Critical Period Of Postnatal Development Research Articles

Synaptic Origin of Early Sensory-evoked Oscillations in the Immature Thalamus.

During the critical period of postnatal development, brain maturation is extremely sensitive to external stimuli. Newborn rodents already have functional somatosensory pathways and the thalamus, but the cortex is still forming. Immature thalamic synapses may produce large postsynaptic potentials in immature neurons, while non-synaptic membrane currents remain relatively weak and slow. The thalamocortical system generates spontaneous and evoked early gamma and spindle-burst oscillations in newborn rodents. How relatively strong synapses and weak intrinsic currents interact with each other and how they contribute to early thalamic activities remains largely unknown. Here, we performed local field potential (LFP), juxtacellular, and patch-clamp recordings in the somatosensory thalamus of urethane-anesthetized rat pups at postnatal days 6-7 with one whisker stimulation. We removed the overlying cortex and hippocampus to reach the thalamus with electrodes. Deflection of only one (the principal) whisker induced spikes in a particular thalamic cell. Whisker deflection evoked a group of large-amplitude excitatory events, likely originating from lemniscal synapses and multiple inhibitory postsynaptic events in thalamocortical cells. Large-amplitude excitatory events produced a group of spike bursts and could evoke a depolarization block. Juxtacellular recordings confirmed the partial inactivation of spikes. Inhibitory events prevented inactivation of action potentials and gamma-modulated neuronal firing. We conclude that the interplay of strong excitatory and inhibitory synapses and relatively weak intrinsic currents produces sensory-evoked early gamma oscillations in thalamocortical cells. We also propose that sensory-evoked large-amplitude excitatory events contribute to evoked spindle-bursts.

Vancomycin-induced gut microbial dysbiosis alters enteric neuron-macrophage interactions during a critical period of postnatal development.

Vancomycin is a broad-spectrum antibiotic widely used in cases of suspected sepsis in premature neonates. While appropriate and potentially lifesaving in this setting, early-life antibiotic exposure alters the developing microbiome and is associated with an increased risk of deadly complications, including late-onset sepsis (LOS) and necrotizing enterocolitis (NEC). Recent studies show that neonatal vancomycin treatment disrupts postnatal enteric nervous system (ENS) development in mouse pups, which is in part dependent upon neuroimmune interactions. This suggests that early-life antibiotic exposure could disrupt these interactions in the neonatal gut. Notably, a subset of tissue-resident intestinal macrophages, muscularis macrophages, has been identified as important contributors to the development of postnatal ENS. We hypothesized that vancomycin-induced neonatal dysbiosis impacts postnatal ENS development through its effects on macrophages. Using a mouse model, we found that exposure to vancomycin in the first 10 days of life, but not in adult mice, resulted in an expansion of pro-inflammatory colonic macrophages by increasing the recruitment of bone-marrow-derived macrophages. Single-cell RNA sequencing of neonatal colonic macrophages revealed that early-life vancomycin exposure was associated with an increase in immature and inflammatory macrophages, consistent with an influx of circulating monocytes differentiating into macrophages. Lineage tracing confirmed that vancomycin significantly increased the non-yolk-sac-derived macrophage population. Consistent with these results, early-life vancomycin exposure did not expand the colonic macrophage population nor decrease enteric neuron density in CCR2-deficient mice. Collectively, these findings demonstrate that early-life vancomycin exposure alters macrophage number and phenotypes in distinct ways compared with vancomycin exposure in adult mice and results in altered ENS development.

NMDA receptor activity during postnatal development determines intrinsic excitability and mossy fiber long-term potentiation of CA3 pyramidal cells.

