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The role of experience in the development and maintenance of emergent network properties such as cortical oscillations and states is poorly understood. To define how early-life experience affects cortical dynamics in the visual cortex of adult, head-fixed mice, we examined the effects of two forms of blindness initiated before eye-opening and continuing through recording in adulthood: (1) bilateral loss of retinal input (enucleation) and (2) degradation of visual input (eyelid-suture). Neither form of deprivation fundamentally altered the state-dependent regulation of firing-rates or local field potentials. However, each form of deprivation did cause a unique set of changes in network behavior. Laminar analysis revealed two different generative mechanisms for low-frequency synchronization, one prevalent during movement, the other during quiet-wakefulness. The former was absent in enucleated mice, suggesting a mouse homolog of human alpha oscillations. In addition, neurons in enucleated animals were less correlated and fired more regularly, but showed no change in mean firing-rate. Chronic lid-suture decreased firing rates during quiet-wakefulness, but not during movement, with no effect on neural correlations or regularity. Sutured animals showed a broadband increase in dEEG power and an increased occurrence, but reduced central frequency, of narrowband gamma oscillations. The complementary--rather than additive--effects of lid-suture and enucleation suggest that the development of these emergent network properties does not require vision but is plastic to modified input. Our results suggest a complex interaction of internal set-points and experience determines the expression of mature cortical activity, with low-frequency synchronization being particularly susceptible to early deprivation.Significance statement The developmental rules that guide how cortex balances internal homeostatic set points with external inputs to establish the emergent network level dynamics critical to its function are unclear. Using multiple methods of early deprivation, we show that the development of dynamics in mouse visual cortex is not dependent on the type of input. Rather, specific neural rhythms, firing-rate set points, and neural correlations are differentially modified by experience. Our deprivations identify one specific rhythm as a likely homolog to human alpha and suggest a mechanism for its loss in blindness. Our results advance our understanding of the regulatory mechanism leading to normal cortical processing, which is altered in blindness and multiple neural disorders.
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We explored the potential for cFOS expression as a marker of functional development of "resting-state" waking activity in the extended network of the hippocampus and entorhinal cortex. We examined sleeping and awake mice at (P)ostnatal days 5, 9, 13, and 17 as well as in adulthood. We find that cFOS expression is state-dependent even at 5 days old, with reliable staining occurring only in the awake mice. Even during waking, cFOS expression was rare and weak at P5. The septal nuclei, entorhinal cortex layer (L)2, and anterodorsal thalamus were exceptional in that they had robust cFOS expression at P5 that was similar to or greater than in adulthood. Significant P5 expression was also observed in the dentate gyrus, entorhinal cortex L6, postsubiculum L4-6, ventral subiculum, supramammillary nucleus, and posterior hypothalamic nucleus. The expression in these regions grew stronger with age, and the expression in new regions was added progressively at P9 and P13 by which point the overall expression pattern in many regions was qualitatively similar to the adult. Six regions-CA1, dorsal subiculum, postsubiculum L2-3, reuniens nucleus, and perirhinal and postrhinal cortices-were very late developing, mostly achieving adult levels only after P17. Our findings support a number of developmental principles. First, early spontaneous activity patterns induced by muscle twitches during sleep do not induce robust cFOS expression in the extended hippocampal network. Second, the development of cFOS expression follows the progressive activation along the trisynaptic circuit, rather than birth date or cellular maturation. Third, we reveal components of the egocentric head-direction and theta-rhythm circuits as the earliest cFOS active circuits in the forebrain. Our results suggest that cFOS staining may provide a reliable and sensitive biomarker for hippocampal formation activity development, particularly in regard to the attainment of a normal waking state and synchronizing rhythms such as theta and gamma.
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The developing visual thalamus and cortex extract positional information encoded in the correlated activity of retinal ganglion cells by synaptic plasticity, allowing for the refinement of connectivity. Here, we use a biophysical model of the visual thalamus during the initial visual circuit refinement period to explore the role of synaptic and circuit properties in the regulation of such neural correlations. We find that the NMDA receptor dominance, combined with weak recurrent excitation and inhibition characteristic of this age, prevents the emergence of spike-correlations between thalamocortical neurons on the millisecond timescale. Such precise correlations, which would emerge due to the broad, unrefined connections from the retina to the thalamus, reduce the spatial information contained by thalamic spikes, and therefore we term them 'parasitic' correlations. Our results suggest that developing synapses and circuits evolved mechanisms to compensate for such detrimental parasitic correlations arising from the unrefined and immature circuit.
