recent findings of defective actin regulation in dendritic spines associated with ASD.