Experimental manipulations that interfere with the functional expression of N-methyl-D-aspartate receptors (NMDARs) during prenatal neurodevelopment or critical periods of postnatal development are models that mimic behavioral and neurophysiological abnormalities of schizophrenia. Blockade of NMDARs with MK-801 during early postnatal development alters glutamate release and impairs the induction of NMDAR-dependent long-term plasticity at the CA1 area of the hippocampus. However, it remains unknown if other forms of hippocampal plasticity, such as α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated short- and long-term potentiation, are compromised in response to neonatal treatment with MK-801. Consistent with this tenet, short- and long-term potentiation between dentate gyrus axons, the mossy fibers (MF), onto CA3 pyramidal cells (CA3 PCs) are mediated by AMPARs. By combining whole-cell patch clamp and extracellular recordings, we have demonstrated that transient blockade of NMDARs during early postnatal development induces a series of pre- and postsynaptic modifications at the MF-CA3 synapse. We found reduced glutamate release from the mossy boutons, increased paired-pulse ratio, and reduced AMPAR-mediated MF LTP levels. At the postsynaptic level, we found an altered NMDA/AMPA ratio and dysregulation of several potassium conductances that increased the excitability of CA3 PCs. In addition, MK-801-treated animals exhibited impaired spatial memory retrieval in the Barnes maze task. Our data demonstrate that transient hypofunction of NMDARs impacts NMDAR-independent forms of synaptic plasticity of the hippocampus.

Secondary Degeneration Impairs Myelin Ultrastructural Development in Adulthood following Adolescent Neurotrauma in the Rat Optic Nerve

Adolescence is a critical period of postnatal development characterized by social, emotional, and cognitive changes. These changes are increasingly understood to depend on white matter development. White matter is highly vulnerable to the effects of injury, including secondary degeneration in regions adjacent to the primary injury site which alters the myelin ultrastructure. However, the impact of such alterations on adolescent white matter maturation is yet to be investigated. To address this, female piebald-virol-glaxo rats underwent partial transection of the optic nerve during early adolescence (postnatal day (PND) 56) with tissue collection two weeks (PND 70) or three months later (PND 140). Axons and myelin in the transmission electron micrographs of tissue adjacent to the injury were classified and measured based on the appearance of the myelin laminae. Injury in adolescence impaired the myelin structure in adulthood, resulting in a lower percentage of axons with compact myelin and a higher percentage of axons with severe myelin decompaction. Myelin thickness did not increase as expected into adulthood after injury and the relationship between the axon diameter and myelin thickness in adulthood was altered. Notably, dysmyelination was not observed 2 weeks postinjury. In conclusion, injury in adolescence altered the developmental trajectory, resulting in impaired myelin maturation when assessed at the ultrastructural level in adulthood.

Perinatal exposure to tetracycline contributes to lasting developmental effects on offspring

BackgroundFor more than 30 years, the tetracycline on/off system of inducible gene expression has been leveraged to study disease mechanisms across many research areas, especially that of metabolism and neuroscience. This system requires acute or chronic exposure to tetracycline derivatives, such as doxycycline, to manipulate gene expression in a temporal and tissue-specific manner, with exposure often being restricted to gestational and early developmental windows. Despite evidence showing that early life antibiotic exposure has adverse effects on gut microbiota, metabolism, physiology, immunity and behavior, little is known regarding the lasting impact of doxycycline treatment on relevant outcomes in experimental offspring.ResultsTo examine the hypothesis that early life doxycycline exposure produces effects on offspring growth, behavior, and gut microbiota, we employed the most commonly used method for tetracycline on/off system by administering a low dose of doxycycline (0.5 mg/ml) in the drinking water to C57Bl/6J and C57BL/6J:129S1/SvImJ dams from embryonic day 15.5 to postnatal day 28. Developmental exposure to low dose doxycycline resulted in significant alterations to growth trajectories and body weight in both strains, which persisted beyond cessation of doxycycline exposure. Developmental doxycycline exposure influenced offspring bacterial community assembly in a temporal and sex-specific manner. Further, gut microbiota composition failed to recover by adulthood, suggesting a lasting imprint of developmental antibiotic exposure.ConclusionsOur results demonstrated that early life doxycycline exposure shifts the homeostatic baseline of prior exposed animals that may subsequently impact responses to experimental manipulations. These results highlight the gut microbiota as an important factor to consider in systems requiring methods of chronic antibiotic administration during pregnancy and critical periods of postnatal development.

