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Newly generated excitatory synapses in the mammalian cortex lack sufficient AMPA-type glutamate receptors to mediate neurotransmission, resulting in functionally silent synapses that require activity-dependent plasticity to mature. Silent synapses are abundant in early development, during which they mediate circuit formation and refinement, but they are thought to be scarce in adulthood 1 . However, adults retain a capacity for neural plasticity and flexible learning that suggests that the formation of new connections is still prevalent. Here we used super-resolution protein imaging to visualize synaptic proteins at 2,234 synapses from layer 5 pyramidal neurons in the primary visual cortex of adult mice. Unexpectedly, about 25% of these synapses lack AMPA receptors. These putative silent synapses were located at the tips of thin dendritic protrusions, known as filopodia, which were more abundant by an order of magnitude than previously believed (comprising about 30% of all dendritic protrusions). Physiological experiments revealed that filopodia do indeed lack AMPA-receptor-mediated transmission, but they exhibit NMDA-receptor-mediated synaptic transmission. We further showed that functionally silent synapses on filopodia can be unsilenced through Hebbian plasticity, recruiting new active connections into a neuron’s input matrix. These results challenge the model that functional connectivity is largely fixed in the adult cortex and demonstrate a new mechanism for flexible control of synaptic wiring that expands the learning capabilities of the mature brain. A study using super-resolution protein imaging to visualize synaptic proteins from layer 5 pyramidal neurons in the primary visual cortex of adult mice shows that filopodia are a structural substrate for silent synapses.

The process by which visual information is incorporated into the brain’s spatial framework to represent landmarks is poorly understood. Studies in humans and rodents suggest that retrosplenial cortex (RSC) plays a key role in these computations. We developed an RSC-dependent behavioral task in which head-fixed mice learned the spatial relationship between visual landmark cues and hidden reward locations. Two-photon imaging revealed that these cues served as dominant reference points for most task-active neurons and anchored the spatial code in RSC. This encoding was more robust after task acquisition. Decoupling the virtual environment from mouse behavior degraded spatial representations and provided evidence that supralinear integration of visual and motor inputs contributes to landmark encoding. V1 axons recorded in RSC were less modulated by task engagement but showed surprisingly similar spatial tuning. Our data indicate that landmark representations in RSC are the result of local integration of visual, motor, and spatial information. When moving through a city, people often use notable or familiar landmarks to help them navigate. Landmarks provide us with information about where we are and where we need to go next. But despite the ease with which we – and most other animals – use landmarks to find our way around, it remains unclear exactly how the brain makes this possible. One area that seems to have a key role is the retrosplenial cortex, which is located deep within the back of the brain in humans. This area becomes more active when animals use visual landmarks to navigate. It is also one of the first brain regions to be affected in Alzheimer's disease, which may help to explain why patients with this condition can become lost and disoriented, even in places they have been many times before. To find out how the retrosplenial cortex supports navigation, Fischer et al. measured its activity in mice exploring a virtual reality world. The mice ran through simulated corridors in which visual landmarks indicated where hidden rewards could be found. The activity of most neurons in the retrosplenial cortex was most strongly influenced by the mouse’s position relative to the landmark; for example, some neurons were always active 10 centimeters after the landmark. In other experiments, when the landmarks were present but no longer indicated the location of a reward, the same neurons were much less active. Fischer et al. also measured the activity of the neurons when the mice were running with nothing shown on the virtual reality, and when they saw a landmark but did not run. Notably, the activity seen when the mice were using the landmarks to find rewards was greater than the sum of that recorded when the mice were just running or just seeing the landmark without a reward, making the “landmark response” an example of so-called supralinear processing. Fischer et al. showed that visual centers of the brain send information about landmarks to retrosplenial cortex. But only the latter adjusts its activity depending on whether the mouse is using that landmark to navigate. These findings provide the first evidence for a “landmark code” at the level of neurons and lay the foundations for studying impaired navigation in patients with Alzheimer's disease. By showing that retrosplenial cortex neurons combine different types of input in a supralinear fashion, the results also point to general principles for how neurons in the brain perform complex calculations.

