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Age-related changes in spine density and size in GFP-S mice. (A) Schematic representation of a frontal section of mouse brain, showing the sub-regions of the medial prefrontal cortex (mPFC) that were imaged: Prelimbic cortex (PrL) and Cingulate cortex (Cg). Bottom panels show an example of one GFP positive neuron expressing GAD-67. Scale bar = 20 µm. (B) shows one GFP positive pyramidal cell in layer III of mPFC. Scale bar = 50 µm. Images in (C) are examples of layer II cortical dendrites from the same GFP mouse at P30: note that spine density varies considerably within the same layer. Scale bar = 10 µm. (D) Average values of spine density per unit of area at P20 (n = 14), P30 (n = 15), and P60 (n = 13). Values represent mean ± SD. ANOVA P = 0.041. (E) Cumulative distributions of spine density per unit of area (µm 2 ) for the entire population of dendrites at P20 (271 dendrites), P30 (347 dendrites), and P60 (261 dendrites). Kolmogorov-Smirnov test (KS test), P20 vs P30, P = 0.001; P30 vs 60, P = 0.011; P20 vs P60, P = 0.032. (F) Box plot showing the distribution of density for the entire population of dendrites at different ages: upper and lower side of boxes represent 75 th and 25 th percentile of spine populations, respectively. (G) Average values, per animal, of filopodia per unit of area. One-way ANOVA P = 0.0023, Bonferroni multi-comparison test P20 vs P30, P > 0.05; P20 vs P60, P < 0.01; P30 vs P60, P < 0.05. (H) Examples of dendrites with numerous filopodia (arrowheads) in a preadolescent mouse (left panel) and in an adult mouse with no filopodia (right panel). Scale bar = 10 µm.
Source publication
In humans sleep slow wave activity (SWA) declines during adolescence. It has been suggested that this decline reflects the elimination of cortical synapses, but this hypothesis has never been tested directly.
We focused on mouse frontal cortex and collected data from early adolescence (∼postnatal day 20, P20) to adulthood (P60) of (1) SWA; (2) expr...
Contexts in source publication
Context 1
... data were not available for medial prefrontal cortex (mPFC), our area of interest, we first assessed the percentage of GFP positive cells in mPFC that also express GAD-67, a GABAergic marker. We counted 270 GFP positive cells (6 mice), of which only 3 (0.9% ± 0.7%, mean ± SEM) were positive for GAD-67 ( Figure 4A). Thus, virtually all dendritic spines identified in layers I-II of mPFC belong to pyramidal neurons ( Figure 4B). ...
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... counted 270 GFP positive cells (6 mice), of which only 3 (0.9% ± 0.7%, mean ± SEM) were positive for GAD-67 ( Figure 4A). Thus, virtually all dendritic spines identified in layers I-II of mPFC belong to pyramidal neurons ( Figure 4B). ...
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... density varied considerably in layers I-II dendrites, even within the same mouse ( Figure 4C). This range of variability led to average values of spine density that changed almost twofold in mice of the same age. ...
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... range of variability led to average values of spine density that changed almost twofold in mice of the same age. As a result, mean spine density showed a slight increase at P30 compared to P20 and P60 ( Figure 4D). Values of spine density from dendrites collected from mice of the same age were then pooled together and the distributions of the P20, P30, and P60 populations were compared. ...
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... of spine density from dendrites collected from mice of the same age were then pooled together and the distributions of the P20, P30, and P60 populations were compared. A group of dendrites with higher spine density emerged at P30, shifting the upper part of the cumulative distribution of this group significantly towards the right ( Figure 4E). Thus, the data suggest that the number of dendrites with high spine density increases from P20 to P30, and then decreases from P30 to P60 (Figure 4E and F). ...
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... group of dendrites with higher spine density emerged at P30, shifting the upper part of the cumulative distribution of this group significantly towards the right ( Figure 4E). Thus, the data suggest that the number of dendrites with high spine density increases from P20 to P30, and then decreases from P30 to P60 (Figure 4E and F). Filopodia were counted separately. ...