Acoustically Enriched Environment during the Critical Period of Postnatal Development Positively Modulates Gap Detection and Frequency Discrimination Abilities in Adult Rats

Throughout life, sensory systems adapt to the sensory environment to provide optimal responses to relevant tasks. In the case of a developing system, sensory inputs induce changes that are permanent and detectable up to adulthood. Previously, we have shown that rearing rat pups in a complex acoustic environment (spectrally and temporally modulated sound) from postnatal day 14 (P14) to P28 permanently improves the response characteristics of neurons in the inferior colliculus and auditory cortex, influencing tonotopical arrangement, response thresholds and strength, and frequency selectivity, along with stochasticity and the reproducibility of neuronal spiking patterns. In this study, we used a set of behavioral tests based on a recording of the acoustic startle response (ASR) and its prepulse inhibition (PPI), with the aim to extend the evidence of the persistent beneficial effects of the developmental acoustical enrichment. The enriched animals were generally not more sensitive to startling sounds, and also, their PPI of ASR, induced by noise or pure tone pulses, was comparable to the controls. They did, however, exhibit a more pronounced PPI when the prepulse stimulus was represented either by a change in the frequency of a background tone or by a silent gap in background noise. The differences in the PPI of ASR between the enriched and control animals were significant at lower (55 dB SPL), but not at higher (65-75 dB SPL), intensities of background sound. Thus, rearing pups in the acoustically enriched environment led to an improvement of the frequency resolution and gap detection ability under more difficult testing conditions, i.e., with a worsened stimulus clarity. We confirmed, using behavioral tests, that an acoustically enriched environment during the critical period of development influences the frequency and temporal processing in the auditory system, and these changes persist until adulthood.

Spinal motoneuron firing properties mature from rostral to caudal during postnatal development of the mouse.

Key points Many mammals are born with immature motor systems that develop through a critical period of postnatal development.In rodents, postnatal maturation of movement occurs from rostral to caudal, correlating with maturation of descending supraspinal and local spinal circuits.We asked whether development of fundamental electrophysiological properties of spinal motoneurons follows the same rostro‐caudal sequence.We show that in both regions, repetitive firing parameters increase and excitability decreases with development; however, these characteristics mature earlier in cervical motoneurons.We suggest that in addition to autonomous mechanisms, motoneuron development depends on activity resulting from their circuit milieu. Altricial mammals are born with immature nervous systems comprised of circuits that do not yet have the neuronal properties and connectivity required to produce future behaviours. During the critical period of postnatal development, neuronal properties are tuned to participate in functional circuits. In rodents, cervical motoneurons are born prior to lumbar motoneurons, and spinal cord development follows a sequential rostro‐caudal pattern. Here we asked whether birth order is reflected in the postnatal development of electrophysiological properties. We show that motoneurons of both regions have similar properties at birth and follow the same developmental profile, with maximal firing increasing and excitability decreasing into the third postnatal week. However, these maturative processes occur in cervical motoneurons prior to lumbar motoneurons, correlating with the maturation of premotor descending and local spinal systems. These results suggest that motoneuron properties do not mature by cell autonomous mechanisms alone, but also depend on developing premotor circuits.

Histaminergic Control of Corticostriatal Synaptic Plasticity during Early Postnatal Development.

