Emergence of layer IV barrel cytoarchitecture is delayed in somatosensory cortex of GAP-43 deficient mice following delayed development of dendritic asymmetry

The emergence of barrel cytoarchitecture in mouse somatosensory cortex is extremely well defined. However, mechanisms underlying the development of this cellular organization are not completely understood. While it is generally accepted that hollows emerge via passive displacement of cortical cells by dense thalamocortical afferent clusters in barrel centers, it is not known what causes cellular segregation of barrel sides and septa. Here, we hypothesized that the emergence of sides and septa is related to the progressive asymmetry of dendrites from the cells of the barrel side toward the barrel hollow during development. We tested this hypothesis in the barrel cortex of growth-associated protein-43 heterozygous mice (GAP43 (+/?) mice) that display a 2-day delay in retraction of septally oriented dendrites compared to (+/+) littermates. We predicted that this delayed retraction would result in a subsequent 2-day delay in the emergence of barrel sides and septa. Using cresyl violet staining of barrel cortex, we found that initial emergence of hollows was not different between GAP43 (+/?) mice and (+/+) littermate controls. However, the emergence of sides and septa was delayed by 2 days, supporting our hypothesis that the emergence of barrel sides and septa is related to, and perhaps reliant upon, the developmental step of dendritic orientation toward barrel hollows. This process, which is mechanistically distinct from the emergence of barrel hollows, is likely due to both active and passive events resulting from asymmetric cell orientation.     

The Primary Visual Cortex Is Differentially Modulated by Stimulus-Driven and Top-Down Attention

Selective attention can be focused either volitionally, by top-down signals derived from task demands, or automatically, by bottom-up signals from salient stimuli. Because the brain mechanisms that underlie these two attention processes are poorly understood, we recorded local field potentials (LFPs) from primary visual cortical areas of cats as they performed stimulus-driven and anticipatory discrimination tasks. Consistent with our previous observations, in both tasks, we found enhanced beta activity, which we have postulated may serve as an attention carrier. We characterized the functional organization of task-related beta activity by (i) cortical responses (EPs) evoked by electrical stimulation of the optic chiasm and (ii) intracortical LFP correlations. During the anticipatory task, peripheral stimulation that was preceded by high-amplitude beta oscillations evoked large-amplitude EPs compared with EPs that followed low-amplitude beta. In contrast, during the stimulus-driven task, cortical EPs preceded by high-amplitude beta oscillations were, on average, smaller than those preceded by low-amplitude beta. Analysis of the correlations between the different recording sites revealed that beta activation maps were heterogeneous during the bottom-up task and homogeneous for the top-down task. We conclude that bottom-up attention activates cortical visual areas in a mosaic-like pattern, whereas top-down attentional modulation results in spatially homogeneous excitation.     

Plasticity and evolution in correlated suites of traits

When organisms are faced with new or changing environments, a central challenge is the coordination of adaptive shifts in many different phenotypic traits. Relationships among traits may facilitate or constrain evolutionary responses to selection, depending on whether the direction of selection is aligned or opposed to the pattern of trait correlations. Attempts to predict evolutionary potential in correlated traits generally assume that correlations are stable across time and space; however, increasing evidence suggests that this may not be the case, and flexibility in trait correlations could bias evolutionary trajectories. We examined genetic and environmental influences on variation and covariation in a suite of behavioural traits to understand if and how flexibility in trait correlations influences adaptation to novel environments. We tested the role of genetic and environmental influences on behavioural trait correlations by comparing Trinidadian guppies (Poecilia reticulata) historically adapted to high‐ and low‐predation environments that were reared under native and non‐native environmental conditions. Both high‐ and low‐predation fish exhibited increased behavioural variance when reared under non‐native vs. native environmental conditions, and rearing in the non‐native environment shifted the major axis of variation among behaviours. Our findings emphasize that trait correlations observed in one population or environment may not predict correlations in another and that environmentally induced plasticity in correlations may bias evolutionary divergence in novel environments.     

Chronic optical access through a polished and reinforced thinned skull

We present a method to form an optical window in the mouse skull that spans millimeters and is stable for months without causing brain inflammation. This enabled us to repeatedly image blood flow in cortical capillaries of awake mice and determine long-range correlations in speed. We also repeatedly imaged dendritic spines, microglia and angioarchitecture, as well as used illumination to drive motor output via optogenetics and induce microstrokes via photosensitizers.     