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... were counted separately. Their density was high in preadolescent mice and decreased significantly in the late phase of adolescence ( Figure 4G and H). ...
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... data were not available for medial prefrontal cortex (mPFC), our area of interest, we first assessed the percentage of GFP positive cells in mPFC that also express GAD-67, a GABAergic marker. We counted 270 GFP positive cells (6 mice), of which only 3 (0.9% ± 0.7%, mean ± SEM) were positive for GAD-67 ( Figure 4A). Thus, virtually all dendritic spines identified in layers I-II of mPFC belong to pyramidal neurons ( Figure 4B). ...
Context 9
... counted 270 GFP positive cells (6 mice), of which only 3 (0.9% ± 0.7%, mean ± SEM) were positive for GAD-67 ( Figure 4A). Thus, virtually all dendritic spines identified in layers I-II of mPFC belong to pyramidal neurons ( Figure 4B). ...
Context 10
... density varied considerably in layers I-II dendrites, even within the same mouse ( Figure 4C). This range of variability led to average values of spine density that changed almost twofold in mice of the same age. ...
Context 11
... range of variability led to average values of spine density that changed almost twofold in mice of the same age. As a result, mean spine density showed a slight increase at P30 compared to P20 and P60 ( Figure 4D). Values of spine density from dendrites collected from mice of the same age were then pooled together and the distributions of the P20, P30, and P60 populations were compared. ...
Context 12
... of spine density from dendrites collected from mice of the same age were then pooled together and the distributions of the P20, P30, and P60 populations were compared. A group of dendrites with higher spine density emerged at P30, shifting the upper part of the cumulative distribution of this group significantly towards the right ( Figure 4E). Thus, the data suggest that the number of dendrites with high spine density increases from P20 to P30, and then decreases from P30 to P60 (Figure 4E and F). ...
Context 13
... group of dendrites with higher spine density emerged at P30, shifting the upper part of the cumulative distribution of this group significantly towards the right ( Figure 4E). Thus, the data suggest that the number of dendrites with high spine density increases from P20 to P30, and then decreases from P30 to P60 (Figure 4E and F). Filopodia were counted separately. ...
Citations
... The decline in sleep spindles amplitude during adolescence is thought to be caused by synaptic pruning [35]. A similar evolution in slow wave characteristics occurs in rodents during the juvenile period (PN [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35], which coincide with changes in synaptic density in the prefrontal cortex [83]. However, changes in the landscape of spindles expression have not been consistently reported. ...
Purpose of Review
Neurodevelopmental disorders are a group of conditions that affect the development and function of the nervous system, typically arising early in life. These disorders can have various genetic, environmental, and/or neural underpinnings, which can impact the thalamocortical system. Sleep spindles, brief bursts of oscillatory activity that occur during NREM sleep, provide a unique in vivo measure of the thalamocortical system. In this manuscript, we review the development of the thalamocortical system and sleep spindles in rodent models and humans. We then utilize this as a foundation to discuss alterations in sleep spindle activity in four of the most pervasive neurodevelopmental disorders—intellectual disability, attention deficit hyperactivity disorder, autism, and schizophrenia.
Recent Findings
Recent work in humans has shown alterations in sleep spindles across several neurodevelopmental disorders. Simultaneously, rodent models have elucidated the mechanisms which may underlie these deficits in spindle activity. This review merges recent findings from these two separate lines of research to draw conclusions about the pathogenesis of neurodevelopmental disorders.
Summary
We speculate that deficits in the thalamocortical system associated with neurodevelopmental disorders are exquisitely reflected in sleep spindle activity. We propose that sleep spindles may represent a promising biomarker for drug discovery, risk stratification, and treatment monitoring.
