Dysfunctions of Cellular Context-sensitivity in Neurodevelopmental Learning Disabilities

Pyramidal neurons have a pivotal role in the cognitive capabilities of neocortex. Though they have been predominantly modeled as integrate-and-fire point processors, many of them have another point of input integration in their apical dendrites that is central to mechanisms endowing them with the sensitivity to context that underlies basic cognitive capabilities. Here we review evidence implicating impairments of those mechanisms in three major neurodevelopmental disabilities, fragile X, Down syndrome


Cellular bases of context-sensitivity in mental life
A central aim of this review is to show that cognitive functions and dysfunctions can now be related to their roots in intracellular processes and their regulation by the local inhibitory microcircuitry in much greater detail than previously supposed.Far from merely providing mechanisms for cognitive capabilities that are already adequately understood, this has major implications for our conceptions of those capabilities.At a minimum it puts emphasis on some capabilities rather than others.In particular, the selective amplification of signals that are relevant in the context of on-going neural activity is shown to be fundamental to the various cognitive capabilities of which the wakeful state is composed.The research reviewed also refines and develops conceptions of those cognitive capabilities.Even more importantly, it is beginning to bridge a gulf that has until now separated the sciences of mind from those of physiology, biophysics, and genetics.That gulf must be bridged if the sciences of brain and mind are to be unified in a way that adequately explains the many psychological, neurobiological, evolutionary, developmental, and pathological phenomena that are central to our understanding of cognition.
Sensitivity to context is fundamental to the generation of coherent percepts, thoughts, and actions that are useful in the current situation.
That includes what you are doing right now.Psychological studies showed long ago that reading depends on using context to select the currently relevant feedforward data and guide its interpretation (Phillips, 1971(Phillips, , 1989)).Automatic forms of context-sensitivity operate so effectively in daily life that they usually go unnoticed.Consider the falling of the twin towers on 9.11.2OO1.Presumably you saw the second and third symbols of the year in that date as digits (even though here they are printed using 'O', as in CONTEXT for example, rather than '0').Coherence is the fundamental objective implied by Festinger's theory of dissonance reduction and related cognitive theories (Kaaronen, 2018).Sensitivity to context is especially important at higher cognitive levels, as emphasized by the theory of constrained rationality (Vlaev, 2018).
Consider 'To celebrate the end of the financial crisis he held a ball in the bank.'This is full of ambiguity.The meaning of 'he' is defined only by the context.Furthermore, 'held', 'ball' and 'bank' are all ambiguous, as shown by comparing the above with 'He held a ball in his hand, then rolled it down the bank'.These and other observations demonstrate the fundamental importance of context-sensitivity for cognitive functions.
Previous reviews show that conscious experience depends on the operation of apical dendrites in the cortex of the mammalian brain (LaBerge, 2006;Bachmann, 2015;Takahashi et al., 2016Takahashi et al., , 2020;;Phillips et al., 2016;Aru et al., 2019Aru et al., , 2020a;;Bachmann et al., 2020;Shepherd and Yamawaki, 2021).The dependence of conscious states on apical function is also indicated by evidence that general anesthetics decouple the apical compartment from the basal compartment counteracting thalamocortical input from higher order thalamic nuclei which enables the interaction between these distant compartments during wakefulness (Suzuki and Larkum, 2020).
Context-sensitivity has been specifically implicated in perceptual disambiguation, selective attention, working memory and imagery, emotional prioritization, cognitive control, and learning (Siegel et al., 2000;Wibral et al., 2017;Heeger and Mackey, 2019;Iyer et al., 2022).It also has a central role in cognitive development -as neuroconstructivists were amongst the first to realize (Karmiloff-Smith, 1998, 2009;Spratling andJohnson, 2004, 2006).That style of computation is cooperative in that it promotes coherent perceptions based on the activity in different groups of neurons representing distinct aspects thereof, thus reducing cognitive dissonance and mental conflict in general.Finally, the effectiveness and energy efficiency of this cooperative context-sensitive style of neuronal computation have been shown by its successful use in machine learning applications (Adeel et al., 2023a(Adeel et al., , 2023b)).All these advances point to the fundamental importance of context-sensitive cellular computations in mental life -as advocated by recent reviews of the field as a whole (Phillips, 2023), including a re-interpretation of the evidence for 'subtractive prediction-error minimization' as evidence for 'prediction success maximization', i.e., coincidence detection (Marvan and Phillips, 2024).
Though notions of excitation, inhibition, and adaptable synaptic connection strengths are common in systems neuroscience and psychological theories, those notions are usually so over-simplified that they can be seriously misleading.Thus, synaptic connections can vary in ways other than in strength.In many pyramidal cells, synapses located far from the cell body on the distant apical dendrites, e.g. in neocortical layer 1, can greatly enhance the cell's response to concurrent excitation of synapses closer to the cell body, while providing little or no direct excitation themselves.Thus, the net effect of those distant synapses is to operate as a context-dependent modulatory signal.Context-dependent modulation is not exclusively mediated by the cholinergic, adrenergic, dopaminergic, or serotonergic systems.The majority of the apical synaptic inputs are glutamatergic from other neocortical pyramidal and thalamic cells residing in other brain areas.In consequence, pyramidal cells have information processing capabilities that greatly exceed those of the integrate-and-fire neurons with a single point of input integration that most of 20th century psychology and systems neuroscience took for granted.The apical site can serve as a context that selectively amplifies the cell's output only when it is useful to do so in the current context.Given the importance of this signal, it is not surprising that it is under tight regulation by local GABAergic interneurons providing feedforward and feedback inhibition from distant and local brain areas.These insights have major implications for our understanding of conscious experience and basic cognitive capabilities.