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Retina , Tálamo , Animais , Tálamo/fisiologia , Retina/fisiologia , Células Ganglionares da Retina/fisiologia , Sinapses/fisiologia , MamíferosRESUMO
In this issue of Neuron, Ibrahim et al. (2021) examine the rules by which top-down connections are made on visual cortical layer 1 interneurons, discovering activity-dependent cooperative interactions with visual input that are specific to neurogliaform cells and anterior cingulate cortex.
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Interneurônios , Córtex Visual , Giro do Cíngulo , NeurôniosRESUMO
Biological neurons can be modeled with different levels of biophysical/biochemical details. The accuracy with which a model reflects the actual physiological processes and ultimately the information function of a neuron, can range from very detailed to a schematic phenomenological representation. This range exists due to the common problem: one needs to find an optimal trade-off between the level of details needed to capture the necessary information processing in a neuron and the computational load needed to compute 1 s of model time. An increase in modeled network size or model-time, for which the solution should be obtained, makes this trade-off pivotal in model development. Numerical simulations become incredibly challenging when an extensive network with a detailed representation of each neuron needs to be modeled over a long time interval to study slow evolving processes, e.g., development of the thalamocortical circuits. Here we suggest a simple, powerful and flexible approach in which we approximate the right-hand sides of differential equations by combinations of functions from three families: Polynomial, piecewise-Linear, Step (PLS). To obtain a single coherent framework, we provide four core principles in which PLS functions should be combined. We show the rationale behind each of the core principles. Two examples illustrate how to build a conductance-based or phenomenological model using the PLS-framework. We use the first example as a benchmark on three different computational platforms: CPU, GPU, and mobile system-on-chip devices. We show that the PLS-framework speeds up computations without increasing the memory footprint and maintains high model fidelity comparable to the fully-computed model or with lookup-table approximation. We are convinced that the full range of neuron models: from biophysical to phenomenological and even to abstract models, may benefit from using the PLS-framework.
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The isocortex of all mammals studied to date shows a progressive increase in the amount and continuity of background activity during early development. In humans the transition from a discontinuous (mostly silent, intermittently bursting) cortex to one that is continuously active is complete soon after birth and is a critical prognostic indicator. In the visual cortex of rodents this switch from discontinuous to continuous background activity occurs during the 2 d before eye-opening, driven by activity changes in relay thalamus. The factors that regulate the timing of continuity development, which enables mature visual processing, are unknown. Here, we test the role of the retina, the primary input, in the development of continuous spontaneous activity in the visual cortex of mice using depth electrode recordings from enucleated mice in vivo Bilateral enucleation at postnatal day (P)6, one week before the onset of continuous activity, acutely silences cortex, yet firing rates and early oscillations return to normal within 2 d and show a normal developmental trajectory through P12. Enucleated animals showed differences in silent period duration and continuity on P13 that resolved on P16, and an increase in low frequency power that did not. Our results show that the timing of cortical activity development is not determined by the major driving input to the system. Rather, even during a period of rapid increase in firing rates and continuity, neural activity in the visual cortex is under homeostatic control that is largely robust to the loss of the primary input.
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Neocórtex , Córtex Visual , Animais , Homeostase , Camundongos , Tálamo , Percepção VisualRESUMO
GABAergic interneurons are proposed to be critical for early activity and synapse formation by directly exciting, rather than inhibiting, neurons in developing hippocampus and neocortex. However, the role of GABAergic neurons in the generation of neonatal network activity has not been tested in vivo, and recent studies have challenged the excitatory nature of early GABA. By locally manipulating interneuron activity in unanesthetized neonatal mice, we show that GABAergic neurons are excitatory in CA1 hippocampus at postnatal day 3 (P3) and are responsible for most of the spontaneous firing of pyramidal cells at that age. Hippocampal interneurons become inhibitory by P7, whereas visual cortex interneurons are already inhibitory by P3 and remain so throughout development. These regional and age-specific differences are the result of a change in chloride reversal potential, because direct activation of light-gated anion channels in glutamatergic neurons drives CA1 firing at P3, but silences it at P7 in CA1, and at all ages in visual cortex. This study in the intact brain reveals that GABAergic interneuron excitation is essential for network activity in neonatal hippocampus and confirms that visual cortical interneurons are inhibitory throughout early postnatal development.
