Explore the vast range of titles available.

In the brain, synaptic connections are formed with exquisite specificity, but the underlying molecular mechanisms remain largely unexplored. Synapse formation is thought to involve bidirectional signaling by proteins that bind to each other across the synaptic cleft. Sando et al. used conditional genetic tools and in vitro assays to investigate the mechanisms of synapse formation. They found that synapse formation in the mouse hippocampus requires latrophilins. Latrophilins are G protein–coupled receptors that bind to cell-surface proteins called teneurins and fibronectin leucine-rich repeat transmembrane proteins (FLRTs). Two different latrophilins mediated formation of distinct synapses on the same hippocampal neuron. This function required binding of both teneurins and FLRTs. Thus, latrophilins may guide synapse formation by coincidence signaling, which could help to explain the specificity of synaptic connections. Science , this issue p. eaav7969 Elucidating the mechanisms involved in input-specific synapse formation in the mouse brain. Bidirectional signaling by cell adhesion molecules is thought to mediate synapse formation, but the mechanisms involved remain elusive. We found that the adhesion G protein–coupled receptors latrophilin-2 and latrophilin-3 selectively direct formation of perforant-path and Schaffer-collateral synapses, respectively, to hippocampal CA1-region neurons. Latrophilin-3 binds to two transcellular ligands: fibronectin leucine-rich repeat transmembrane proteins (FLRTs) and teneurins. In transgenic mice in vivo, both binding activities were required for input-specific synapse formation, which suggests that coincident binding of both ligands is necessary for synapse formation. In cultured neurons in vitro, teneurin or FLRT alone did not induce excitatory synapse formation, whereas together they potently did so. Thus, postsynaptic latrophilins promote excitatory synapse formation by simultaneous binding of two unrelated presynaptic ligands, which is required for formation of synaptic inputs at specific dendritic localizations.

The two universally required components of the intracellular membrane fusion machinery, SNARE and SM (Sec1/Munc18-like) proteins, play complementary roles in fusion. Vesicular and target membrane-localized SNARE proteins zipper up into an α-helical bundle that pulls the two membranes tightly together to exert the force required for fusion. SM proteins, shaped like clasps, bind to trans-SNARE complexes to direct their fusogenic action. Individual fusion reactions are executed by distinct combinations of SNARE and SM proteins to ensure specificity, and are controlled by regulators that embed the SM-SNARE fusion machinery into a physiological context. This regulation is spectacularly apparent in the exquisite speed and precision of synaptic exocytosis, where synaptotagmin (the calcium-ion sensor for fusion) cooperates with complexin (the clamp activator) to control the precisely timed release of neurotransmitters that initiates synaptic transmission and underlies brain function.

The brain processes information by transmitting signals at synapses, which connect neurons into vast networks of communicating cells. In these networks, synapses not only transmit signals but also transform and refine them. Neurexins and neuroligins are synaptic cell-adhesion molecules that connect presynaptic and postsynaptic neurons at synapses, mediate signalling across the synapse, and shape the properties of neural networks by specifying synaptic functions. In humans, alterations in genes encoding neurexins or neuroligins have recently been implicated in autism and other cognitive diseases, linking synaptic cell adhesion to cognition and its disorders.

Increased fear memory generalization is associated with posttraumatic stress disorder, but the circuit mechanisms that regulate memory specificity remain unclear. Here, we define a neural circuit—composed of the medial prefrontal cortex, the nucleus reuniens (NR), and the hippocampus—that controls fear memory generalization. Inactivation of prefrontal inputs into the NR or direct silencing of NR projections enhanced fear memory generalization, whereas constitutive activation of NR neurons decreased memory generalization. Direct optogenetic activation of phasic and tonic action-potential firing of NR neurons during memory acquisition enhanced or reduced memory generalization, respectively. We propose that the NR determines the specificity and generalization of memory attributes for a particular context by processing information from the medial prefrontal cortex en route to the hippocampus.