Context-sensitive neocortical pyramidal cells
Though twentieth century psychology and systems neuroscience largely relied on the simplifying assumption that neurons in general operate as integrate-and-fire point processors, we now know that many neocortical pyramidal neurons have at least two functionally distinct points of integration.This transforms their capabilities and thus those of the systems containing them.The new perspective on thalamo-cortical function is built on anatomical, physiological, psychological, and computational grounds.A great part of the supporting experimental data is derived from the rodent brain.We sketch it briefly here.

Anatomical distinctions between apical and basal dendritic trees
Apical and basal dendritic trees are clearly distinct in the morphology of neocortical pyramidal cells.Furthermore, they receive inputs from very different sources.In the neocortex input to basal dendrites is typically feedforward inter-regional input from locally specific subsets of cells at lower levels of abstraction.Input to dendrites of the apical dendritic tree, aka the tuft, is predominately from diverse internal sources, including lateral connections within and between regions, higher-order thalamus, inter-regional feedback or top-down input from higher levels of abstraction, and the amygdala (e.g., Cauller and Connors, 1994;Schuman et al., 2021).Furthermore, the distinction between these two sets of inputs to pyramidal cells is clearly echoed in the anatomy of the inhibitory and disinhibitory microcircuitry in which they are embedded.

Amplification via apical dendrites
Our focus here is on the distinct functions of the apical dendrites.Basal dendrites feed directly into the cell body, or soma, from which the cell's output spikes are generated.Apical dendrites, aka the tuft, are connected to the soma via the apical trunk.In pyramidal cells with long apical trunks, effects of tuft input on the cell's output are highly dependent on active ion flow into and out of the trunk because without it the tuft is effectively disconnected from the soma (Migliore and Shepherd, 2002).Apical trunks and tuft dendrites vary in their length and electrical compactness (Fletcher and Williams, 2019), which determines how much influence input to the tuft has on the soma without the assistance of active ionic currents.In general, there are partially different complements of ion channels in the apical and basal dendrites, particularly with respect to calcium channels, so input to the distal apical dendrites has a distinct functional influence on action potential generation.In the rat visual cortex, it is only neocortical pyramidal cells with apical trunks longer than about 480 microns that have a second point of input integration near the top of the trunk.That includes many layer 5b pyramidal neurons, and all or nearly all in higher areas because there is a gradient of increasing length from posterior to frontal cortical areas (Fletcher and Williams, 2019).For most layer 5 neurons, the apical tuft dendrites contribute little or nothing to action potential generation at the cell body via direct excitation or inhibition but rather enable active ion flows to operate as a context-sensitive regulator of the strength of the cell's response to basal and perisomatic excitation.In such pyramidal cells, tuft input that would otherwise have little or no effect by itself rapidly converts a weak response to coincident basal/perisomatic excitation into a strong response (Larkum et al., 1999(Larkum et al., , 2001;;Williams and Stuart, 2002).In primates, apical trunks are typically much longer than 480 microns, often being twice that length, or even more.So, these distinct functions of apical dendrites are likely to be even more common in species with thicker cortices, and especially in humans.
In summary, there is ample evidence that active ion flows in apical trunks and tufts of pyramidal neurons give them a specific functional role that enhances the neuron's context-sensitivity specifically when apical excitation coincides with basal excitation.
Evolutionary enhancements in cognitive capabilities are commonly assumed to be due simply to increases in gross brain size with cellular capabilities remaining unchanged.This interpretation gives an incomplete picture (e.g., Emes et al., 2008;Ryan et al., 2013;Zhu et al., 2018).The evolution and ontogenetic development that occurs at a cellular level can transform a system's capabilities without necessarily implying any increase in brain size or the number of cells.The discoveries of A. Granato et al. complex dendritic computations, like the direction-sensitivity in retinal starburst amacrine cell (Euler et al., 2002) and the context-sensitivity of apical pyramidal tuft dendrites, strongly support the relevance of these cellular computations for the capabilities of the entire system.