... However, sleep architecture demonstrates a clear developmental trajectory. Total sleep time decreases from infancy through adolescence to adulthood 4 , and compared to adult sleep, electroencephalogram (EEG) of sleep during development contains more components beneficial to memory and cognition, such as slow waves and sleep spindles [5][6][7] . In juvenile animals, sleep regulates synaptic plasticity both functionally and structurally 3,[8][9][10][11][12][13][14][15] and likely plays important roles in developmental wiring of neural circuits. ...
... For detailed statistics information, see Supplementary Table 1. component and the main feature of NREM sleep, SWA increases from early childhood to adolescence 51,57 and then decreases as the brain matures into adulthood 5,6 and thus is correlated with the development of brain connectivity 58 . Consistent with this logic, the NREM silencing of VTA DA neurons during adolescence was essential for this sleep function because adolescent inhibition of VTA activity restored the social novelty preference in both SD mice ( Fig. 5f-i) and InsG3680 +/+ mice ( Fig. 6o-r). ...
Sleep disturbances frequently occur in neurodevelopmental disorders such as autism, but the developmental role of sleep is largely unexplored, and a causal relationship between developmental sleep defects and behavioral consequences in adulthood remains elusive. Here, we show that in mice, sleep disruption (SD) in adolescence, but not in adulthood, causes long-lasting impairment in social novelty preference. Furthermore, adolescent SD alters the activation and release patterns of dopaminergic neurons in the ventral tegmental area (VTA) in response to social novelty. This developmental sleep function is mediated by balanced VTA activity during adolescence; chemogenetic excitation mimics, whereas silencing rescues, the social deficits of adolescent SD. Finally, we show that in Shank3-mutant mice, improving sleep or rectifying VTA activity during adolescence ameliorates adult social deficits. Together, our results identify a critical role of sleep and dopaminergic activity in the development of social interaction behavior. Bian et al. show that sleep during adolescence is crucial for shaping the preference for novel social stimulation in adulthood. This developmental role of sleep is mediated by balanced levels of VTA activity during adolescent brain development.
... The body of work studying this has revealed an important role for inhibition in regulating UDS activity, including the impact of different types of interneurons (Fanselow & Connors, 2010;Neske & Connors, 2016;Puig et al., 2008) and of distinct types of GABA receptors (Barbero-Castillo et al., 2021;Mann et al., 2009). However, while both slow oscillations (De Vivo et al., 2014;Kurth et al., 2010) and UDSs have been shown to change with age, there have been no studies so far examining how GABA receptors affect the pattern of UDS activity throughout the lifespan. This is surprising, since it is well known that the GABAergic circuitry is also significantly modified with age. ...
Slow oscillations, the hallmark of non‐REM sleep, and their cellular counterpart, Up and Down states (UDSs), are considered a signature of cortical dynamics that reflect the intrinsic network organization. Although previous studies have explored the role of inhibition in regulating UDSs, little is known about whether this role changes with maturation. This is surprising since both slow oscillations and UDSs exhibit significant age‐dependent alterations. To elucidate the developmental impact of GABAB and GABAA receptors on UDS activity, we conducted simultaneous local field potentials and intracellular recordings ex vivo, in brain slices of young and adult male mice, using selective blockers, CGP55845 and a non‐saturating concentration of gabazine, respectively. Blockade of both GABAB and GABAA signalling showed age‐differentiated functions. CGP55845 caused an increase in Down state duration in young animals, but a decrease in adults. Gabazine evoked spike and wave discharges in both ages; however, while young networks became completely epileptic, adults maintained the ability to generate UDSs. Furthermore, voltage clamp recordings of miniature inhibitory postsynaptic currents revealed that gabazine selectively blocks phasic currents, particularly involving postsynaptic mechanisms. The latter exhibit clear maturational changes, suggesting a different subunit composition of GABAA receptors in young vs. adult animals. Indeed, subsequent local field potential recordings under diazepam (nanomolar or micromolar concentrations) revealed that mechanisms engaging the drug's classical binding site, mediated by α1‐subunit‐containing GABAA receptors, make a bigger contribution to Up state initiation in young networks compared to adults. Taken together, these findings help clarify the mechanisms that underlie the maturation of cortical network activity and enhance our understanding regarding the emergence of neurodevelopmental disorders.