A reduction in the synthesis of the neuromodulator histamine has been associated with Tourette's syndrome and obsessive-compulsive disorder. Symptoms of these disorders are thought to arise from a dysfunction or aberrant development ofcorticostriatal circuits. Here, we investigated how histamine affects developing corticostriatal circuits, both acutely and longer-term, during the first postnatal weeks, using patch-clamp and field recordings in mouse brain slices (C57Bl/6, male and female). Immunohistochemistry for histamine-containing axons reveals striatal histaminergic innervation by the second postnatal week, and qRT-PCR shows transcripts for H1, H2, and H3 histamine receptors in striatum from the first postnatal week onwards, with pronounced developmental increases in H3 receptor expression. Whole-cell patch-clamp recordings of striatal spiny projection neurons and histamine superfusion demonstrates expression of functional histamine receptors from the first postnatal week onwards, with histamine having diverse effects on their electrical properties, including depolarization of the membrane potential while simultaneously decreasing action potential output. Striatal field recordings and electrical stimulation of corticostriatal afferents revealed that histamine, acting at H3 receptors, negatively modulates corticostriatal synaptic transmission from the first postnatal week onwards. Last, we investigated effects of histamine on longer-term changes at developing corticostriatal synapses and show that histamine facilitates NMDA receptor-dependent LTP via H3 receptors during the second postnatal week, but inhibits synaptic plasticity at later developmental stages. Together, these results show that histamine acutely modulates developing striatal neurons and synapses and controls longer-term changes in developing corticostriatal circuits, thus providing insight into the possible etiology underlying neurodevelopmental disorders resulting from histamine dysregulation.SIGNIFICANCE STATEMENT Monogenic causes of neurologic disorders, although rare, can provide opportunities to both study and understand the brain. For example, a nonsense mutation in the coding gene for the histamine-synthesizing enzyme has been associated with Tourette's syndrome and obsessive-compulsive disorder, and dysfunction of corticostriatal circuits. Nevertheless, the etiology of these neurodevelopmental disorders and histamine's role in the development of corticostriatal circuits have remained understudied. Here we show that histamine is an active neuromodulator during the earliest periods of postnatal life and acts at developing striatal neurons and synapses. Crucially, we show that histamine permits NMDA receptor-dependent corticostriatal synaptic plasticity during an early critical period of postnatal development, which suggests that genetic or environmental perturbations of histamine levels can impact striatal development.

Dynamics of morphometric parameters of α-endocrinocytes of mammal pancreas

In domestic animals in postnatal ontogenesis, statistically significant changes in the number of α-endocrinocytes and the values of their nuclear-cytoplasmic ratio in the endocrine islets of pancreas have been revealed, which reflects the species and age-related dynamic processes of its morphofunctional development in animals. In cattle and small cattle (sheep), pigs, dogs and cats, two critical periods of postnatal development of the pancreas have been identified. The first critical period is observed from the birth to the age of three months. It is associated with an alimentary factor: the transition from a dairy diet to roughage, which leads to a decrease in the values of morphometric indicators of the pancreas and the restructuring of the functional work of the organ as a whole. The second critical period is registered in animals during puberty, that is, at 6 months of age, which is associated with the release of hormonal inducers aimed primarily at the implementation of physiological changes in the body.

Acoustical Enrichment during Early Development Improves Response Reliability in the Adult Auditory Cortex of the Rat.

It is well known that auditory experience during early development shapes response properties of auditory cortex (AC) neurons, influencing, for example, tonotopical arrangement, response thresholds and strength, or frequency selectivity. Here, we show that rearing rat pups in a complex acoustically enriched environment leads to an increased reliability of responses of AC neurons, affecting both the rate and the temporal codes. For a repetitive stimulus, the neurons exhibit a lower spike count variance, indicating a more stable rate coding. At the level of individual spikes, the discharge patterns of individual neurons show a higher degree of similarity across stimulus repetitions. Furthermore, the neurons follow more precisely the temporal course of the stimulus, as manifested by improved phase-locking to temporally modulated sounds. The changes are persistent and present up to adulthood. The results document that besides basic alterations of receptive fields presented in our previous study, the acoustic environment during the critical period of postnatal development also leads to a decreased stochasticity and a higher reproducibility of neuronal spiking patterns.

Effects of neonatal hyperoxia on the critical period of postnatal development of neurochemical expressions in brain stem respiratory-related nuclei in the rat.