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Interneurônios , Neocórtex , Animais , Neurônios GABAérgicos/fisiologia , Hipocampo/fisiologia , Interneurônios/fisiologia , Camundongos , Células Piramidais/fisiologiaRESUMO
Nervous system maturation occurs on multiple levels-synaptic, circuit, and network-at divergent timescales. For example, many synaptic properties mature gradually, whereas emergent network dynamics can change abruptly. Here we combine experimental and theoretical approaches to investigate a sudden transition in spontaneous and sensory evoked thalamocortical activity necessary for the development of vision. Inspired by in vivo measurements of timescales and amplitudes of synaptic currents, we extend the Wilson and Cowan model to take into account the relative onset timing and amplitudes of inhibitory and excitatory neural population responses. We study this system as these parameters are varied within amplitudes and timescales consistent with developmental observations to identify the bifurcations of the dynamics that might explain the network behaviors in vivo. Our findings indicate that the inhibitory timing is a critical determinant of thalamocortical activity maturation; a gradual decay of the ratio of inhibitory to excitatory onset time drives the system through a bifurcation that leads to a sudden switch of the network spontaneous activity from high-amplitude oscillations to a nonoscillatory active state. This switch also drives a change from a threshold bursting to linear response to transient stimuli, also consistent with in vivo observation. Thus we show that inhibitory timing is likely critical to the development of network dynamics and may underlie rapid changes in activity without similarly rapid changes in the underlying synaptic and cellular parameters.NEW & NOTEWORTHY Relying on a generalization of the Wilson-Cowan model, which allows a solid analytic foundation for the understanding of the link between maturation of inhibition and network dynamics, we propose a potential explanation for the role of developing excitatory/inhibitory synaptic delays in mediating a sudden switch in thalamocortical visual activity preceding vision onset.
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Córtex Cerebral/fisiologia , Fenômenos Eletrofisiológicos/fisiologia , Modelos Teóricos , Rede Nervosa/fisiologia , Tálamo/fisiologia , Animais , Córtex Cerebral/crescimento & desenvolvimento , Humanos , Rede Nervosa/crescimento & desenvolvimento , Tálamo/crescimento & desenvolvimentoRESUMO
Inhibitory circuits in thalamus and cortex shape the major activity patterns observed by electroencephalogram (EEG) in the adult brain. Their delayed maturation and circuit integration, relative to excitatory neurons, suggest inhibitory neuronal development could be responsible for the onset of mature thalamocortical activity. Indeed, the immature brain lacks many inhibition-dependent activity patterns, such as slow-waves, delta oscillations and sleep-spindles, and instead expresses other unique oscillatory activities in multiple species including humans. Thalamus contributes significantly to the generation of these early oscillations. Compared to the abundance of studies on the development of inhibition in cortex, however, the maturation of thalamic inhibition is poorly understood. Here we review developmental changes in the neuronal and circuit properties of the thalamic relay and its interconnected inhibitory thalamic reticular nucleus (TRN) both in vitro and in vivo, and discuss their potential contribution to early network activity and its maturation. While much is unknown, we argue that weak inhibitory function in the developing thalamus allows for amplification of thalamocortical activity that supports the generation of early oscillations. The available evidence suggests that the developmental acquisition of critical thalamic oscillations such as slow-waves and sleep-spindles is driven by maturation of the TRN. Further studies to elucidate thalamic GABAergic circuit formation in relation to thalamocortical network function would help us better understand normal as well as pathological brain development.
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Núcleos da Linha Média do Tálamo/fisiologia , Rede Nervosa/fisiologia , Tálamo/metabolismo , Potenciais de Ação/fisiologia , Animais , Encéfalo/fisiologia , Córtex Cerebral/fisiologia , Eletroencefalografia/métodos , Humanos , Neurônios/fisiologia , Sono/fisiologia , Núcleos Talâmicos/fisiologia , Tálamo/fisiologiaRESUMO
Two major checkpoints of development in cerebral cortex are the acquisition of continuous spontaneous activity and the modulation of this activity by behavioral state. Despite the critical importance of these functions, the circuit mechanisms of their development remain unknown. Here we use the rodent visual system as a model to test the hypothesis that the locus of circuit change responsible for the developmental acquisition of continuity and state dependence measured in sensory cortex is relay thalamus, rather than the local cortical circuitry or the interconnectivity of the two structures. We conducted simultaneous recordings in the dorsal lateral geniculate nucleus (dLGN) and primary visual cortex (VC) of awake, head-fixed male and female rats using linear multielectrode arrays throughout early development. We find that activity in dLGN becomes continuous and positively correlated with movement (a measure of state dependence) on P13, the same day as VC, and that these properties are not dependent on VC activity. By contrast, silencing dLGN after P13 causes activity in VC to become discontinuous and movement to suppress, rather than augment, cortical firing, effectively reversing development. Thalamic bursting, a core characteristic of non-aroused states, emerged later, on P16, suggesting these processes are developmentally independent. Together our results indicate that cellular or circuit changes in relay thalamus are critical drivers for the maturation of background activity, which occurs around term in humans.SIGNIFICANCE STATEMENT The developing brain acquires two crucial features, continuous spontaneous activity and its modulation by arousal state, around term in humans and before the onset of sensory experience in rodents. This developmental transition in cortical activity, as measured by electroencephalogram (EEG), is an important milestone for normal brain development and indicates a good prognosis for babies born preterm and/or suffering brain damage such as hypoxic-ischemic encephalopathy. By using the awake rodent visual system as a model, we identify changes occurring at the level of relay thalamus, the major input to cortex, as the critical driver of EEG maturation. These results could help understand the circuit basis of human EEG development to improve diagnosis and treatment of infants in vulnerable situations.
