Animals adapt their behavior by integrating sensory evidence with prior experience and contextual information. Understanding how animals employ specific behavioral strategies to integrate these variables and how neural mechanisms support such strategies remains unclear. We trained mice on a tactile reversal learning task and used a trial-by-trial computational model to infer latent decision strategies. Early in learning, mice relied on action-based (“choice-driven”) policies but progressively transitioned to stimulus-guided choices (“cue-driven”) as they learned the task. Following a rule reversal, mice flexibly reinstated this policy to adapt their behavior. Chemogenetic silencing of the lateral orbitofrontal cortex (lOFC) delayed this transition and impaired reversal learning. To identify the neural basis of strategy learning, we developed a novel approach combining low-dimensional analysis of neural activity with decoding of behavioral strategies from longitudinal two-photon imaging. We revealed reward- and error-strategy representations in excitatory layer 2/3 neurons in the primary somatosensory cortex (S1) that were differentially modulated by OFC instructive signals. Within S1, distinct subpopulations of positive and negative-valence-coding neurons tracked evolving decision strategies through trial-history integration. Together, these findings revealed how mice flexibly deploy distinct exploratory strategies during adaptive behavior, highlighting OFC’s role in supporting reward and error-guided learning through distinct corticocortical interactions.

It is frequently assumed that the phenotypic heterogeneity in autism spectrum disorder reflects underlying pathobiological variation. However, direct evidence in support of this hypothesis is lacking. Here, we leverage cross-species functional neuroimaging to examine whether variability in brain functional connectivity reflects distinct biological mechanisms. We find that fMRI connectivity alterations in 20 distinct mouse models of autism (n=549 individual mice) can be clustered into two prominent hypo- and hyperconnectivity subtypes. We show that these connectivity profiles are linked to distinct signaling pathways, with hypoconnectivity being associated with synaptic dysfunction, and hyperconnectivity reflecting transcriptional and immune-related alterations. Extending these findings to humans, we identify analogous hypo- and hyperconnectivity subtypes in a large, multicenter resting state fMRI dataset of n=940 autistic and n=1036 neurotypical individuals. Remarkably, hypo- and hyperconnectivity autism subtypes are replicable across independent cohorts (accounting for 25.1% of all autism data), exhibit distinct functional network architecture, are behaviorally dissociable, and recapitulate synaptic and immune mechanisms identified in corresponding mouse subtypes. Our cross-species investigation, thus, decodes the heterogeneity of fMRI connectivity in autism into distinct pathway-specific etiologies, offering a new empirical framework for targeted subtyping of autism.

The orbitofrontal cortex (OFC) is a hub for value-guided decision-making, linked reciprocally with both cortical and subcortical regions. While projections from sensory areas to the OFC - and vice versa - are known to support goal-directed learning, these projections have often been studied in isolation, and their joint effect remains poorly understood. Here, we revisit these circuits through a unifying computational framework. We propose that sensory cortices send compressed task knowledge to the OFC to build abstract task models, while OFC feedback provides teaching signals that reshape sensory representations within the cortical hierarchy. This bidirectional exchange equips sensory areas with cognitive functions that extend well beyond passive feature detection, with significant implications for our understanding of learning, cognitive models, and artificial neural networks.

How sensory information is interpreted depends on context. Yet, how context shapes sensory processing in the brain remains elusive. To investigate this question, we combined computational modeling and in vivo functional imaging of cortical neurons in mice during reversal learning of a tactile sensory discrimination task. During learning, layer 2/3 somatosensory neurons enhanced their response to reward-predictive stimuli, explainable as gain amplification from apical dendrites. Reward-prediction errors were reduced and confidence in the outcome prediction increased. Upon rule reversal, the lateral orbitofrontal cortex, through disinhibitory VIP interneurons, encoded a context-prediction error, signaling a loss of confidence. The hierarchy of prediction errors in cortical areas is mirrored in top-down signals modulating apical activity in the primary sensory cortex. Our model explains how contextual changes are detected in the brain and how errors in different cortical regions interact to reshape and update the sensory representation. ### Competing Interest Statement The authors have declared no competing interest.