Three-compartment context-sensitive cells
Context-sensitive pyramidal cells have at least three functionally distinct compartments (Larkum et al., 2001).Their distinct properties are predominantly dictated in three ways: by active voltage-sensitive ion channels in the cell's membrane at that location, by differences in their neuromodulatory regulation, and by differences in their excitatory and inhibitory synaptic inputs.Overactivation or underactivation of these compartments could be involved in various cognitive disabilities.The analogy here is to picture each zone as having a dial that controls the level of activity in each compartment, and therefore its contribution to the input-output function of the cell (Fig. 1).
Thick-tufted pyramidal cells with their soma in L5 (TTL5 pyramidal cells) epitomize those with two functionally distinct sites of integration (e.g., Larkum, 2013Larkum, , 2022aLarkum, , 2022b;;Major et al., 2013;Ramaswamy and Markram, 2015;Larkum et al., 2018).It has long been clear that these cells have a second site of integration near the top of the apical dendrite, also known as the calcium spike/plateau initiation zone (Schiller et al., 1997;Stuart and Spruston, 2015).Such spikes are generated across several 100 µms of the apical dendritic trunk that constitutes the apical initiation zone, or nexus, by which inputs from diverse sources provide a context that modulates the cell's excitability by the feedforward inputs to which it is selectively sensitive.The influence of synaptic inputs to the apical tuft dendrites on the cell's output therefore depends on the active non-linear properties of the apical trunk (Larkum et al., 2001;Suzuki and Larkum, 2020;Schulz et al., 2021;Kay et al., 2022).It follows that regulation of these properties greatly influences the overall computational capabilities of the neuron (Phillips, 2017(Phillips, , 2023;;Tantirigama et al., 2020;Poirazi and Papoutsi, 2020;Shine et al., 2021;Larkum, 2022a).Most recently, discovery of the two functionally distinct sets of inputs to many pyramidal cells has led to the proposal of a new paradigm for learning and computing, which has capabilities that exceed those of networks of leaky integrate-and-fire point neurons.They include the ability to learn without error propagation, to perform context-dependent tasks robustly, contextual disambiguation in perception, and the ability to implement hierarchical policies by decomposing complex long-horizon tasks into a sequence of sub-goals (Sacramento et al., 2018;Capone et al., 2023).
An overactive basal compartment may contribute to the sensory overload experienced in various forms of autism spectrum disorder.Under-activation of the apical compartment could also produce a bias toward feedforward information transmission, but without the selective effects of context that amplify only the information that is currently relevant.Note, however, that while such suppositions may be useful as a first-pass estimate of possible consequences of under or overactivation of these compartments, in practice it should be expected that changes in the activity levels of more than one compartment or confined to specific cortical areas would cause more nuanced outcomes, as indicated by the evidence reviewed in the following.

Dependence of dendritic integration and coupling on NMDA spikes
Clusters of synaptic inputs to a small local dendritic site give rise to another form of dendritic spiking, i.e., NMDA spikes (Schiller et al., 2000;Larkum et al., 2009).These form dynamically in small, 10-30 µm, stretches of thin dendrites such that NMDA spikes transform the input-output relationship of the neuron from linear integration to one of pattern matching for specific spatio-temporal inputs (Major et al., 2013;Palmer et al., 2014).Activity in these tiny compartments depends on the active ion flows in that local dendritic membrane, and it also interacts with local GABAergic inhibition (Schulz et al., 2018) and A. Granato et al. neuromodulatory influences.
It has been proposed that layer 5 pyramidal neurons integrate synaptic information through a unifying principle whereby thin distal tuft and basal dendrites generate NMDA spikes due to local clusters of synaptic inputs (Larkum et al., 2009).While the inputs are integrated in semi-independent compartments in the basal and distal apical trees, their combined influence is determined at the somatic sodium spike initiation and apical calcium spike initiation zones respectively.Treadmill motor learning induces NMDA-dependent local spikes on apical tuft branches of L5 pyramidal neurons in the motor cortex (Cichon and Gan, 2015).This suggests that individual dendritic branches may serve as a basic unit for synaptic plasticity and information storage.Using novel 2-photon calcium imaging approaches, it has also been found that calcium signals related to task-dependent operations are organized into many different compartments in pyramidal neurons of the anterior lateral motor cortex in a way that depends on the local dendritic branching structure (Kerlin et al., 2019).Furthermore, activation of specific combinations of distal tuft segments, mutually co-amplified by NMDA spikes, form spatial dendritic amplification maps for specific motor behaviors, allowing dynamic combinatorial representation of numerous motor variables and sequences within the same dendritic tuft branches of layer 5 pyramidal tract neurons (Otor et al., 2022).
Thus, many studies show that local integration and longer-distance communication within pyramidal neurons depends on NMDAreceptor-dependent local dendritic spikes in multiple local dendritic compartments.Therefore, the net input to each of the apical and somatic initiation zones is the result of nonlinear multicompartmental integration within each of the basal and apical dendritic trees.