We have identified a critical period of respiratory development in rats at postnatal days P12‐13, when inhibitory influence dominates and when the response to hypoxia is at its weakest. This critical period has significant implications for Sudden Infant Death Syndrome (SIDS), the cause of which remains elusive. One of the known risk factors for SIDS is prematurity. A common intervention used in premature infants is hyperoxic therapy, which, if prolonged, can alter the ventilatory response to hypoxia and induce sustained inhibition of lung alveolar growth and pulmonary remodeling. The goal of this study was to test our hypothesis that neonatal hyperoxia from postnatal day (P) 0 to P10 in rat pups perturbs the critical period by altering the normal progression of neurochemical development in brain stem respiratory‐related nuclei. An in‐depth, semiquantitative immunohistochemical study was undertaken at P10 (immediately after hyperoxia and before the critical period), P12 (during the critical period), P14 (immediately after the critical period), and P17 (a week after the cessation of hyperoxia). In agreement with our previous findings, levels of cytochrome oxidase, brain‐derived neurotrophic factor (BDNF), TrkB (BDNF receptor), and several serotonergic proteins (5‐HT1A and 2A receptors, 5‐HT synthesizing enzyme tryptophan hydroxylase [TPH], and serotonin transporter [SERT]) all fell in several brain stem respiratory‐related nuclei during the critical period (P12) in control animals. However, in hyperoxic animals, these neurochemicals exhibited a significant fall at P14 instead. Thus, neonatal hyperoxia delayed but did not eliminate the critical period of postnatal development in multiple brain stem respiratory‐related nuclei, with little effect on the nonrespiratory cuneate nucleus.

Attention-deficit/hyperactivity disorder, joint hypermobility-related disorders and pain: expanding body-mind connections to the developmental age.

Attention-deficit/hyperactivity disorder (ADHD) and generalized joint hypermobility (JH) are two separated conditions, assessed, and managed by different specialists without overlapping interests. Recently, some researchers highlighted an unexpected association between these two clinical entities. This happens in a scenario of increasing awareness on the protean detrimental effects that congenital anomalies of the connective tissue may have on human health and development. To review pertinent literature to identify possible connections between ADHD and GJH, special emphasis was put on musculoskeletal pain and syndromic presentations of GJH, particularly the hypermobile Ehlers-Danlos syndrome. A comprehensive search of scientific databases and references lists was conducted, encompassing publications based on qualitative and quantitative research. Impaired coordination and proprioception, fatigue, chronic pain, and dysautonomia are identified as potential bridges between ADHD and JH. Based on these findings, a map of the pathophysiological and psychopathological pathways connecting both conditions is proposed. Although ADHD and JH are traditionally separated human attributes, their association may testify for the dyadic nature of mind-body connections during critical periods of post-natal development. Such a mixed picture has potentially important consequences in terms of disability and deserves more clinical and research attention.

The Effect of Complex Acoustic Environment during Early Development on the Responses of Auditory Cortex Neurons in Rats

Acoustical environment plays an important role during the maturation of the auditory system. It has been shown that the sensory inputs to the developing centres influence the development of the structure of projections, neuronal responsiveness, excitatory-inhibitory balance, or tonotopical arrangement, throughout the auditory pathway. Our previous study (Bures et al., 2014) showed that rats reared in a complex acoustic environment (spectrally and temporally modulated sound reinforced by an active behavioural paradigm with a positive feedback) exhibit permanently improved response characteristics of the inferior colliculus (IC) neurons. Extending these results, the current work provides evidence that the changes occur also at the level of auditory cortex (AC). In particular, the enriched animals have lower excitatory thresholds, sharper frequency selectivity, and a lower proportion of non-monotonic rate-intensity functions. In contrast to the changes observed in the IC, the cortical neurons of enriched animals have lower response magnitudes. In addition, the enrichment changed the AC responsiveness to frequency-modulated and also to a lesser extent, amplitude-modulated stimuli. Significantly, the alterations span the entire hearing range and may be regarded as general and not directly linked to the characteristics of the acoustical stimulation. Furthermore, these developmentally induced changes are permanent and detectable in adulthood. The findings indicate that an acoustically enriched environment during the critical period of postnatal development influences basic properties of neuronal receptive fields in the AC, which may have implications for the ability to detect and discriminate sounds.