The ability to respond flexibly to an ever-changing environment relies on the orbitofrontal cortex (OFC). However, how the OFC associates sensory information with predicted outcomes to enable flexible sensory learning in humans remains elusive. Here, we combine a probabilistic tactile reversal learning task with functional magnetic resonance imaging (fMRI) to investigate how lateral OFC (lOFC) interacts with the primary somatosensory cortex (S1) to guide flexible tactile learning in humans. fMRI results reveal that lOFC and S1 exhibit distinct task-dependent engagement: while the lOFC responds transiently to unexpected outcomes immediately following reversals, S1 is persistently engaged during re-learning. Unlike the contralateral stimulus-selective S1, activity in ipsilateral S1 mirrors the outcomes of behavior during re-learning, closely related to top-down signals from lOFC. These findings suggest that lOFC contributes to teaching signals to dynamically update representations in sensory areas, which implement computations critical for adaptive behavior.

Evolution has molded individual species' sensory capacities and abilities. In rodents, who mostly inhabit dark tunnels and burrows, the whisker-based somatosensory system has developed as the dominant sensory modality, essential for environmental exploration and spatial navigation. In contrast, humans rely more on visual and auditory inputs when collecting information from their surrounding sensory space in everyday life. As a result of such species-specific differences in sensory dominance, cognitive relevance and capacities, the evidence for analogous sensory-cognitive mechanisms across species remains sparse. However, recent research in rodents and humans yielded surprisingly comparable processing rules for detecting tactile stimuli, integrating touch information into percepts, and goal-directed rule learning. Here, we review how the brain, across species, harnesses such processing rules to establish decision-making during tactile learning, following canonical circuits from the thalamus and the primary somatosensory cortex up to the frontal cortex. We discuss concordances between empirical and computational evidence from micro- and mesoscopic circuit studies in rodents to findings from macroscopic imaging in humans. Furthermore, we discuss the relevance and challenges for future cross-species research in addressing mutual context-dependent evaluation processes underpinning perceptual learning.