Key points
Slow oscillations, the EEG hallmark of non‐REM sleep, and their cellular counterpart, Up and Down states (UDSs), are considered the default activity of the cerebral cortex and reflect the underlying neural connectivity.
GABAB‐ and GABAA‐receptor‐mediated inhibition play a major role in regulating UDS activity.
Although slow oscillations and UDSs exhibit significant alterations as a function of age, it is unknown how developmental changes in inhibition contribute to the developmental profile of this activity.
In this study, we reveal for the first time age‐dependent effects of GABAB and GABAA signalling on UDSs. We also document the differential subunit composition of postsynaptic GABAA receptors in young and adult animals, highlighting the α1‐subunit as a major component of the age‐differentiated regulation of UDSs.
These findings help clarify the mechanisms that underlie the maturation of cortical network activity, and enhance our understanding regarding the emergence of neurodevelopmental disorders.
... The increase of spindle density has been proposed to reflect the maturation of thalamocortical circuitry [34,105] and, in a longitudinal study, correlated with better sleep-dependent memory consolidation [32]. SO amplitude declined with age, consistent with a body of literature showing decreased slow-wave activity and sleep depth during adolescence [35,36,39] that has been hypothesized to reflect the functional optimization of cortical circuits through a process of synaptic refinement that increases the specificity of connections [42,106,107]. Relative SO amplitude, which reflects the SO amplitude relative to background EEG activity, increased with age in TD, but declined in ASD, a group difference that reached significance in N3. This finding is novel and requires replication, but we interpret this difference to reflect atypical cortical circuit maturation in ASD. ...
Study Objectives
Converging evidence from neuroimaging, sleep, and genetic studies suggests that dysregulation of thalamocortical interactions mediated by the thalamic reticular nucleus (TRN) contribute to autism spectrum disorder (ASD). Sleep spindles assay TRN function, and their coordination with cortical slow oscillations (SOs) indexes thalamocortical communication. These oscillations mediate memory consolidation during sleep. In the present study, we comprehensively characterized spindles and their coordination with SOs in relation to memory and age in children with ASD.
Methods
Nineteen children and adolescents with ASD, without intellectual disability, and 18 typically developing (TD) peers, aged 9-17, completed a home polysomnography study with testing on a spatial memory task before and after sleep. Spindles, SOs, and their coordination were characterized during stages 2 (N2) and 3 (N3) non-rapid eye movement sleep.
Results
ASD participants showed disrupted SO-spindle coordination during N2 sleep. Spindles peaked later in SO upstates and their timing was less consistent. They also showed a spindle density (#/min) deficit during N3 sleep. Both groups showed significant sleep-dependent memory consolidation, but its relations with spindle density differed. While TD participants showed the expected positive correlations, ASD participants showed the opposite.
Conclusions
The disrupted SO-spindle coordination and spindle deficit provide further evidence of abnormal thalamocortical interactions and TRN dysfunction in ASD. The inverse relations of spindle density with memory suggest a different function for spindles in ASD than TD. We propose that abnormal sleep oscillations reflect genetically mediated disruptions of TRN-dependent thalamocortical circuit development that contribute to the manifestations of ASD and are potentially treatable.
... Many lines of research have demonstrated that receiving adequate sleep is important for facilitating and maintaining spine dynamics and synaptic efficacy (Abel, Havekes, Saletin, & Walker, 2013;De Vivo et al., 2017;Frank, 2015;Tononi & Cirelli, 2014). Consequently, deviations from normal sleep can lead to disruptions in synaptic homeostasis, potentially resulting in maladaptive learning, memory, and mood (De Vivo et al., 2014;Raven, Van der Zee, Meerlo, & Havekes, 2018;Spano et al., 2019;Tononi & Cirelli, 2014). Alcohol misuse is one factor that can produce long-term deviation in sleep, and this effect is particularly concerning during adolescence as it has the potential to impact adolescent brain development. ...