Neural circuit assembly in the brain requires precise establishment of synaptic connections, but the mechanisms of synapse assembly remain incompletely understood. Latrophilins are postsynaptic adhesion-GPCRs that engage in trans-synaptic complexes with presynaptic teneurins and FLRTs. In mouse CA1-region neurons, Latrophilin-2 and Latrophilin-3 are essential for formation of entorhinal-cortex-derived and Schaffer-collateral-derived synapses, respectively. However, it is unknown whether latrophilins function as GPCRs in synapse formation. Here, we show that Latrophilin-2 and Latrophilin-3 exhibit constitutive GPCR activity that increases cAMP levels, which was blocked by a mutation interfering with G-protein and arrestin interactions of GPCRs. The same mutation impaired the ability of Latrophilin-2 and Latrophilin-3 to rescue the synapse-loss phenotype in Latrophilin-2 and Latrophilin-3 knockout neurons in vivo. Our results suggest that Latrophilin-2 and Latrophilin-3 require GPCR signaling in synapse formation, indicating that latrophilins promote synapse formation in the hippocampus by activating a classical GPCR-signaling pathway.

Memory encodes past experiences, thereby enabling future plans. The basolateral amygdala is a centre of salience networks that underlie emotional experiences and thus has a key role in long-term fear memory formation 1 . Here we used spatial and single-cell transcriptomics to illuminate the cellular and molecular architecture of the role of the basolateral amygdala in long-term memory. We identified transcriptional signatures in subpopulations of neurons and astrocytes that were memory-specific and persisted for weeks. These transcriptional signatures implicate neuropeptide and BDNF signalling, MAPK and CREB activation, ubiquitination pathways, and synaptic connectivity as key components of long-term memory. Notably, upon long-term memory formation, a neuronal subpopulation defined by increased Penk and decreased Tac expression constituted the most prominent component of the memory engram of the basolateral amygdala. These transcriptional changes were observed both with single-cell RNA sequencing and with single-molecule spatial transcriptomics in intact slices, thereby providing a rich spatial map of a memory engram. The spatial data enabled us to determine that this neuronal subpopulation interacts with adjacent astrocytes, and functional experiments show that neurons require interactions with astrocytes to encode long-term memory. Spatial and single-cell transcriptomic analyses of the mouse basolateral amygdala reveal transcriptomic signatures, spatial resolution and interactions of cells that constitute the memory engram, including crucial neuron–astrocyte interactions.

Cellular differentiation and lineage commitment are considered to be robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. This raised the question of whether transcription factors could directly induce other defined somatic cell fates, and not only an undifferentiated state. We hypothesized that combinatorial expression of neural-lineage-specific transcription factors could directly convert fibroblasts into neurons. Starting from a pool of nineteen candidate genes, we identified a combination of only three factors, Ascl1 , Brn2 (also called Pou3f2 ) and Myt1l , that suffice to rapidly and efficiently convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro . These induced neuronal (iN) cells express multiple neuron-specific proteins, generate action potentials and form functional synapses. Generation of iN cells from non-neural lineages could have important implications for studies of neural development, neurological disease modelling and regenerative medicine. Nerve cells direct The discovery that differentiated cells such as fibroblasts can be reprogrammed to pluripotency, producing iPS (induced pluripotent stem) cells, has generated much interest because of their potential therapeutic uses. Now Vierbuchen et al . show that mature differentiated cells can be directed, using a cocktail of transcription factors distinct from those used for generating iPS cells, to form functional neurons in vitro , without having to revert the fibroblasts to an embryonic state. Just three factors, Ascl1 , Brn2 ( Pou3f2 ) and Myt1l , suffice to convert mouse embryonic and postnatal fibroblasts into functional neurons. Mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. Here, mature differentiated cells are directed, via a combination of a few transcription factors (distinct from those described for generating iPS cells), to form functional neurons in vitro , without having to revert the fibroblasts to an embryonic state.