The increasing molecular, anatomical and temporal precision of modern neuroscientific methods continues to unveil a rich diversity of synapses, cells and brain regions. This heterogeneity spans all scales and allows the brain to adapt to the vast array of experiences, options and outcomes encountered across a lifetime. The prefrontal cortex (PFC) is typically portrayed as the pinnacle of this adaptation, a central hub of cognition able to flexibly integrate, process and route information according to external demands and internal state (Friedman & Robbins, 2022; Le Merre et al., 2021; Miller & Cohen, 2001). How do PFC inputs, cell-types and outputs mediate these complex interactions? How does PFC physiology configure and coordinate downstream circuits via top-down outputs to distributed recipients? And how do we move beyond “high-resolution phrenology” to capture the convergent features of PFC physiology required to inform both understanding and clinical and societal applications? A symposium entitled ‘Decoding Prefrontal Cortical Physiology: Circuits of Cognition’ debated these questions during the annual conference of The Physiological Society held online in the summer of 2021. This editorial summarises the symposium objectives, which centred on integrating rodent and non-human primate models to understand the connectivity, computational capabilities, and behavioural impacts of PFC circuits. A key goal was to synthesise evidence across experimental species and paradigms, identifying potential canonical features of PFC physiology and function. Two of the symposium speakers expand on these topics in detailed reviews: Alexander, Wood et al. (2023) interrogate the roles of ventromedial PFC in emotional regulation, integrating comparative evidence from mice, rats, marmosets and humans; and Perry et al. (2023) navigate the loops of cortico-thalamo-cortical interactions to highlight the importance of distributed, network information processing in cognition, cognitive impairment and future cognitive therapeutics. Both Alexander et al., and Roberts (2023) and Perry et al., and Mitchell (2023) exemplify the power of behavioural neuroscience in non-human primates. However, the symposium also harnessed the potential of mouse models to delineate the cellular and circuit mechanisms of PFC function, mapping the local and long-range connections that underpin prefrontal computations (Anastasiades & Carter, 2021) and the cortico-cortical population coding that enables flexible behaviour (Banerjee et al., 2020). It is clear that sustaining and integrating these complementary approaches across scales and species remains essential if we are to understand PFC well enough to treat the many disorders associated with its dysfunction (Chini & Hanganu-Opatz, 2021, Anastasiades, De Vivo et al., 2022). No two moments of life are ever identical, demanding constant updates to our mental model and behaviour. While theoretical models suggest how these updates may be achieved, there is little understanding of how they are represented in the brain. Behavioural adaptations allow us to maximise the likelihood of receiving desirable outcomes, such as rewards, whilst avoiding negative experiences, such as punishments. Flexible decision-making is strongly linked to the PFC, and work from Banerjee et al. (2020) harnessed the power of rodent circuit analyses to uncover the cellular mechanisms through which such top-down control of behaviour is mediated. They found that neurons in the lateral orbitofrontal cortex (lOFC), a subdivision of PFC, become highly active in response to unexpected rewards that occur when the association between a tactile stimulus and a sucrose-water reward is reversed in a texture discrimination based reversal learning task. Using an array of sophisticated techniques, including neural population calcium imaging and viral projection tracing, they went on to show how OFC projections to the somatosensory cortex are essential for neurons in the sensory cortex to “remap” their response to different sensory stimuli after behavioural contingencies are reversed (Banerjee et al., 2020). Reversal learning is foundational to a range of flexible behaviours; this work highlights how prefrontal outputs can signal to other brain areas, including primary sensory areas, to guide context-dependent adaptation. The myriad functions attributed to the PFC depend upon the diversity of its afferent and efferent projections, which include limbic, cognitive, autonomic and neuromodulatory brain areas. In recent years, thanks largely to the advent of optogenetics, we have developed a more precise understanding of how different inputs engage the PFC to recruit local circuit components such as inhibitory GABAergic interneurons and how this influences the activity of long-range projection neurons that mediate prefrontal outputs. These studies reveal how individual inputs are biased towards distinct regions (for example, prelimbic or infralimbic), layers, and cell types. A prime example of this is the connectivity of individual thalamic nuclei. Anastasiades, Collins et al. (2021) applied genetic and viral tools to delineate how the mediodorsal (MD) and ventromedial thalamus engage the prefrontal network. Their findings revealed that, despite both inputs originating in the higher-order thalamus, these two inputs display remarkably distinct connectivity at the level of cortical sub-layers, cell types and even specific regions of the dendritic arbour. The distinct circuit motifs activated by these two inputs have important implications for prefrontal activity during the various cognitive tasks known to require direct communication between the PFC and thalamus. The role of the cognitive thalamus in behaviour is the focus of Perry et al's. (2023) review, which outlines the cortico-thalamic and thalamo-cortical networks dynamically recruited to mediate healthy attentional control, learning and decision-making, alongside their disruption in cognitive impairment and their potential as therapeutic targets. The review focuses on the MD, anterior thalamic and pulvinar nuclei – motivated by their implication in a range of