Inhibition and disinhibition specific to the apical tuft
A key factor in regulating the excitability of pyramidal cell dendrites is the activity of interneurons that target only apical dendrites or only the soma and basal dendrites (Palmer et al., 2012;Schulz et al., 2018;Wang and Yang, 2018;Ma et al., 2021).
Different classes of interneuron project to different locations on the dendritic trees of pyramidal neurons.Inhibitory interneurons that predominantly inhibit apical dendrites are neurogliaform cells and interneurons that typically express somatostatin (SST).Interneurons that disinhibit them typically express vasoactive intestinal peptide/calretinin (VIP/CR).Interneurons that inhibit or disinhibit distal apical locations are clearly distinct from the parvalbumin (PV) interneurons that inhibit mainly basal and perisomatic locations (Karnani et al., 2014;Harris and Shepherd, 2015;Tremblay et al., 2016;Wang and Yang, 2018;Ma et al., 2021;Schuman et al., 2021;Wu et al., 2023).
The net effect of VIP interneuron activation is to disinhibit selected cells within the blanket of apical inhibition cast by SST interneurons (Karnani et al., 2014).This complex (dis)inhibitory microcircuitry greatly strengthens the grounds for distinguishing between apical and basal initiation zones, as VIP interneurons less frequently interact with PV interneurons and do not provide a mechanism for the disinhibition of specific basal/perisomatic locations (Pfeffer et al., 2013).Thus, the effects on cellular output of excitatory input to the tuft is increased by activating VIP interneurons.

Physiology and possible pathologies of context-sensitive cells
The findings reviewed above mandate a view of intracellular processes and inhibitory microcircuit organization that is sufficiently differentiated to relate cognitive capabilities and their disorders to cellular physiology, pathophysiology, and genetic mutations, and thus to explain the commonalities and differences within and between various neurodevelopmental disorders (Fig. 2).
Here we focus chiefly on three neurodevelopmental disorders, fragile X syndrome (FXS), Down syndrome (DS), and fetal alcohol spectrum disorders (FASD).Each involves dysfunction of cellular contextsensitivity, with major consequences for perception, thought, and learning.The monogenic origins of FXS and chromosomal origins of DS are well known (Nelson and Bender, 2021).The disabilities associated with FASD are caused by prenatal exposure to alcohol.All three disorders have a known (but not necessarily homogenous) etiology, with prominent impairments of basic cognitive processes, including learning.
Down syndrome, the most common form of intellectual disability, is caused by triplication of chromosome 21.Despite the well-known etiology, the pathogenetic mechanism leading to the phenotypic manifestations of DS is still a matter of debate (Antonarakis et al., 2020).Direct or downstream effects of the increased expression of genes harbored by chromosome 21 represents the most probable causal link.For instance, the increased susceptibility to early onset Alzheimer disease observed in individuals with DS is the consequence of the overexpression of the amyloid precursor protein, whose coding gene is located on chromosome 21.Several mouse models have been developed to study the molecular and cellular bases of DS.Among them, the ts65dn mouse, with a partial translocation of the mouse chromosome 16, is the most widely used model, capturing many of the geno-and phenotypic features of human trisomy 21 (Klein and Haydar, 2022).
Fragile X syndrome is the leading monogenic cause of intellectual disability and autism spectrum disorder (see Protic et al., 2022, for review).The mutation consists of > 200 CGG repeats in the FMR1 gene, located on the X chromosome and encoding the RNA-binding fragile X mental retardation protein (FMRP).The repeat is responsible for silencing the transcription of the gene, with consequent reduction of FMRP levels.FMRP is implicated in several cell functions, including synaptic structure and plasticity (e.g., Darnell et al., 2001;Antar and Bassell, 2003).The most accredited experimental model of FXS is the FMR1 knockout mouse, reproducing several behavioral and neuropathologic features observed in humans affected by FXS (Kazdoba et al., 2014).
Fetal alcohol spectrum disorders are the consequence of in utero exposure to alcohol and represent the most common preventable cause of intellectual disability (Popova et al., 2023).Alcohol crosses the placental barrier and harms the fetal brain through multiple mechanisms, such as the increase of apoptosis, the interference with synaptic plasticity, and the activation of neuroinflammatory pathways (reviewed in Granato and Dering, 2018).Studies based on animal models of FASD have been carried out mainly in rodents and made it possible to shed light on the manifold factors influencing the detrimental effects of ethanol on brain development, including dose, time of exposure, and sex-specific susceptibility (see Valenzuela et al., 2012, for review).
We first identified four key properties of dendrites and three most relevant types of inhibitory interneuron on which sensitivity to context via apical dendrites depends.Then, we collected evidence for all seven aspects in each of the three disorders.The outcomes of that extensive search are summarized in Table 1.They show that there is evidence for anomalies in nearly all seven aspects across indications, as we will discuss in the next section.