Functional and Brainstem Neurochemical Changes During a Critical Period of Postnatal Development

There are distinct developmentally regulated changes in the constitutive expression of various neurochemical factors that occur in brainstem cardio‐respiratory control regions. Many of these neurodevelopmental events occur towards the end of the second postnatal (P) week of life in the rat and consist of abrupt and in some cases transient changes in the expression of various neurotransmitters (e.g. 5‐HT), glia (Iba‐1), cytokines (TNFα, IL1β), as well as components of the extracellular matrix (ECM). Such key events appear necessary for appropriate architectural organization of the maturing cardio‐respiratory nervous system, although their timing also coincides with a critical window during which the neonate exhibits a uniquely heightened and lethal vulnerability to “inflammatory” stressors. Specifically, exposure to five days of sustained hypoxia (SH, 11% O2) starting on day P11, or a single bolus injection of LPS (P12) cause profound disturbances in the acute hypoxic ventilatory response (HVR). The effects of SH and LPS appear unique to hypoxia as the hypercapnic ventilatory response is relatively less affected. LPS and SH are similar in that they each also cause an unexpected incidence of mortality which is unique to this age group as younger (P1–5) or older age groups (P21–25) appear relatively unaffected by exposure to the same stimuli, thus revealing a critical window of heightened cardio‐respiratory vulnerability. The heightened vulnerability to SH or LPS is associated with increased brainstem expression of microglia, the ECM, markers of neurogenesis and cytokines (mRNA), and a disruption to the serotonergic system. We propose, therefore, that the heightened vulnerability to either SH or LPS likely manifests as an aberrant “inflammatory” response during a critical period of brainstem neurochemical development and ECM formation, resulting in a lethal disturbance in crucial neurochemical/neurodevelopmental events. However, inhibition of microglia or enzymatic degradation of the ECM protects against the adverse effects of SH, whereas high serum TNFα represents an early biomarker that predicts vulnerability to LPS. These data have begun to shed light on the interactions between early life experiences and the cardio‐respiratory control system and the profound unintended consequences that they have during critical periods of development.

Partial Raphe Dysfunction in Neurotransmission Is Sufficient to Increase Mortality after Anoxic Exposures in Mice at a Critical Period in Postnatal Development.

Many sudden infant death syndrome (SIDS) cases exhibit a partial (∼26%) brainstem serotonin deficiency. Using recombinase drivers, we targeted different fractions of serotonergic and raphe neurons in mice for tetanus toxin light chain expression, which prevented vesicular neurotransmitter release. In one model, approximately one-third of medullary Tph2(+) neurons are silenced by postnatal (P) days 5 and 12, along with some Pet1(+),Tph2(low or negative) raphe cells; in the other, approximately three-fourths of medullary Tph2(+) neurons, also with some Tph2(low or negative) cells. Both models demonstrated excessive mortality to anoxia (a postulated SIDS stressor) at P5 and P8. We demonstrated fatal vulnerability to anoxic stress at a specific time in postnatal life induced by a partial defect in raphe function. This models features of SIDS.

D-Serine and Glycine Differentially Control Neurotransmission during Visual Cortex Critical Period.

N-methyl-D-aspartate receptors (NMDARs) play a central role in synaptic plasticity. Their activation requires the binding of both glutamate and d-serine or glycine as co-agonist. The prevalence of either co-agonist on NMDA-receptor function differs between brain regions and remains undetermined in the visual cortex (VC) at the critical period of postnatal development. Here, we therefore investigated the regulatory role that d-serine and/or glycine may exert on NMDARs function and on synaptic plasticity in the rat VC layer 5 pyramidal neurons of young rats. Using selective enzymatic depletion of d-serine or glycine, we demonstrate that d-serine and not glycine is the endogenous co-agonist of synaptic NMDARs required for the induction and expression of Long Term Potentiation (LTP) at both excitatory and inhibitory synapses. Glycine on the other hand is not involved in synaptic efficacy per se but regulates excitatory and inhibitory neurotransmission by activating strychnine-sensitive glycine receptors, then producing a shunting inhibition that controls neuronal gain and results in a depression of synaptic inputs at the somatic level after dendritic integration. In conclusion, we describe for the first time that in the VC both D-serine and glycine differentially regulate somatic depolarization through the activation of distinct synaptic and extrasynaptic receptors.

Effects of PSA Removal from NCAM on the Critical Period Plasticity Triggered by the Antidepressant Fluoxetine in the Visual Cortex.