Dendritic spines operate as high-impedance input structures that amplify local synaptic depolarization to enhance electrical interaction among coactive inputs. Neuronal performance boosted by dendritic spines Neuronal excitation in the mammalian brain relies on small dendritic compartments called 'spines', whose size, shape and molecular composition vary with experience. Here, Jeff Magee and colleagues show that spine-neck resistance is large enough (at about 500 MΩ) to amplify 1.5- to 45-fold the spine-head depolarization associated with unitary synaptic inputs. The authors thus confirm that spines enhance neurons' computational and memory capabilities, by promoting nonlinear signal processing in dendrites. Dendritic spines are the nearly ubiquitous site of excitatory synaptic input onto neurons 1 , 2 and as such are critically positioned to influence diverse aspects of neuronal signalling. Decades of theoretical studies have proposed that spines may function as highly effective and modifiable chemical and electrical compartments that regulate synaptic efficacy, integration and plasticity 3 , 4 , 5 , 6 , 7 , 8 . Experimental studies have confirmed activity-dependent structural dynamics and biochemical compartmentalization by spines 9 , 10 , 11 , 12 . However, there is a longstanding debate over the influence of spines on the electrical aspects of synaptic transmission and dendritic operation 3 , 4 , 5 , 6 , 7 , 8 , 13 , 14 , 15 , 16 , 17 , 18 . Here we measure the amplitude ratio of spine head to parent dendrite voltage across a range of dendritic compartments and calculate the associated spine neck resistance ( R neck ) for spines at apical trunk dendrites in rat hippocampal CA1 pyramidal neurons. We find that R neck is large enough (∼500 MΩ) to amplify substantially the spine head depolarization associated with a unitary synaptic input by ∼1.5- to ∼45-fold, depending on parent dendritic impedance. A morphologically realistic compartmental model capable of reproducing the observed spatial profile of the amplitude ratio indicates that spines provide a consistently high-impedance input structure throughout the dendritic arborization. Finally, we demonstrate that the amplification produced by spines encourages electrical interaction among coactive inputs through an R neck -dependent increase in spine head voltage-gated conductance activation. We conclude that the electrical properties of spines promote nonlinear dendritic processing and associated forms of plasticity and storage, thus fundamentally enhancing the computational capabilities of neurons 19 , 20 , 21 .

Recordings from cortical neuron dendrites of head-fixed mice during an object-localization task provide direct evidence that a novel global nonlinearity has a role in integrating sensory and motor information during a behaviour-related computation. Role of neuronal dendrites in touch perception Neuronal dendrites, the branch-like projections on nerve cells, are increasingly seen as more than just passive integrators of synaptic inputs, but whether their nonlinear electrical properties have a role in vivo has remained unclear. Now Jeffrey Magee and colleagues have recorded from cortical neuron dendrites from mice engaged in object localization using rhythmic whisker movements known as whisking, and show that sensory-evoked dendritic activity is dependent on input from the adjacent motor cortex. The results demonstrate that active nonlinear dendritic integration in cortical neurons is central to the production of a behaviour-related computation — the integration of sensory and motor information. Active dendrites provide neurons with powerful processing capabilities. However, little is known about the role of neuronal dendrites in behaviourally related circuit computations. Here we report that a novel global dendritic nonlinearity is involved in the integration of sensory and motor information within layer 5 pyramidal neurons during an active sensing behaviour. Layer 5 pyramidal neurons possess elaborate dendritic arborizations that receive functionally distinct inputs, each targeted to spatially separate regions 1 , 2 . At the cellular level, coincident input from these segregated pathways initiates regenerative dendritic electrical events that produce bursts of action potential output 3 , 4 and circuits featuring this powerful dendritic nonlinearity can implement computations based on input correlation 5 . To examine this in vivo we recorded dendritic activity in layer 5 pyramidal neurons in the barrel cortex using two-photon calcium imaging in mice performing an object-localization task. Large-amplitude, global calcium signals were observed throughout the apical tuft dendrites when active touch occurred at particular object locations or whisker angles. Such global calcium signals are produced by dendritic plateau potentials that require both vibrissal sensory input and primary motor cortex activity. These data provide direct evidence of nonlinear dendritic processing of correlated sensory and motor information in the mammalian neocortex during active sensation.

Viral infection during pregnancy is correlated with increased frequency of neurodevelopmental disorders, and this is studied in mice prenatally subjected to maternal immune activation (MIA). We previously showed that maternal T helper 17 cells promote the development of cortical and behavioural abnormalities in MIA-affected offspring. Here we show that cortical abnormalities are preferentially localized to a region encompassing the dysgranular zone of the primary somatosensory cortex (S1DZ). Moreover, activation of pyramidal neurons in this cortical region was sufficient to induce MIA-associated behavioural phenotypes in wild-type animals, whereas reduction in neural activity rescued the behavioural abnormalities in MIA-affected offspring. Sociability and repetitive behavioural phenotypes could be selectively modulated according to the efferent targets of S1DZ. Our work identifies a cortical region primarily, if not exclusively, centred on the S1DZ as the major node of a neural network that mediates behavioural abnormalities observed in offspring exposed to maternal inflammation. The authors define a specific cortical subregion of the somatosensory cortex as a critical region of dysfunction that is causal to the emergence of abnormal social and repetitive behaviours in mice exposed to maternal inflammation. Brain patches behind behavioural defects Viral infection and activation of the maternal immune system (MIA) during pregnancy has been linked to behavioural abnormalities in the offspring. In this study, Gloria Choi, Jun Huh and colleagues identify a specific cortical subregion of the somatosensory cortex as a critical region of dysfunction, and show that the presence and size of cortical patches correlate with specific social behaviours. In a related paper published this week, Gloria Choi, Jun Huh and colleagues provide evidence that MIA-mediated abnormal behavioural phenotypes require defined gut commensal bacteria for the induction of interleukin-17 (IL-17)-producing T helper 17 (T H 17) cells, in accordance with previous studies that have demonstrated a role in this association.