Malformations of dendritic branches and spines
Many neurodevelopmental disabilities involve alterations to the morphology of neocortical pyramidal cells, with reduced branching and spine malformations.Alterations of their dendritic geometry often reflect the dualism between apical and basal dendrites.FXS, congenital hypothyroidism, Down Syndrome, and Rett Syndrome, all involve malformations that are specific to either the apical or the basal dendritic domains.They range from reductions of dendritic length, changes in metric properties of dendritic arbors, to alterations in spine density, that are specifically oriented towards either the apical or basal domains (Ipiña et al., 1987;Comery et al., 1997;Berman et al., 2012;Stuss et al., 2012;Bartesaghi, 2022;Uguagliati et al., 2022).
Differential effects on apical and basal dendrites have also been shown to be a result of prenatal exposure to alcohol (FASD), including differential reduction in branching or spine densities of the apical versus basal dendrites (Granato et al., 2003(Granato et al., , 2012;;Whitcher and Klintsova, 2008;Hamilton et al., 2010;De Giorgio and Granato, 2015).In the prefrontal cortex, the effects of developmental ethanol exposure on the apical dendritic branching are layer-specific (Louth et al., 2018).

Dysfunctions of dendritic Ca 2+ signaling via voltage-gated Ca 2+ channels and NMDA receptors
The apical dendrites of neocortical pyramidal neurons are endowed with ion channels that can generate various types of dendritic spike (Migliore and Shepherd, 2002;Larkum, 2022b).Among them, dendritic calcium spikes are particularly relevant.They are crucial to the modulation of ongoing-processing (Phillips, 2017(Phillips, , 2023) ) and are required for the induction of certain forms of cortical synaptic plasticity (Kampa et al., 2006;Cichon and Gan, 2015).
FXS is associated with impairment of spike timing dependent plasticity in prefrontal cortex (Meredith et al., 2007), and hyperexcitability of layer 5 pyramidal cell apical dendrites due to multiple channelopathies including voltage-gated Ca 2+ channels (VGCCs) (Brager and Johnston, 2014;Zhang et al., 2014).Calcium channel modulators have recently been suggested for the treatment of syndromes characterized by intellectual disability (Kessi et al., 2021).Further understanding of the molecular mechanisms underlying altered signaling via VGCCs, including the precise role of the loss of FMRP and the resulting tendency to more immature neural connections, will therefore have implications not only for FXS, but also for other forms of autism (Bagni and Zukin, 2019).
NMDA receptor channels lead to regenerative NMDA spikes in both the basal and apical dendrites by activation of local clusters of synaptic inputs (Larkum, 2022b;Larkum et al., 2009) and are an important source of local calcium.NMDA spikes also have a major role in sensory processing (Palmer et al., 2014) and learning (Cichon and Gan, 2015).In a rodent model of FXS an increase in NMDA receptor density has been observed in the neocortex (Pyronneau et al., 2017) and in hippocampus (Pilpel et al., 2009).In contrast, a reduction in NMDA receptor density in apical dendrites has been reported in the hippocampus of the Ts65Dn model of Down Syndrome (Schulz et al., 2019).
FASD are associated with strong impairment of calcium electrogenesis in the apical dendrite that abolishes dendritic calcium plateaus (Granato et al., 2012).A dysregulation of NMDA receptor subunit expression has also been found after early exposure to alcohol mimicking the effects of FASD (Goodfellow et al., 2016;Ieraci and Herrera, 2020) as well as in other disorders characterized by cognitive impairment (reviewed in Paoletti et al., 2013).Finally, Licheri et al.
A. Granato et al. (2021) report a sex-specific dysregulation of NMDA currents in pyramidal neurons of the orbitofrontal cortex of adult mice prenatally exposed to ethanol.Based on these preclinical studies, pharmacological modulation of NMDA receptors may represent one potential therapeutic strategy (Bird and Valenzuela, 2023) for FASD.