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Nível de Alerta , Corpos Geniculados/crescimento & desenvolvimento , Corpos Geniculados/fisiologia , Neurônios/fisiologia , Córtex Visual/crescimento & desenvolvimento , Córtex Visual/fisiologia , Potenciais de Ação , Animais , Feminino , Masculino , Movimento , Ratos Long-EvansRESUMO
Thalamocortical activity patterns, both spontaneous and evoked, undergo a dramatic shift in preparation for the onset of rich sensory experience (e.g. birth in humans; eye-opening in rodents). This change is the result of a switch from thalamocortical circuits tuned for transmission of spontaneous bursting in sense organs, to circuits capable of high resolution, active sensory processing. Early 'pre-sensory' tuning uses amplification generated by corticothalamic excitatory feedback and early-born subplate neurons to ensure transmission of bursts, at the expense of stimulus discrimination. The switch to sensory circuits is due, at least in part, to the coordinated remodeling of inhibitory circuits in thalamus and cortex. Appreciation of the distinct rules that govern early circuit function can, and should, inform translational studies of genetic and acquired developmental dysfunction.
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Córtex Cerebral/fisiologia , Fenômenos Eletrofisiológicos/fisiologia , Rede Nervosa/fisiologia , Sensação/fisiologia , Tálamo/fisiologia , Animais , Córtex Cerebral/crescimento & desenvolvimento , Humanos , Rede Nervosa/crescimento & desenvolvimento , Tálamo/crescimento & desenvolvimentoRESUMO
Synchronous firing among the elements of forming circuits is critical for stabilization of synapses. Understanding the nature of these local network interactions during development can inform models of circuit formation. Within cortex, spontaneous activity changes throughout development. Unlike the adult, early spontaneous activity occurs in discontinuous population bursts separated by long silent periods, suggesting a high degree of local synchrony. However, whether the micro-patterning of activity within early bursts is unique to this early age and specifically tuned for early development is poorly understood, particularly within the column. To study this we used single-shank multi-electrode array recordings of spontaneous activity in the visual cortex of non-anesthetized neonatal mice to quantify single-unit firing rates, and applied multiple measures of network interaction and synchrony throughout the period of map formation and immediately after eye-opening. We find that despite co-modulation of firing rates on a slow time scale (hundreds of ms), the number of coactive neurons, as well as pair-wise neural spike-rate correlations, are both lower before eye-opening. In fact, on post-natal days (P)6-9 correlated activity was lower than expected by chance, suggesting active decorrelation of activity during early bursts. Neurons in lateral geniculate nucleus developed in an opposite manner, becoming less correlated after eye-opening. Population coupling, a measure of integration in the local network, revealed a population of neurons with particularly strong local coupling present at P6-11, but also an adult-like diversity of coupling at all ages, suggesting that a neuron's identity as locally or distally coupled is determined early. The occurrence probabilities of unique neuronal "words" were largely similar at all ages suggesting that retinal waves drive adult-like patterns of co-activation. These findings suggest that the bursts of spontaneous activity during early visual development do not drive hyper-synchronous activity within columns. Rather, retinal waves provide windows of potential activation during which neurons are active but poorly correlated, adult-like patterns of correlation are achieved soon after eye-opening.