Prolonged adolescent binge drinking can disrupt sleep quality and increase the likelihood of alcohol-induced sleep disruptions in young adulthood in rodents and in humans. Striking changes in spine density and morphology have been seen in many cortical and subcortical regions after adolescent alcohol exposure in rats. However, there is little known about the impact of alcohol exposure has on dendritic spines in the same motor and sensory cortices that EEG sleep is typically recorded from in rats. The aim of this study is to investigate whether an established model of chronic intermittent ethanol vapor in rats, that has been demonstrated to disrupt sleep during adolescence (AIE) or adulthood (CIE), also significantly alters cortical dendritic spine density and morphology. To this end, adolescent and adult Wistar rats were exposed to 5 weeks of ethanol vapor or control air exposure. After a 13-day withdrawal, primary motor cortex (M1) and primary/secondary visual cortex (V1/V2) layer V dendrites were analyzed for differences in spine density and morphology. Spines were classified into 4 categories (stubby, long, filopodia, and mushroom) based on the spine length and the width of the spine head and neck. The main results indicate an age-specific effect of AIE exposure decreasing spine density in the M1 cortex compared to age-matched controls. Reductions in the density of M1 long-shaped spine subclassifications were seen in AIE rats, but not CIE rats compared to their air-controls. Irrespective of age, there was an overall reduction produced by ethanol exposure on the density of filopodia and the length of long-shaped spines in V1/V2 cortex as compared to their air-exposed controls. Together, these data add to growing evidence that some cortical circuits are vulnerable to the effects of alcohol during adolescence and begin to elucidate potential mechanisms that may influence brain plasticity following early alcohol use.
... Like the latter, the ASI increases with synaptic potentiation (Buchs and Muller, 1996;Cheetham et al., 2014;Desmond and Levy, 1988;Fukazawa et al., 2003). The goal of our experiments was to use the ASI to test the synaptic homeostasis hypothesis of sleep function (Tononi and Cirelli, 2014Cirelli, , 2020. According to this hypothesis, ongoing learning during wake leads to a net increase in synaptic strength in many brain circuits, and sleep is needed to renormalize synaptic weights to save energy, avoid saturation, and benefit memory consolidation and integration. ...
... We also found that, in primary motor cortex, the ASI was larger in two-week-old mouse pups kept awake for 4-5 hours during the day as compared to siblings allowed to sleep during the same time window . Together, these findings show that the ASI of cortical synapses is larger after wake than after sleep independent of circadian time, both in early development and during adolescence, in line with the synaptic homeostasis hypothesis (Tononi and Cirelli, 2014Cirelli, , 2020. ...
... Synaptogenesis and synaptic pruning in rodents occur mainly during the second postnatal week . In line with this, in the same mouse line used in the current study (YFP-H) we previously found that the cortical levels of synapsin I, a ubiquitous presynaptic marker, increase greatly from P10 to P20 and slightly from P20 to P25, but are stable afterwards (de Vivo et al., 2014). Thus, it may not be surprising that sustained wake at P13, even if "just" for 15 hours, had synaptic effects that went beyond those seen after shorter periods of wake, while chronic sleep restriction at P30 did not. ...
There is molecular, electrophysiological, and ultrastructural evidence that a net increase in synaptic strength occurs in many brain circuits during spontaneous wake (SW) or short sleep deprivation, reflecting ongoing learning. Sleep leads instead to a broad but selective weakening of many forebrain synapses, thus preventing synaptic saturation and decreasing the energy cost of synaptic activity. Whether synaptic potentiation can persist or further increase after long sleep deprivation is unknown. Whether synaptic renormalization can occur during chronic sleep restriction (CSR) is also unknown. Here, we addressed these questions by measuring an established ultrastructural measure of synaptic strength, the axon-spine interface (ASI), in the primary motor cortex (M1) of (1) one-month-old adolescent mice CSR using a paradigm that decreases NREM and REM sleep by two/thirds; (2) in two-week-old mouse pups sleep deprived for 15 h, or allowed afterward to recover for 16 h. Both groups were compared with mice of the same age that were asleep or awake for a few hours (both sexes). The ASI size of CSR mice (n = 3) was comparable to that measured after SW or short sleep deprivation and larger than after sleep (n = 4/group). In pups, the ASI size increased after short sleep loss (n = 3) relative to sleep (n = 4), fell below sleep levels after long sleep deprivation (n = 4), and remained low after recovery (n = 3). Long sleep deprived pups also lost some weight. These results suggest that (1) severe sleep restriction is incompatible with synaptic renormalization; (2) very young mice cannot maintain high synaptic strength during prolonged wake.