neurological and psychiatric disorders and by evidence from various perturbation studies in rodents and non-human primates. Convergent evidence shows this circuitry is recruited during rapid learning of visuospatial discriminations and probabilistic decision-making, with neurons in both PFC and MD tuned to complementary but dissociable task features. Perry et al. highlight a broader network embedding the MD thalamus as a mediator and coordinator of both limbic-cortical dialogues and cortical processing hierarchies. For instance, their brain imaging work in macaques shows that learning-associated changes in thalamic-PFC connectivity coincide with altered connectivity between PFC and parietal and temporal cortical territories. Combining such macroscopic analyses with microscopic, single-neuron recordings in network hubs, including MD thalamus and PFC, and with genetically-defined circuit mapping in mice (as outlined by other symposium speakers) holds great promise in decoding the circuit architectures of cognition. This is particularly vital given the potential utility – but enigmatic mechanisms – of circuit-targeting therapies such as deep brain stimulation (DBS) of thalamic nuclei and PFC subregions. One striking example of DBS's potential is in treatment of depression: some patients with Major Depressive Disorder (MDD) respond positively to DBS of the ventromedial PFC (vmPFC; Kennedy, Giacobbe et al., 2011). Determining which patients respond to DBS and why is essential if we are to fine-tune and improve the impact and applicability of these therapies. Alexander et al. (2023) zoom in on vmPFC and its roles in regulating cognitive and peripheral facets of emotion, for example in response to threatening stimuli and situations. The authors highlight the considerable translational challenges posed by heterogeneous cross-species anatomical definitions of vmPFC and its subdivisions – indeed, considerable efforts have been invested in agonising over which parts of the rodent brain are more or less like human equivalents (Carlén, 2017, Laubach, Amarante et al., 2018, Preuss & Wise, 2022). Nevertheless, judicious comparative studies enable translation across species, harnessing the predictive power of mouse 2-photon imaging, for example, to help design primate experiments and/or interpret human brain imaging studies. In this regard, Alexander et al. (2023) champion studies in marmosets, new world monkeys with a vmPFC anatomical and functional architecture well-suited to modelling the human brain. In particular, they review an elegant series of multi-modal measures and interventions delineating the behavioural and autonomic consequences of vmPFC stimulation and inactivation. For example, they describe how over-activation of a vmPFC subdivision (sgACC-25) in marmosets reduces tolerance and increases anxiety in response to an “uncertain threat” (an unfamiliar human experimenter), plus blunts physiological signatures of reward anticipation. These marmoset results are consistent with ACC hyperactivity associating with anxiety and anhedonia in humans and present opportunities to interrogate novel antidepressant modalities including ketamine (Alexander et al., 2019). Ultimately, Alexander et al. (2023) underscore the critical importance of aligning comparative anatomical and physiological studies with the appropriate behavioural domains. Emotion is multifaceted and some aspects – for example appetitive signalling – may be rooted in comparatively conserved circuitries encompassing rodent, non-human primate and human PFC; others, for example threat responses, may demand more judicious use of experimental species during forward- and back-translation. The PFC's complexity and flexibility make it fundamentally fascinating and clinically vital; this symposium highlighted recent advances in understanding both facets by applying the array of neuroscience tools and behavioural analyses currently available. From a translational perspective, the PFC is centre-stage in many neuropsychiatric conditions, including neurodevelopmental disorders, anxiety and depression, psychosis spectrum disorders and neurodegenerative diseases. Although the PFC's complexity and protracted development may render its wiring particularly vulnerable to genetic and/or environmental disruptors (Chini & Hanganu-Opatz, 2021, Anastasiades, De Vivo et al., 2022), none of these afflictions “reside” in a single brain region, making it vital to set PFC dysfunction in its network context. If we are to do so successfully, some contentious considerations remain: for example, how good a model of human PFC is rodent PFC and which aspects of our behaviours can be usefully modelled in rodents? The symposium reminded us that the mouse PFC is not, of course, an accurate model of the human or primate PFC – but it is a consistently informative model, allowing us to map cognition and its component algorithms onto genetically and anatomically defined circuits that are largely conserved across species. The repertoire of complex behaviours classically studied in humans and non-human primates is now extending to rodent experiments; and the molecular and cellular measures and manipulations developed in rodents are increasingly applicable to non-human primates and humans. As such, the prospects of using bidirectional translation to decode heterogeneity in the PFC and beyond is increasingly realistic and useful. Importantly, as in this symposium, such efforts will hinge on dialogue between researchers working with different species, collaborating and comparing to frame understanding of this intriguingly complex brain region. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None. Paul Anastasiades: Conception or design of the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work Abhishek Banerjee: Conception or design of the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work Matt Jones: Conception or design of the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work. All authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. The authors thank The Wellcome Trust (PA, AB, MJ) and The Academy of Medical Sciences (PA) for support.

Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modeled minimizing environmental contributions. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches.

COPYRIGHT © 2022 Tropea, Scimemi and Banerjee. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Editorial: Biology of brain disorders—Cellular substrates for disrupted synaptic function and experience-dependent plasticity

The classical concepts of reinforcement learning in the mammalian brain focus on dopamine release in the basal ganglia as the neural substrate of reward prediction errors, which drive plasticity in striatal and cortico-striatal synapses to maximize the expected aggregate future reward. This temporal difference framework, however, even when augmented with deep credit assignment, does not fully capture higher-order processes such as the influence of goal representations, planning based on learned internal models, and hierarchical decision-making implemented by diverse neocortical areas. Candidate functions for such neocortical contributions to reinforcement learning are increasingly being considered in artificial intelligence algorithms. Here, we review recent experimental neurophysiological findings focusing on the orbitofrontal cortex, a key higher-order association cortex, and highlight emerging concepts that emphasize the role of the neocortex in reward-driven computation, in addition to its role as an input to striatal structures. In this framework, reward drives plasticity in various neocortical regions, implementing multiple distinct reinforcement learning algorithms.

Rett syndrome (RTT) is characterized by dysfunction in neuronal excitation/inhibition (E/I) balance, potentially impacting seizure susceptibility via deficits in K+/Cl- cotransporter 2 (KCC2) function. Mice lacking the Methyl-CpG binding protein 2 (MeCP2) recapitulate many symptoms of RTT, and recombinant human insulin-like growth factor-1 (rhIGF-1) restores KCC2 expression and E/I balance in MeCP2 KO mice. However, clinical trial outcomes of rhIGF-1 in RTT have been variable, and increasing its therapeutic efficacy is highly desirable. To this end, the neuropeptide oxytocin (OXT) is promising, as it also critically modulates KCC2 function during early postnatal development. We measured basal KCC2 expression levels in MeCP2 KO mice and identified 3 key frontal brain regions showing KCC2 alterations in young adult mice, but not in postnatal P10 animals. We hypothesized that deficits in an IGF-1/OXT signaling crosstalk modulating KCC2 may occur in RTT during postnatal development. Consistently, we detected alterations of IGF-1 receptor and OXT receptor levels in those brain areas. rhIGF-1 and OXT treatments in KO mice rescued KCC2 expression in a region-specific and complementary manner. These results suggest that region-selective combinatorial pharmacotherapeutic strategies could be most effective at normalizing E/I balance in key brain regions subtending the RTT pathophysiology.

Flexible decision-making is crucial for adaptive behaviour. Such behaviour in mammals largely relies on the frontal cortex, and specifically, the orbitofrontal cortex (OFC). How OFC neurons encode decision variables and instruct sensory areas to guide adaptive behaviour is a key open question. Here we developed a reversal learning task for head-fixed mice together with two-photon calcium imaging to monitor the activity of lateral OFC neuronal populations and investigated their dynamic interaction with primary somatosensory cortex (S1). Mice trained on this task learned to discriminate go/no-go tactile stimuli and adapt their behaviour upon changes in stimulus–reward contingencies (‘rule-switch’). Longitudinal imaging at cellular resolution across weeks during all behavioural phases revealed a distinct engagement of S1 and lateral OFC neurons: S1 neural activity reflected task learning-related responses, while neurons in the lateral OFC saliently and transiently responded to the rule-switch. A subset of OFC neurons conveyed a value prediction error signal via feedback projections to S1, as direct anatomical long-range projections were revealed by retrograde tracing combined with whole-brain light-sheet microscopy. Top-down signals implemented an update of sensory representations and functionally reconfigured a small subpopulation of S1 neurons that were differentially modulated by reward-history. Functional remapping of these neurons crucially depended on top-down inputs, as chemogenetic silencing of lateral OFC neurons disrupted reversal learning and impaired plastic changes in these outcome-sensitive S1 neurons. Our results reveal the presence of long-range cortical interactions between cellular ensembles in higher and lower-order brain areas specifically recruited during context-dependent learning and task-switching. Such interactions crucially implement history-dependent reward-value computations and error heuristics, which, in turn, help guide adaptive behaviour.