Sodium channel dysfunctions
The main influence of dendritic sodium channels on intracellular communication is on the propagation of suprathreshold signalling via the apical trunk in pyramidal neurons (Stuart and Sakmann, 1994), which is shown as the coupling compartment in Figs. 1 and 2. The gene SCN2A codes for the sodium ion channel Na V 1.2 that transmits backpropagating action potentials from the soma to the apical integration zone.SCN2A mutations impair the function or expression of these sodium ion channels (Sanders et al., 2018) and generate behavioral symptoms including learning deficits typical of autism spectrum disorders (ASD) (Kruth et al., 2020).Studies of SCN2A mutations in mice suggest that these effects are greater in males, in agreement with a higher incidence of ASD in boys.Until late in infancy this sodium channel is also responsible for axonal action potential transmission.Their over-activation early in development produces diverse forms of infantile epilepsy with various degrees of severity.At later stages of development, however, this sub-type of sodium channel becomes necessary for backpropagation of action potentials from the soma to the apical integration zone (Spratt et al., 2019;Nelson et al., 2024).When activity of dendritic Na V 1.2 is decreased, as in some forms of ASD including SCN2A and ANK2 haploinsufficiency, the backpropagation of signals from the soma to the apical dendrites fails (Spratt et al., 2019;Nelson et al., 2024).That greatly weakens the context-sensitive amplifying effects of apical input on action potential generation, and thus on their consequences for processing and learning.Reduction of fragile X mental retardation protein (FMRP) in FXS reduces dendritic sodium channels, possibly via downregulation of SCN2A, thus reducing the amplifying capabilities of input to the apical tuft (Nelson and Bender, 2021;Brandalise et al., 2023).Despite the potential importance of this topic, there is only scanty and indirect suggestions of dendritic sodium channel defects in Down syndrome or FASD (Stoll and Galdzicki, 1996;Meisler et al., 2021).

Dysfunctions of HCN currents
Though unfamiliar to most psychologists and many neuroscientists, currents mediated by hyperpolarization-activated cyclic nucleotidegated (HCN) ion channels, or 'I h ', are of crucial importance to the regulation of apical function, and thus of context-sensitivity (Harnett et al., 2015;2023).HCN channel density is highest in the apical tuft dendrites of layer 5 pyramidal neurons (Williams and Stuart, 2000;Berger et al., 2001) where they increase the threshold for local calcium spike generation (Suzuki and Larkum, 2017).I h tends to disconnect the tuft from the soma at resting membrane potential (Schulz et al., 2021), so that aberrantly high expression can impair the amplifying effects of context; whereas too low expression means that inputs to the apical dendrite can directly contribute to somatic spike output and, in consequence, disrupt the contribution of apical inputs as contextual modulatory signals.
of the HCN channels in humans are responsible for conditions resembling the Dravet syndrome, in which epilepsy and intellectual disability are associated (Nava et al., 2014).Furthermore, a recent study has shown that the dissociative state-an altered behavioral state that can occur as a result of trauma, epilepsy or dissociative drug use-can be caused by the HCN-mediated current in layer 5 pyramidal neurons in the retrosplenial cortex (Vesuna et al., 2020).
A reduction of I h in pyramidal neurons of rodent somatosensory cortex (S1) has been convincingly shown in a mouse model of FXS (Zhang et al., 2014).The consequence is dendritic and somatic hyperexcitability including the overactivation of the apical integration zone as shown in Figs. 1 and 2. The importance of these findings are supported by recent work carried out on L5 pyramidal neurons of Fmr1 KO mice, suggesting that synaptic integration of inputs to the basal compartment is impaired and that the hypersensitivity observed in FXS cannot be driven by increased sensitivity to sensory input via the basal compartment (Mitchell et al., 2023).Interestingly, the underlying mutation in the fmr1 gene appears to have very different effects on hippocampal cells (Brager et al., 2012;Zhang et al., 2014).Although I h is decreased in layer 5 pyramidal tract cells by the fmr1 mutation, it is increased in CA1 cells (Kalmbach et al., 2015;Brandalise et al., 2020).Links between I h and neurodevelopmental learning disorders are further strengthened by findings showing that mutation of a gene associated with ASD, SHANK3, also impairs I h (Yi et al., 2016).
An increase of I h has also been observed in hippocampal neuronal cultures from a rodent model of Down syndrome (Stern et al., 2015).This observation awaits confirmation in other experimental preparations, however.To our knowledge, there are no experimental FASD studies analyzing the I h current in neocortical pyramidal neurons.However, HCN channels are increased in cerebellar Purkinje cells after developmental exposure to ethanol (Light et al., 2015).Furthermore, they undergo a long-lasting dysregulation in prefrontal pyramidal neurons of adolescent mice after binge drinking (Salling et al., 2018).Therefore, the possible role of the I h current in FASD deserves further investigation.