... Multiple studies (Buchmann et al., 2010;Goldstone et al., 2018) have found a relation between the adolescent decline in slow wave EEG activity and the decrease in structural MRI measured cortical thickness, another measure proposed to be associate with synaptic density. However, a direct comparison of slow wave EEG activity and synaptic density in mice did not find a decrease in dendritic spines across the adolescent period when slow wave activity decreased (de Vivo et al., 2014). The authors, instead, proposed that the adolescent decrease in EEG amplitude may be associated with synaptic rearrangement and functional optimization of cortical circuits. ...
Sleep spindles are intermittent bursts of 11-15 Hz electroencephalogram (EEG) waves that occur during non-rapid eye movement (NREM) sleep. Spindles are believed to help maintain sleep and to play a role in sleep dependent memory consolidation. Here we applied an automated sleep spindle detection program to our large longitudinal sleep EEG dataset (98 human subjects, 6-18 y, >2000 uninterrupted nights) to evaluate maturational trends in spindle wave frequency, density, amplitude, and duration. This large dataset enabled us to apply non-linear as well as linear age models, thereby extending the findings of prior cross-sectional studies that used linear models. We found that spindle wave frequency increased with remarkable linearity across the age range. Central spindle density increased nonlinearly to a peak at age 15.1 years. Central spindle wave amplitude declined in a sigmoidal pattern with the age of fastest decline at 13.5 years. Spindle duration decreased linearly with age. Of the four measures, only spindle amplitude showed a sex difference in dynamics such that the age of most rapid decline in females preceded that in males by 1.4 years. This amplitude pattern, including the sex difference in timing, paralleled the maturational pattern for delta wave power. We interpret these age-related changes in spindle characteristics as indicators of maturation of thalamocortical circuits and changes in sleep depth. These robust age-effects could facilitate the search for cognitive-behavioral correlates of spindle waveforms and might also help guide basic research on EEG mechanisms and post-natal brain maturation.SIGNIFICANCE STATEMENT:The brain reorganization of adolescence produces massive changes in sleep electrophysiology (EEG). These changes include the morphology and abundance of sleep spindles, an EEG marker of NREM sleep believed to reflect offline memory processes and/or protection of the sleep state. We analyzed over 2000 nights of longitudinal sleep EEG from 98 subjects, age 6-18 y, to investigate maturational changes in spindle amplitude, frequency, density, and duration. The large dataset enabled us to detect non-linear as well as linear age changes. All measures showed robust age effects that we hypothesize reflect the maturation of thalamocortical circuits and decreasing sleep depth. These findings could guide further research into the cognitive-behavioral correlates of sleep spindles and their underlying brain mechanisms.
... In older mice (approximately 56-60 days old at time of measurement), changes in spine heads and organelle structure (in barrel cortex) are instead consistent with increases in synaptic efficacy during the sleep phase [101,102]. Other findings are inconclusive regarding the role of SHY in brain development [103][104][105] or suggest that down-scaling does not occur during sleep in juvenile mice under certain conditions [106,107]. The precise role of REM and NREM sleep in this (or related processes [108]) is also not entirely clear. ...
Purpose of Review
To present an up-to-date review and synthesis of findings about perinatal sleep development and function. I discuss landmark events in sleep ontogenesis, evidence that sleep promotes brain development and plasticity, and experimental considerations in this topic.