With the recent 50th anniversary of the first publication on Rett syndrome, and the almost 20 years since the first report on the link between Rett syndrome and MECP2 mutations, it is important to reflect on the tremendous advances in our understanding and their implications for the diagnosis and treatment of this neurodevelopmental disorder. Rett syndrome features an interesting challenge for biologists and clinicians, as the disorder lies at the intersection of molecular mechanisms of epigenetic regulation and neurophysiological alterations in synapses and circuits that together contribute to severe pathophysiological endophenotypes. Genetic, clinical, and neurobiological evidences support the notion that Rett syndrome is primarily a synaptic disorder, and a disease model for both intellectual disability and autism spectrum disorder. This review examines major developments in both recent neurobiological and preclinical findings of Rett syndrome, and to what extent they are beginning to impact our understanding and management of the disorder. It also discusses potential applications of knowledge on synaptic plasticity abnormalities in Rett syndrome to its diagnosis and treatment.

Rett syndrome (RTT) arises from loss-of-function mutations in methyl-CpG binding protein 2 gene (Mecp2), but fundamental aspects of its physiological mechanisms are unresolved. Here, by whole-cell recording of synaptic responses in MeCP2 mutant mice in vivo, we show that visually driven excitatory and inhibitory conductances are both reduced in cortical pyramidal neurons. The excitation-to-inhibition (E/I) ratio is increased in amplitude and prolonged in time course. These changes predict circuit-wide reductions in response reliability and selectivity of pyramidal neurons to visual stimuli, as confirmed by two-photon imaging. Targeted recordings reveal that parvalbumin-expressing (PV+) interneurons in mutant mice have reduced responses. PV-specific MeCP2 deletion alone recapitulates effects of global MeCP2 deletion on cortical circuits, including reduced pyramidal neuron responses and reduced response reliability and selectivity. Furthermore, MeCP2 mutant mice show reduced expression of the cation-chloride cotransporter KCC2 (K+/Cl-exporter) and a reduced KCC2/NKCC1 (Na+/K+/Cl-importer) ratio. Perforated patch recordings demonstrate that the reversal potential for GABA is more depolarized in mutant mice, but is restored by application of the NKCC1 inhibitor bumetanide. Treatment with recombinant human insulin-like growth factor-1 restores responses of PV+ and pyramidal neurons and increases KCC2 expression to normalize the KCC2/NKCC1 ratio. Thus, loss of MeCP2 in the brain alters both excitation and inhibition in brain circuits via multiple mechanisms. Loss of MeCP2 from a specific interneuron subtype contributes crucially to the cell-specific and circuit-wide deficits of RTT. The joint restoration of inhibition and excitation in cortical circuits is pivotal for functionally correcting the disorder.

Rett Syndrome was long considered to be simply a disorder of postnatal development, with phenotypes that manifest only late in development and into adulthood. A variety of recent evidence demonstrates that the phenotypes of Rett Syndrome are present at the earliest stages of brain development, including developmental stages that define neurogenesis, migration, and patterning in addition to stages of synaptic and circuit development and plasticity. These phenotypes arise from the pleotropic effects of MeCP2, which is expressed very early in neuronal progenitors and continues to be expressed into adulthood. The effects of MeCP2 are mediated by diverse signaling, transcriptional, and epigenetic mechanisms. Attempts to reverse the effects of Rett Syndrome need to take into account the developmental dynamics and temporal impact of MeCP2 loss.

Presynaptic NMDA receptors (preNMDARs) play pivotal roles in excitatory neurotransmission and synaptic plasticity. They facilitate presynaptic neurotransmitter release and modulate mechanisms controlling synaptic maturation and plasticity during formative periods of brain development. There is an increasing understanding of the roles of preNMDARs in experience-dependent synaptic and circuit-specific computation. In this review we summarize the latest understanding of compartment-specific expression and function of preNMDARs, and how they contribute to synapse-specific and circuit-level information processing.