Developmental neuroethology of insect metamorphosis.

During metamorphosis, the insect nervous system must change to accomodate alterations in body form and behavior. Studies primarily on moths have shown that these changes involve the death of some larval neurons, the conservation and remodeling of others, and the maturation of new, adult-specific cells. The motor and sensory sides of the adult CNS vary in this regard with the former being constructed primarily from remodeled larval components, whereas the latter arises primarily from new neurons. Neuronal remodeling has received considerable attention. Larval-specific dendritic fields are pruned back during the larval-pupal transition, followed by the sprouting of adult-specific dendrites. Simple reflexes have been used to correlate these neuronal changes with the acquisition or loss of particular behaviors. The loss of the proleg retraction reflex is associated with the regression of the dendritic arbors of the proleg motoneurons. By contrast, expansion of axon arbors of the gin-trap afferents is necessary, but not sufficient, for the assembly of the gin-trap reflex in the pupal stage. The stretch receptor reflex provides a third example in which a new dendritic field in the adult form of a neuron is associated with new adult-specific connections. Interestingly, these connections are masked by persisting larval contacts until the emergence of the adult moth. For the metamorphosis of more complex behavioral circuits, some, such as that for flight behavior, seem to be assembled de novo, whereas others, like that for adult ecdysis behavior, show conservation of some circuit elements from the larval stage but with the superposition of some adult-specific components.     

Class-specific features of neuronal wiring

Brain function relies on specificity of synaptic connectivity patterns among different classes of neurons. Yet, the substrates of specificity in complex neuropil remain largely unknown. We search for imprints of specificity in the layout of axonal and dendritic arbors from the rat neocortex. An analysis of 3D reconstructions of pairs consisting of pyramidal cells (PCs) and GABAergic interneurons (GIs) revealed that the layout of GI axons is specific. This specificity is manifested in a relatively high tortuosity, small branch length of these axons, and correlations of their trajectories with the positions of postsynaptic neuron dendrites. Axons of PCs show no such specificity, usually taking a relatively straight course through neuropil. However, wiring patterns among PCs hold a large potential for circuit remodeling and specificity through growth and retraction of dendritic spines. Our results define distinct class-specific rules in establishing synaptic connectivity, which could be crucial in formulating a canonical cortical circuit.     

Experience-driven axon retraction without binocular imbalance in developing visual cortex

Refinement of the neural circuit during brain maturation is regulated by experience-driven neural activity. In the mammalian visual cortex, monocular visual deprivation (MD) in the early postnatal life causes a significant loss of cortical responses to a deprived eye and the retraction of input axons serving the deprived eye. A competitive interaction between inputs serving both eyes has been supposed to underlie the effects of MD because the loss of cortical response is much weaker when both eyes are deprived of vision. Also, the input axons do not retract after binocular deprivation. Here, we report that uncorrelated activity between presynaptic and postsynaptic neurons can solely lead to the retraction of geniculocortical axons in the absence of activity imbalance between two inputs. We analyzed the morphology of geniculocortical axons in a pharmacologically inhibited visual cortex of animals with normal vision and of binocularly deprived animals. In the normal vision animals, the axonal arbors in the inhibited cortex showed robust retraction. On the other hand, the arbors in binocularly deprived animals remained mostly intact. These results suggest that a homosynaptic associative mechanism, rather than a heterosynaptic competition between inputs, may play an important role in experience-driven axon retraction.     

Combined Role of Seizure-Induced Dendritic Morphology Alterations and Spine Loss in Newborn Granule Cells with Mossy Fiber Sprouting on the Hyperexcitability of a Computer Model of the Dentate Gyrus