Dysfunctions of (dis)inhibitory regulation
Neurodevelopmental learning disabilities have often been associated with disturbances in inhibitory interneurons, leading to an imbalance of excitation and inhibition (Rubenstein and Merzenich, 2003;Levitt et al., 2004;Fernandez and Garner, 2007;Cresto et al., 2019;Nomura, 2021).Those views do not distinguish between inhibition of apical and basal/perisomatic locations, however.By treating inhibitory inputs in an undifferentiated way with respect to their target sites at either apical or basal/perisomatic locations, the evidence demonstrating anomalies of context-sensitive modulation dependent on distal apical dendrites is obscured or becomes hard to interpret (e.g., Karnani et al., 2014;Tremblay et al., 2016;Wang and Yang, 2018).
Our central goal here is therefore to review evidence for pathological neurodevelopmental changes in the balance between somatic inhibition and distal apical inhibition or disinhibition.First, we note evidence implicating apical inhibition and disinhibition in cognitive processing and learning.The VIP-SST disinhibitory circuit plays a crucial role in enhancing adult plasticity in the visual cortex (Fu et al., 2015).There is also strong evidence on relations between apical inhibition by SST interneurons and plasticity (Cichon and Gan, 2015;Schulz et al., 2018;Liguz-Lecznar et al., 2022).Several studies have shown regulation of synaptic plasticity involving the activation of VIP, PV and/or inactivation of SST neurons (Pfeffer et al., 2013;Cichon and Gan, 2015;Williams and Holtmaat, 2019;Lukacs et al., 2022).These findings make sense in the light of which cellular compartments are up-or down-regulated.Apical dendritic excitability is increased by inhibiting SST inhibitory interneurons that target this compartment.Along the same line, activating VIP inhibitory interneurons increases the relative effectiveness of apical amplification as these interneurons inhibit SST interneurons.Paluszkiewicz et al. (2011) have suggested that the inhibitory dysfunctions in FXS may specifically affect SST interneuron-mediated dendritic inhibition.In mouse models of Down Syndrome, several groups have found clear signs for increased dendritic inhibition (Schulz et al., 2019;Valbuena et al., 2019;Zorrilla de San Martin et al., 2020).Zorrilla de San Martin and colleagues (2020) directly showed increased inhibition from SST interneurons on the apical dendrite of layer 2/3 pyramidal cells during paired recordings in the prefrontal cortex.In addition, neurogliaform cells, a class of interneurons that specifically inhibit tuft dendrites in layer 1 via slowly operating receptors, could also play a prominent role in DS (Tamás et al., 2003;Jiang et al., 2013;Schulz et al., 2018).Trisomy of chromosome 21 results in triplication of the KCNJ6 gene encoding a potassium channel (GIRK2), which acts as an effector of GABA B receptors.These currents are largely increased in neurons of DS mouse models (Harashima et al., 2006;Best et al., 2007;Kleschevnikov et al., 2012).Neurogliaform cells directly activate the same signalling pathway, and a higher density of markers for neurogliaform cells have been reported in DS mouse models (Pérez-Cremades et al., 2010;Raveau et al., 2018).Therefore, aberrantly increased dendritic GABA B inhibition by neurogliaform cells would be expected to directly contribute to both deficits in apical amplification and synaptic plasticity in DS, though that hypothesis awaits direct testing.
In addition, an increase in the number of VIP interneurons has been observed in Down syndrome mouse models pointing to altered disinhibitory microcircuitry (Hill et al., 2003;Pérez-Cremades et al., 2010;Hernández et al., 2012).
As shown in Table 1, anomalies of inhibitory or disinhibitory function have also been reported in experimental models of FASD.It is worth noting that most studies demonstrate increased or decreased number of interneuron populations.However, an altered number of interneurons might be counterbalanced by compensatory mechanisms.For instance, the reduced number of PV interneurons after early postnatal exposure to ethanol might be compensated by an enhancement of PV interneuronmediated neurotransmission (Bird et al., 2021).
Across all three forms of disability reviewed there are prominent dysfunctions of the inhibitory regulation of pyramidal cell activity.Anomalous activity of VIP interneurons, which exert a far stronger disinhibitory influence on apical than on basal dendrites, may be prominent in several of those dysfunctions.Thus, interventions that target indication-specific aberrant interneuron signalling may be a promising therapeutic strategy in general (e.g., Tempio et al., 2023, for FXS).However, further research is now needed to distinguish between anomalies that are a direct consequence of the primary pathology, and those that are due to homeostatic mechanisms that compensate for the primary pathology.

From primary pathologies to cognitive disabilities via cellular dysfunctions
Many genetic mutations and deleterious prenatal conditions underlying neurodevelopmental learning disabilities have been identified, including over a hundred risk genes for autism spectrum disorders.There is a great gap in our understanding of the mechanisms underlying these disorders, however, because the paths leading from cellular processes to cognitive capabilities have been obscure.In recent years, evidence about these paths is accumulating rapidly (Larkum, 2013;Major et al., 2013;Phillips, 2017Phillips, , 2023;;Heeger and Mackey, 2019;Aru et al., 2020aAru et al., , 2020b;;Shepherd and Yamawaki, 2021).Thus, it is now possible, for each of the three disabilities reviewed, to sketch routes from primary etiologies to their effects on cellular context-sensitivity, and thus on to their consequences for cognitive capabilities and disabilities (Fig. 3).This shows that the three very different primary pathologies affect much of the same set of cognitive functions, though by distinct effects on the mechanisms underlying neuronal context-sensitivity.