Rett Syndrome is a neurodevelopmental disorder that arises from mutations in the X-linked gene methyl-CpG binding protein 2 (MeCP2). MeCP2 has a large number of targets and a wide range of functions, suggesting the hypothesis that functional signaling mechanisms upstream of synaptic and circuit maturation may contribute to our understanding of the disorder and provide insight into potential treatment. Here, we show that insulin-like growth factor-1 (IGF1) levels are reduced in young male Mecp2-null (Mecp2(-/y)) mice, and systemic treatment with recombinant human IGF1 (rhIGF1) improves lifespan, locomotor activity, heart rate, respiration patterns, and social and anxiety behavior. Furthermore, Mecp2-null mice treated with rhIGF1 show increased synaptic and activated signaling pathway proteins, enhanced cortical excitatory synaptic transmission, and restored dendritic spine densities. IGF1 levels are also reduced in older, fully symptomatic heterozygous (Mecp2(-/+)) female mice, and short-term treatment with rhIGF1 in these animals improves respiratory patterns, reduces anxiety levels, and increases exploratory behavior. In addition, rhIGF1 treatment normalizes abnormally prolonged plasticity in visual cortex circuits of adult Mecp2(-/+) female mice. Our results provide characterization of the phenotypic development of Rett Syndrome in a mouse model at the molecular, circuit, and organismal levels and demonstrate a mechanism-based therapeutic role for rhIGF1 in treating Rett Syndrome.

CRISPR-Cas9 can be used to edit both single and multiple genes in postmitotic neurons in adult mice enabling rapid assessment of gene functions in the brain. Probing gene function in the mammalian brain can be greatly assisted with methods to manipulate the genome of neurons in vivo. The clustered, regularly interspaced, short palindromic repeats (CRISPR)-associated endonuclease (Cas)9 from Streptococcus pyogenes (SpCas9)1 can be used to edit single or multiple genes in replicating eukaryotic cells, resulting in frame-shifting insertion/deletion (indel) mutations and subsequent protein depletion. Here, we delivered SpCas9 and guide RNAs using adeno-associated viral (AAV) vectors to target single (Mecp2) as well as multiple genes (Dnmt1, Dnmt3a and Dnmt3b) in the adult mouse brain in vivo. We characterized the effects of genome modifications in postmitotic neurons using biochemical, genetic, electrophysiological and behavioral readouts. Our results demonstrate that AAV-mediated SpCas9 genome editing can enable reverse genetic studies of gene function in the brain.

Probing gene function in the mammalian brain can be greatly assisted with methods to manipulate the genome of neurons in vivo. The clustered, regularly interspaced, short palindromic repeats (CRISPR)-associated endonuclease (Cas)9 from Streptococcus pyogenes (SpCas9)1 can be used to edit single or multiple genes in replicating eukaryotic cells, resulting in frame-shifting insertion/deletion (indel) mutations and subsequent protein depletion. Here, we delivered SpCas9 and guide RNAs using adeno-associated viral (AAV) vectors to target single (Mecp2) as well as multiple genes (Dnmt1, Dnmt3a and Dnmt3b) in the adult mouse brain in vivo. We characterized the effects of genome modifications in postmitotic neurons using biochemical, genetic, electrophysiological and behavioral readouts. Our results demonstrate that AAV-mediated SpCas9 genome editing can enable reverse genetic studies of gene function in the brain.

Spike timing-dependent plasticity (STDP) is an attractive candidate to mediate the synaptic changes that support circuit plasticity in sensory cortices during development. STDP is prevalent at excitatory synapses, but it is not known whether the underlying mechanisms are universal, or whether distinct mechanisms underpin STDP at different synapses. Here, we set out to compare and contrast STDP at vertical layer 4 and horizontal layer 2/3 inputs onto postsynaptic layer 2/3 neurons in the mouse barrel cortex. We find that both vertical and horizontal inputs show STDP, but that they display different time windows for induction of timing-dependent long-term depression (t-LTD). Moreover, whereas t-LTD at vertical inputs requires presynaptic NMDA receptors and is expressed presynaptically, using paired recordings we find that t-LTD at horizontal inputs requires postsynaptic NMDA receptors and is expressed postsynaptically. These results demonstrate that similar forms of plasticity on the same postsynaptic neuron can be mediated by distinct mechanisms, and suggest that these forms of plasticity may enable these two types of cortical synapses to support different functions.