Recent Findings
Mammalian sleep undergoes dramatic changes in expression and regulation during perinatal development. This includes a progressive decrease in rapid-eye-movement (REM) sleep time, corresponding increases in nonREM sleep and wake time, and the appearance of mature sleep regulatory processes (homeostatic and circadian). These developmental events coincide with periods of rapid brain maturation and heightened synaptic plasticity. The latter involve an initial experience-independent phase, when circuit development is guided by spontaneous activity, and later occurring critical periods, when these circuits are shaped by experience.
Summary
These ontogenetic changes suggest important interactions between sleep and brain development. More specifically, sleep may promote developmental programs of synaptogenesis and synaptic pruning and influence the opening and closing of critical periods of brain plasticity.
... Dendritic spine densities on apical dendrites continued to increase between P21 and P35 in the control condition alone. This indicates that, unlike other dendrite types [22,61], proximal secondary apical dendrites (distinct from apical tufts) may be slower to increase dendritic spine densities after eye opening and may not undergo pruning over the critical period for ODP. Overexpression of nectin-3 most significantly decreased apical dendritic spine densities at P35, further indicating that the unique development of this dendrite type may be dependent on precise levels of nectin-3 expression. ...
Background
Developing cortical neurons express a tightly choreographed sequence of cytoskeletal and transmembrane proteins to form and strengthen specific synaptic connections during circuit formation. Nectin-3 is a cell-adhesion molecule with previously described roles in synapse formation and maintenance. This protein and its binding partner, nectin-1, are selectively expressed in upper-layer neurons of mouse visual cortex, but their role in the development of cortical circuits is unknown.
Methods
Here we block nectin-3 expression (via shRNA) or overexpress nectin-3 in developing layer 2/3 visual cortical neurons using in utero electroporation. We then assay dendritic spine densities at three developmental time points: eye opening (postnatal day (P)14), one week following eye opening after a period of heightened synaptogenesis (P21), and at the close of the critical period for ocular dominance plasticity (P35).
Results
Knockdown of nectin-3 beginning at E15.5 or ~ P19 increased dendritic spine densities at P21 or P35, respectively. Conversely, overexpressing full length nectin-3 at E15.5 decreased dendritic spine densities when all ages were considered together. The effects of nectin-3 knockdown and overexpression on dendritic spine densities were most significant on proximal secondary apical dendrites. Interestingly, an even greater decrease in dendritic spine densities, particularly on basal dendrites at P21, was observed when we overexpressed nectin-3 lacking its afadin binding domain.
Conclusion
These data collectively suggest that the proper levels and functioning of nectin-3 facilitate normal synapse formation after eye opening on apical and basal dendrites in layer 2/3 of visual cortex.
... In both humans and mice, slow-wave activity declines from early adolescence to adulthood [55]. This developmental decrease in slow-wave activity does not account for the changes in dendritic spine density in the mouse frontal cortex [56]. ...
Synaptic plasticity is important for learning and memory. With increasing evidence linking sleep states to changes in synaptic strength, an emerging view is that sleep promotes learning and memory by facilitating experience-induced synaptic plasticity. In this review, we summarize the recent progress on the function of sleep in regulating cortical synaptic plasticity. Specifically, we outline the electroencephalogram signatures of sleep states (e.g. slow-wave sleep, rapid eye movement sleep, spindles), sleep state-dependent changes in gene and synaptic protein expression, synaptic morphology, and neuronal and network activity. We highlight studies showing that post-experience sleep potentiates experience-induced synaptic changes and discuss the potential mechanisms that may link sleep-related brain activity to synaptic structural remodelling. We conclude that both synapse formation or strengthening and elimination or weakening occur across sleep. This sleep-dependent synaptic plasticity plays an important role in neuronal circuit refinement during development and after learning, while sleep disorders may contribute to or exacerbate the development of common neurological diseases.
This article is part of the Theo Murphy meeting issue ‘Memory reactivation: replaying events past, present and future’.