Summary of conclusions and issues raised
This review shows that in FXS, DS, FASD, and other intellectual disabilities, there are multiple abnormalities of the key properties specific to the apical dendritic tree and their regulation that endow pyramidal cells with the ability to amplify their outputs depending on the current context.These include processes by which synaptic input to distal apical synapses regulate action potential output from neocortical pyramidal cells.In each of the disabilities there are multiple abnormalities, some of which make the effects of input to distal apical synapses on action potential generation too strong, and some of which make those effects too weak.A major issue raised by these abnormalities is that some may reflect the primary pathology, whereas others may reflect the response of homeostatic mechanisms to the primary pathology.For instance, is the increase of disinhibitory interneurons observed in FASD a compensatory mechanism, secondary to the reduced dendritic excitability caused by the shutdown of calcium spikes (Granato et al., 2012)?Or, conversely, can the reduced calcium electrogenesis represent a way to counteract a primary increase of dendritic disinhibition?The same question can be raised for the opposite effect of increased dendritic inhibition and disinhibition found in animal models of DS (e.g., Zorrilla de San Martin et al., 2020;Pérez-Cremades et al., 2010; see Table 1).Other compensatory mechanisms, such as the upregulation of neurotransmitter receptors, can be operant in neurodevelopmental disorders (e.g., Bailey et al., 2001).Clearly distinguishing between these processes is one of the challenges for future research.
Finally, advances in our understanding of the cellular mechanisms implicated in these disabilities provides grounds for hoping that it will soon become possible to engineer individualized combinations of genetic, pharmacological, psychological, and/or social management strategies for these disabilities.A major task for the future is to quantify the extent to which each of the primary pathologies affects each of the cognitive abilities.For evidence on which this figure is based see Table 1 and the main text.

Fig. 1 .
Fig. 1.The three compartments of context-sensitive pyramidal cells: basal and apical spike initiation zones plus the compartment coupling them, together with examples of possible cognitive consequences of their overactivation or underactivation.Left: a reconstruction of a rat L5 pyramidal neuron, showing the basal/ perisomatic sodium-spike initiation zone (blue), the apical calcium-spike initiation zone (red), and the apical trunk, which is the coupling compartment (black).Centre: logically independent variability in the activity levels of each compartment.Right: examples of cognitive consequences that could arise from over-or underactivity of each compartment.DCD: developmental coordination disorder.

Fig. 2 .
Fig. 2.Processes by which activation of the apical initiation zone (AIZ) amplifies response to feedforward activation and the inhibitory microcircuitry specific to each class of activation, together with possible anomalies or dysfunctions.Dysfunctions tending to produce under-amplification are shown in dark blue and on the left; those tending to produce over-amplification are shown in red.When high, I h , SST, and BK Ca currents all tend to reduce the effects of apical excitation on action potential generation because they restrain apical amplification.When they are low there is over-amplification, which, if systemic can provoke epileptic seizures.In contrast to that, when high, VIP, Ca 2+ , and Na V 1.2 currents all tend to increase amplification.Inputs to the inhibitory interneurons (not shown) have both locally specific and more general components.Apical tufts also receive input from neurogliaform inhibitory interneurons (not shown).SIZ = somatic integration zone; SST = somatostatin interneurons; PV = parvalbumin inteneurons; VIP = vasoactive intestinal peptide interneurons.IINs=Inhibitory InterNeurons.

Fig. 3 .
Fig.3.Cellular Dysfunctions Linking Cognitive Disabilities to underlying causes for a common form of intellectual disability (Fragile X), for a chromosomal anomaly (Down syndrome), and for a common non-genetic form of neurodevelopmental learning disability (Fetal Alcohol Spectrum Disorder).These primary pathologies are not mutually exclusive.The FMR1 mutation of FXS, for example, provides no protection against polygenic risk factors for other causes of learning disability nor against the effects of alcohol on prenatal development.The more severe the dysfunctions of cellular context-sensitivity the more severe the likely cognitive disabilities.The large overlap between the cognitive consequences of different primary pathologies provides some support for the generic concept of 'neurodevelopmental learning disabilities'.Both over-and under-amplification can impair cognitive capabilities.Over-amplification does so by amplifying irrelevant signals; under-amplification by inadequately amplifying relevant signals.A major task for the future is to quantify the extent to which each of the primary pathologies affects each of the cognitive abilities.For evidence on which this figure is based see Table1and the main text.

Table 1
Dysfunctions of cellular properties underlying context-sensitivity in three neurodevelopmental syndromes; upwards and downwards arrows indicate those tending to increase effects of tuft activation and those tending to decrease them, respectively.