Temporal lobe epilepsy strongly affects hippocampal dentate gyrus granule cells morphology. These cells exhibit seizure-induced anatomical alterations including mossy fiber sprouting, changes in the apical and basal dendritic tree and suffer substantial dendritic spine loss. The effect of some of these changes on the hyperexcitability of the dentate gyrus has been widely studied. For example, mossy fiber sprouting increases the excitability of the circuit while dendritic spine loss may have the opposite effect. However, the effect of the interplay of these different morphological alterations on the hyperexcitability of the dentate gyrus is still unknown. Here we adapted an existing computational model of the dentate gyrus by replacing the reduced granule cell models with morphologically detailed models coming from three-dimensional reconstructions of mature cells. The model simulates a network with 10% of the mossy fiber sprouting observed in the pilocarpine (PILO) model of epilepsy. Different fractions of the mature granule cell models were replaced by morphologically reconstructed models of newborn dentate granule cells from animals with PILO-induced Status Epilepticus, which have apical dendritic alterations and spine loss, and control animals, which do not have these alterations. This complex arrangement of cells and processes allowed us to study the combined effect of mossy fiber sprouting, altered apical dendritic tree and dendritic spine loss in newborn granule cells on the excitability of the dentate gyrus model. Our simulations suggest that alterations in the apical dendritic tree and dendritic spine loss in newborn granule cells have opposing effects on the excitability of the dentate gyrus after Status Epilepticus. Apical dendritic alterations potentiate the increase of excitability provoked by mossy fiber sprouting while spine loss curtails this increase.     

Local cortical interactions determine the form of cortical plasticity.

Competitive interactions between left and right eye inputs to visual cortex during development are usually explained by the thalamocortical axons competing more or less well for cortical territory during retraction into eye specific domains. Here we review the evidence for competitive and co-operative interactions between cortical columns in barrel cortex which are present several weeks after retraction of thalamocortical axons into barrels. Sensory responses in barrel cortex can be altered by a period of vibrissa deprivation. It was found that responses to previously deprived vibrissae (that had been allowed to regrow) were depressed more if neighboring vibrissae were spared than if all vibrissae were removed simultaneously. Depression of the deprived vibrissa response was greater the closer the cell lay to a spared barrel. It was also found that spared vibrissae responses were potentiated more if several neighboring vibrissae were left intact than if only a single vibrissae was spared. These results suggest a mechanism of cooperative potentiation, perhaps due to intracortical summation of excitation evoked by neighbouring vibrissa stimulation. Thalamic responses to vibrissa stimulation were unaffected by deprivation indicating a cortical origin. One of the consequences of deprivation was that the speed of transmission between barrels was increased for spared and decreased for deprived vibrissa. These results imply that inherent interactions between cortical columns give rise to a property of competition and co-operativity which amplify the effects of sensory deprivation.     

Life-history variation in relation to time constraints in a damselfly

Although variation within populations in plasticity to time constraints is expected with regard to hatching date, empirical studies are largely lacking. We studied life-history responses to time constraints manipulated by photoperiod and associated with hatching date in larvae of the damselfly Lestes viridis for two populations with a different hydroperiod. In a common garden experiment, early- and late-hatched larvae from both populations were reared at two photoperiods mimicking the start and the end of the egg-hatching season. In a reciprocal transplant experiment, early- and late-hatched larvae from both populations were reared in both ponds. In all these experiments, larvae were reared from egg hatching until adult emergence. Within both populations, larvae reared at the photoperiod indicating a late time point in the growing season, reduced development time to compensate for their perceived shorter development period. Growth rate, however, did not respond to photoperiod, resulting in a lower mass at emergence. As expected, both in the laboratory and in the field, larvae from eggs that hatched later in the season generally had a shorter development time and a faster growth rate, resulting in a higher mass at emergence compared to early-hatched larvae. This may explain the intriguing seasonal increase in mass at emergence in this species, and affect the predictions of optimality models. None of these life-history responses differed between the two populations, despite clear differences in time constraints linked to hydroperiod, suggesting the robustness of the observed patterns. Given the ubiquity of asynchronous hatching in nature, and the adaptive value of the observed differences between early- and late-hatched larvae, we expect the effects of hatching date on life-history plasticity to be widespread.     

Chondroitin sulfate proteoglycans down-regulate spine formation in cortical neurons by targeting tropomyosin-related kinase B (TrkB) protein

Chondroitin sulfate proteoglycans (CSPGs) are components of the extracellular matrix that inhibit axonal sprouting and experience-dependent plasticity. Although protein-tyrosine phosphatase σ (PTPσ) has been proven to be a receptor for CSPGs, its downstream signaling has remained a mystery. Here, we show that CSPGs target and dephosphorylate tropomyosin-related kinase B, the receptor of brain-derived neurotrophic factor (BDNF), via PTPσ in embryonic cortical neurons in vitro. Whereas BDNF promoted dendritic spine formation in embryonic cortical neurons, CSPGs abolished the effects of BDNF and eliminated existing dendritic spines when BDNF was present. The latter effect was dependent on the p75 receptor, presumably because BDNF binding to the p75 receptor elicits elimination of dendritic spines. These results suggest that the inhibitory activity of CSPGs on dendritic spine formation operates through the targeting of neurotrophins at the receptor level.     