The goal of this study was to determine whether a phosphodiesterase-4D (PDE4D) allosteric inhibitor (BPN14770) would improve cognitive function and behavioral outcomes in patients with fragile X syndrome (FXS). This phase 2 trial was a 24-week randomized, placebo-controlled, two-way crossover study in 30 adult male patients (age 18–41 years) with FXS. Participants received oral doses of BPN14770 25 mg twice daily or placebo. Primary outcomes were prespecified as safety and tolerability with secondary efficacy outcomes of cognitive performance, caregiver rating scales and physician rating scales (ClinicalTrials.gov identifier: NCT03569631 ). The study met the primary outcome measure since BPN14770 was well tolerated with no meaningful differences between the active and placebo treatment arms. The study also met key secondary efficacy measures of cognition and daily function. Cognitive benefit was demonstrated using the National Institutes of Health Toolbox Cognition Battery assessments of Oral Reading Recognition (least squares mean difference +2.81, P  = 0.0157), Picture Vocabulary (+5.81, P  = 0.0342) and Cognition Crystallized Composite score (+5.31, P  = 0.0018). Benefit as assessed by visual analog caregiver rating scales was judged to be clinically meaningful for language (+14.04, P  = 0.0051) and daily functioning (+14.53, P  = 0.0017). Results from this study using direct, computer-based assessment of cognitive performance by adult males with FXS indicate significant cognitive improvement in domains related to language with corresponding improvement in caregiver scales rating language and daily functioning. A randomized crossover study of BPN14770 in adult males with fragile X syndrome shows significant cognitive improvement in domains related to language with corresponding improvement in caregiver scales rating language and daily functioning.

Animals strategically scan the environment to form an accurate perception of their surroundings. Here we investigated the neuronal representations that mediate this behavior. Ca2+ imaging and selective optogenetic manipulation during an active sensing task reveals that layer 5 pyramidal neurons in the vibrissae cortex produce a diverse and distributed representation that is required for mice to adapt their whisking motor strategy to changing sensory cues. The optogenetic perturbation degraded single-neuron selectivity and network population encoding through a selective inhibition of active dendritic integration. Together the data indicate that active dendritic integration in pyramidal neurons produces a nonlinearly mixed network representation of joint sensorimotor parameters that is used to transform sensory information into motor commands during adaptive behavior. The prevalence of the layer 5 cortical circuit motif suggests that this is a general circuit computation.

The biophysical properties of neurons are the foundation for computation in the brain. Neuronal size is a key determinant of single neuron input–output features and varies substantially across species 1 – 3 . However, it is unknown whether different species adapt neuronal properties to conserve how single neurons process information 4 – 7 . Here we characterize layer 5 cortical pyramidal neurons across 10 mammalian species to identify the allometric relationships that govern how neuronal biophysics change with cell size. In 9 of the 10 species, we observe conserved rules that control the conductance of voltage-gated potassium and HCN channels. Species with larger neurons, and therefore a decreased surface-to-volume ratio, exhibit higher membrane ionic conductances. This relationship produces a conserved conductance per unit brain volume. These size-dependent rules result in large but predictable changes in somatic and dendritic integrative properties. Human neurons do not follow these allometric relationships, exhibiting much lower voltage-gated potassium and HCN conductances. Together, our results in layer 5 neurons identify conserved evolutionary principles for neuronal biophysics in mammals as well as notable features of the human cortex. Analyses of layer 5 cortical pyramidal neurons in 10 mammalian species show that human neurons are distinct in that they do not follow the expected allometric relationship between neuron size and membrane conductance.

A single-wavelength genetically encoded sensor of extracellular glutamate is reported. The sensor—iGluSnFR—is bright and photostable under both one- and two-photon illumination and is shown to work for in vivo imaging in worms, zebrafish and mice. We describe an intensity-based glutamate-sensing fluorescent reporter (iGluSnFR) with signal-to-noise ratio and kinetics appropriate for in vivo imaging. We engineered iGluSnFR in vitro to maximize its fluorescence change, and we validated its utility for visualizing glutamate release by neurons and astrocytes in increasingly intact neurological systems. In hippocampal culture, iGluSnFR detected single field stimulus–evoked glutamate release events. In pyramidal neurons in acute brain slices, glutamate uncaging at single spines showed that iGluSnFR responds robustly and specifically to glutamate in situ , and responses correlate with voltage changes. In mouse retina, iGluSnFR-expressing neurons showed intact light-evoked excitatory currents, and the sensor revealed tonic glutamate signaling in response to light stimuli. In worms, glutamate signals preceded and predicted postsynaptic calcium transients. In zebrafish, iGluSnFR revealed spatial organization of direction-selective synaptic activity in the optic tectum. Finally, in mouse forelimb motor cortex, iGluSnFR expression in layer V pyramidal neurons revealed task-dependent single-spine activity during running.