Synaptic adhesion molecules (SAMs) shape the structural and functional properties of synapses and thereby control the information processing power of neural circuits. SAMs are broadly expressed in the brain, suggesting that they may instruct synapse formation and specification via a combinatorial logic. Here, we generate sextuple conditional knockout mice targeting all members of the two major families of presynaptic SAMs, Neurexins and leukocyte common antigen-related-type receptor phospho-tyrosine phosphatases (LAR-PTPRs), which together account for the majority of known trans-synaptic complexes. Using synapses formed by cerebellar Purkinje cells onto deep cerebellar nuclei as a model system, we confirm that Neurexins and LAR-PTPRs themselves are not essential for synapse assembly. The combinatorial deletion of both neurexins and LAR-PTPRs, however, decreases Purkinje-cell synapses on deep cerebellar nuclei, the major output pathway of cerebellar circuits. Consistent with this finding, combined but not separate deletions of neurexins and LAR-PTPRs impair motor behaviors. Thus, Neurexins and LAR-PTPRs are together required for the assembly of a functional cerebellar circuit. Whether presynaptic ‘hub’ adhesion molecules are essential for synapse formation is still unclear. Here, the authors generate sextuple conditional knockout mice that target Neurexins and LAR-PTPRs and find that their combinatorial expression instructs the assembly of a cerebellar circuit.

Fifty years ago, Bernard Katzs seminal work revealed that calcium triggers neurotransmitter release by stimulating ultrafast synaptic vesicle fusion. How a presynaptic terminal achieves the speed and precision of calcium-triggered fusion remained unknown.

Neurons from fibroblasts Three papers in this issue demonstrate the production of functional induced neuronal (iN) cells from human fibroblasts, a procedure that holds great promise for regenerative medicine. Pang et al . show that a combination of the three transcription factors Ascl1 (also known as Mash1 ), Brn2 (or Pou3f2 ) and Myt1l greatly enhances the neuronal differentiation of human embryonic stem cells. When combined with the basic helix–loop–helix transcription factor NeuroD1, these factors can also convert fetal and postnatal human fibroblasts into iN cells. Caiazzo et al . use a cocktail of three transcription factors to convert prenatal and adult mouse and human fibroblasts into functional dopaminergic neurons. The three are Mash1 , Nurr1 (or Nr4a2 ) and Lmx1a . Conversion is direct with no reversion to a progenitor cell stage, and it occurs in cells from Parkinson's disease patients as well as from healthy donors. Yoo et al . use an alternative approach. They show that microRNAs can have an instructive role in neural fate determination. Expression of miR-9/9* and miR-124 in human fibroblasts induces their conversion into functional neurons, and the process is facilitated by the addition of some neurogenic transcription factors. Somatic cell nuclear transfer, cell fusion, or expression of lineage-specific factors have been shown to induce cell-fate changes in diverse somatic cell types 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 . We recently observed that forced expression of a combination of three transcription factors, Brn2 (also known as Pou3f2 ), Ascl1 and Myt1l , can efficiently convert mouse fibroblasts into functional induced neuronal (iN) cells 13 . Here we show that the same three factors can generate functional neurons from human pluripotent stem cells as early as 6 days after transgene activation. When combined with the basic helix–loop–helix transcription factor NeuroD1 , these factors could also convert fetal and postnatal human fibroblasts into iN cells showing typical neuronal morphologies and expressing multiple neuronal markers, even after downregulation of the exogenous transcription factors. Importantly, the vast majority of human iN cells were able to generate action potentials and many matured to receive synaptic contacts when co-cultured with primary mouse cortical neurons. Our data demonstrate that non-neural human somatic cells, as well as pluripotent stem cells, can be converted directly into neurons by lineage-determining transcription factors. These methods may facilitate robust generation of patient-specific human neurons for in vitro disease modelling or future applications in regenerative medicine.