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Children with Fragile X syndrome (FXS) have deficits of attention and arousal. To begin to identify the neural causes of these deficits, we examined juvenile rats lacking the Fragile X mental retardation protein (FMR-KO) for disruption of cortical activity related to attention and arousal. Specifically, we examined the switching of visual cortex between activated and inactivated states that normally occurs during movement and quiet rest, respectively. In both wild-type and FMR-KO rats, during the third and fourth postnatal weeks cortical activity during periods of movement was dominated by an activated state with prominent 18-52 Hz activity. However, during quiet rest, when activity in wild-type rats became dominated by the inactivated state (3-9 Hz activity), FMR-KO rat cortex abnormally remained activated, resulting in increased high-frequency and reduced low-frequency power during rest. Firing rate correlations revealed reduced synchronization in FMR-KO rats, particularly between fast-spiking interneurons, that developmentally precede cortical state defects. Together our data suggest that disrupted inhibitory connectivity impairs the ability of visual cortex to regulate exit from the activated state in a behaviorally appropriate manner, potentially contributing to disrupted attention and sensory processing observed in children with FXS by making it more difficult to decrease cortical drive by unattended stimuli.
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Atenção/fisiologia , Pareamento Cromossômico/fisiologia , Síndrome do Cromossomo X Frágil/fisiopatologia , Interneurônios/fisiologia , Animais , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Eletroencefalografia/métodos , Síndrome do Cromossomo X Frágil/genética , Ratos Sprague-Dawley , Ratos TransgênicosRESUMO
Evaluation of the magnitudes of intrinsically rewarding stimuli is essential for assigning value and guiding behavior. By combining parametric manipulation of a primary reward, medial forebrain bundle (MFB) microstimulation, with functional magnetic imaging (fMRI) in rodents, we delineated a broad network of structures activated by behaviorally characterized levels of rewarding stimulation. Correlation of psychometric behavioral measurements with fMRI response magnitudes revealed regions whose activity corresponded closely to the subjective magnitude of rewards. The largest and most reliable focus of reward magnitude tracking was observed in the shell region of the nucleus accumbens (NAc). Although the nonlinear nature of neurovascular coupling complicates interpretation of fMRI findings in precise neurophysiological terms, reward magnitude tracking was not observed in vascular compartments and could not be explained by saturation of region-specific hemodynamic responses. In addition, local pharmacological inactivation of NAc changed the profile of animals' responses to rewards of different magnitudes without altering mean reward response rates, further supporting a hypothesis that neural population activity in this region contributes to assessment of reward magnitudes.
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Núcleo Accumbens/fisiologia , Recompensa , Animais , Encéfalo/fisiologia , Mapeamento Encefálico , Estimulação Elétrica , Imageamento por Ressonância Magnética , Masculino , Feixe Prosencefálico Mediano/fisiologia , Psicometria , Ratos Endogâmicos LewRESUMO
A comprehensive developmental timeline of activity in the mouse cortex in vivo is lacking. Understanding the activity changes that accompany synapse and circuit formation is important to understand the mechanisms by which activity molds circuits and would help to identify critical checkpoints for normal development. To identify key principles of cortical activity maturation, we systematically tracked spontaneous and sensory-evoked activity with extracellular recordings of primary visual cortex (V1) in nonanesthetized mice. During the first postnatal week (postnatal days P4-P7), V1 was not visually responsive and exhibited long (>10 s) periods of network silence. Activation consisted exclusively of "slow-activity transients," 2-10 s periods of 6-10 Hz "spindle-burst' oscillations; the response to spontaneous retinal waves. By tracking daily changes in this activity, two key components of spontaneous activity maturation were revealed: (1) spindle-burst frequency acceleration (eventually becoming the 20-50 Hz broadband activity caused by the asynchronous state) and (2) "filling-in" of silent periods with low-frequency (2-4 Hz) activity (beginning on P10 and complete by P13). These two changes are sufficient to create the adult-like pattern of continuous activity, alternation between fast-asynchronous and slow-synchronous activity, by eye opening. Visual responses emerged on P8 as evoked spindle-bursts and neuronal firing with a signal-to-noise ratio higher than adult. Both were eliminated by eye opening, leaving only the mature, short-latency response. These results identify the developmental origins of mature cortical activity and implicate the period before eye opening as a critical checkpoint. By providing a systematic description of electrical activity development, we establish the murine visual cortex as a model for the electroencephalographic development of fetal humans. SIGNIFICANCE STATEMENT: Cortical activity is an important indicator of long-term health and survival in preterm infants and molds circuit formation, but gaps remain in our understanding of the origin and normal progression of this activity in the developing cortex. We aimed to rectify this by monitoring daily changes in cortical activity in the nonanesthetized mouse, an important preclinical model of disease and development. At ages approximately equivalent to normal human term birth, mouse cortex exhibits primarily network silence, with spontaneous "spindle bursts" as the only form of activity. In contrast, mature cortex is noisy, alternating between asynchronous/discontinuous and synchronous/continuous states. This work identifies the key processes that produce this maturation and provides a normative reference for murine-based studies of cortical circuit development.