Neuronal plasticity peaks during critical periods of postnatal development and is reduced towards adulthood. Recent data suggests that windows of juvenile-like plasticity can be triggered in the adult brain by antidepressant drugs such as Fluoxetine. Although the exact mechanisms of how Fluoxetine promotes such plasticity remains unknown, several studies indicate that inhibitory circuits play an important role. The polysialylated form of the neural cell adhesion molecules (PSA-NCAM) has been suggested to mediate the effects of Fluoxetine and it is expressed in the adult brain by mature interneurons. Moreover, the enzymatic removal of PSA by neuroaminidase-N not only affects the structure of interneurons but also has been shown to play a role in the onset of critical periods during development. We have here used ocular dominance plasticity in the mouse visual cortex as a model to investigate whether removal of PSA might influence the Fluoxetine-induced plasticity. We demonstrate that PSA removal in the adult visual cortex alters neither the baseline ocular dominance, nor the fluoxetine-induced shift in the ocular dominance. We also show that both chronic Fluoxetine treatment and PSA removal independently increase the basal FosB expression in parvalbumin (PV) interneurons in the primary visual cortex. Therefore, our data suggest that although PSA-NCAM regulates inhibitory circuitry, it is not required for the reactivation of juvenile-like plasticity triggered by Fluoxetine.

Otx2-PNN Interaction to Regulate Cortical Plasticity.

The ability of the environment to shape cortical function is at its highest during critical periods of postnatal development. In the visual cortex, critical period onset is triggered by the maturation of parvalbumin inhibitory interneurons, which gradually become surrounded by a specialized glycosaminoglycan-rich extracellular matrix: the perineuronal nets. Among the identified factors regulating cortical plasticity in the visual cortex, extracortical homeoprotein Otx2 is transferred specifically into parvalbumin interneurons and this transfer regulates both the onset and the closure of the critical period of plasticity for binocular vision. Here, we review the interaction between the complex sugars of the perineuronal nets and homeoprotein Otx2 and how this interaction regulates cortical plasticity during critical period and in adulthood.

Metabotropic glutamate receptor signaling is required for NMDA receptor-dependent ocular dominance plasticity and LTD in visual cortex

A feature of early postnatal neocortical development is a transient peak in signaling via metabotropic glutamate receptor 5 (mGluR5). In visual cortex, this change coincides with increased sensitivity of excitatory synapses to monocular deprivation (MD). However, loss of visual responsiveness after MD occurs via mechanisms revealed by the study of long-term depression (LTD) of synaptic transmission, which in layer 4 is induced by acute activation of NMDA receptors (NMDARs) rather than mGluR5. Here we report that chronic postnatal down-regulation of mGluR5 signaling produces coordinated impairments in both NMDAR-dependent LTD in vitro and ocular dominance plasticity in vivo. The data suggest that ongoing mGluR5 signaling during a critical period of postnatal development establishes the biochemical conditions that are permissive for activity-dependent sculpting of excitatory synapses via the mechanism of NMDAR-dependent LTD.

Retinal Input Directs the Recruitment of Inhibitory Interneurons into Thalamic Visual Circuits

Inhibitory interneurons (INs) critically control the excitability and plasticity of neuronal networks, but whether activity can direct INs into specific circuits during development is unknown. Here, we report that in the dorsal lateral geniculate nucleus (dLGN), which relays retinal input to the cortex, circuit activity is required for the migration, molecular differentiation, and functional integration of INs. We first characterize the prenatal origin and molecular identity of dLGN INs, revealing their recruitment from an Otx2(+) neuronal pool located in the adjacent ventral LGN. Using time-lapse and electrophysiological recordings, together with genetic and pharmacological perturbation of retinal waves, we show that retinal activity directs the navigation and circuit incorporation of dLGN INs during the first postnatal week, thereby regulating the inhibition of thalamocortical circuits. These findings identify an input-dependent mechanism regulating IN migration and circuit inhibition, which may account for the progressive recruitment of INs into expanding excitatory circuits during evolution.