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Potenciais de Ação/fisiologia , Envelhecimento/fisiologia , Relógios Biológicos/fisiologia , Rede Nervosa/fisiologia , Córtex Visual/fisiologia , Percepção Visual/fisiologia , Animais , Animais Recém-Nascidos , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/fisiologiaRESUMO
Spontaneous retinal waves are critical for the development of receptive fields in visual thalamus (LGN) and cortex (VC). Despite a detailed understanding of the circuit specializations in retina that generate waves, whether central circuit specializations also exist to control their propagation through visual pathways of the brain is unknown. Here we identify a developmentally transient, corticothalamic amplification of retinal drive to thalamus as a mechanism for retinal wave transmission in the infant rat brain. During the period of retinal waves, corticothalamic connections excite LGN, rather than driving feedforward inhibition as observed in the adult. This creates an excitatory feedback loop that gates retinal wave transmission through the LGN. This cortical multiplication of retinal wave input ends just prior to eye-opening, as cortex begins to inhibit LGN. Our results show that the early retino-thalamo-cortical circuit uses developmentally specialized feedback amplification to ensure powerful, high-fidelity transmission of retinal activity despite immature connectivity.
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Retroalimentação , Retina/fisiologia , Tálamo/fisiologia , Córtex Visual/fisiologia , Animais , Animais Recém-Nascidos , Rede Nervosa , RatosRESUMO
Fragile X syndrome (FXS) is characterized by sensory hyper-sensitivity, and animal models suggest that neuronal hyper-excitability contributes to this phenotype. To understand how sensory dysfunction develops in FXS, we used the rat model (FMR-KO) to quantify the maturation of cortical visual responses from the onset of responsiveness prior to eye-opening, through age equivalents of human juveniles. Rather than hyper-excitability, visual responses before eye-opening had reduced spike rates and an absence of early gamma oscillations, a marker for normal thalamic function at this age. Despite early hypo-excitability, the developmental trajectory of visual responses in FMR-KO rats was normal, and showed the expected loss of visually evoked bursting at the same age as wild-type, two days before eye-opening. At later ages, during the third and fourth post-natal weeks, signs of mild hyper-excitability emerged. These included an increase in the visually-evoked firing of regular spiking, presumptive excitatory, neurons, and a reduced firing of fast-spiking, presumptive inhibitory, neurons. Our results show that early network changes in the FMR-KO rat arise at ages equivalent to fetal humans and have consequences for excitability that are opposite those found in adults. This suggests identification and treatment should begin early, and be tailored in an age-appropriate manner.
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Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/fisiopatologia , Córtex Visual/fisiopatologia , Animais , Modelos Animais de Doenças , Desenvolvimento Embrionário , Síndrome do Cromossomo X Frágil/genética , Técnicas de Inativação de Genes , Humanos , Neurônios/fisiologia , RatosRESUMO
Circuit computation requires precision in the timing, extent, and synchrony of principal cell (PC) firing that is largely enforced by parvalbumin-expressing, fast-spiking interneurons (PVFSIs). To reliably coordinate network activity, PVFSIs exhibit specialized synaptic and membrane properties that promote efficient afferent recruitment such as expression of high-conductance, rapidly gating, GluA4-containing AMPA receptors (AMPARs). We found that PVFSIs upregulate GluA4 during the second postnatal week coincident with increases in the AMPAR clustering proteins NPTX2 and NPTXR. Moreover, GluA4 is dramatically reduced in NPTX2(-/-)/NPTXR(-/-) mice with consequent reductions in PVFSI AMPAR function. Early postnatal NPTX2(-/-)/NPTXR(-/-) mice exhibit delayed circuit maturation with a prolonged critical period permissive for giant depolarizing potentials. Juvenile NPTX2(-/-)/NPTXR(-/-) mice display reduced feedforward inhibition yielding a circuit deficient in rhythmogenesis and prone to epileptiform discharges. Our findings demonstrate an essential role for NPTXs in controlling network dynamics highlighting potential therapeutic targets for disorders with inhibition/excitation imbalances such as schizophrenia.