A critical role for system A amino acid transport in the regulation of dendritic development by brain-derived neurotrophic factor (BDNF)

Dendritic development is essential for the establishment of a functional nervous system. Among factors that control dendritic development, brain-derived neurotrophic factor (BDNF) has been shown to regulate dendritic length and complexity of cortical neurons. However, the cellular and molecular mechanisms that underlie these effects remain poorly understood. In this study, we examined the role of amino acid transport in mediating the effects of BDNF on dendritic development. We show that BDNF increases System A amino acid transport in cortical neurons by selective up-regulation of the sodium-coupled neutral amino acid transporter (SNAT)1. Up-regulation of SNAT1 expression and System A activity is required for the effects of BDNF on dendritic growth and branching of cortical neurons. Further analysis revealed that induction of SNAT1 expression and System A activity by BDNF is necessary in particular to enhance synthesis of tissue-type plasminogen activator, a protein that we demonstrate to be essential for the effects of BDNF on cortical dendritic morphology. Together, these data reveal that stimulation of neuronal differentiation by BDNF requires the up-regulation of SNAT1 expression and System A amino acid transport to meet the increased metabolic demand associated with the enhancement of dendritic growth and branching.     

Calcium control of triphasic hippocampal STDP

Synaptic plasticity is believed to represent the neural correlate of mammalian learning and memory function. It has been demonstrated that changes in synaptic conductance can be induced by approximately synchronous pairings of pre- and post- synaptic action potentials delivered at low frequencies. It has also been established that NMDAr-dependent calcium influx into dendritic spines represents a critical signal for plasticity induction, and can account for this spike-timing dependent plasticity (STDP) as well as experimental data obtained using other stimulation protocols. However, subsequent empirical studies have delineated a more complex relationship between spike-timing, firing rate, stimulus duration and post-synaptic bursting in dictating changes in the conductance of hippocampal excitatory synapses. Here, we present a detailed biophysical model of single dendritic spines on a CA1 pyramidal neuron, describe the NMDAr-dependent calcium influx generated by different stimulation protocols, and construct a parsimonious model of calcium driven kinase and phosphatase dynamics that dictate the probability of stochastic transitions between binary synaptic weight states in a Markov model. We subsequently demonstrate that this approach can account for a range of empirical observations regarding the dynamics of synaptic plasticity induced by different stimulation protocols, under regimes of pharmacological blockade and metaplasticity. Finally, we highlight the strengths and weaknesses of this parsimonious, unified computational synaptic plasticity model, discuss differences between the properties of cortical and hippocampal plasticity highlighted by the experimental literature, and the manner in which further empirical and theoretical research might elucidate the cellular basis of mammalian learning and memory function.     

Effects of chronic iTBS‐rTMS and enriched environment on visual cortex early critical period and visual pattern discrimination in dark‐reared rats

Early cortical critical period resembles a state of enhanced neuronal plasticity enabling the establishment of specific neuronal connections during first sensory experience. Visual performance with regard to pattern discrimination is impaired if the cortex is deprived from visual input during the critical period. We wondered how unspecific activation of the visual cortex before closure of the critical period using repetitive transcranial magnetic stimulation (rTMS) could affect the critical period and the visual performance of the experimental animals. Would it cause premature closure of the plastic state and thus worsen experience‐dependent visual performance, or would it be able to preserve plasticity? Effects of intermittent theta‐burst stimulation (iTBS) were compared with those of an enriched environment (EE) during dark‐rearing (DR) from birth. Rats dark‐reared in a standard cage showed poor improvement in a visual pattern discrimination task, while rats housed in EE or treated with iTBS showed a performance indistinguishable from rats reared in normal light/dark cycle. The behavioral effects were accompanied by correlated changes in the expression of brain‐derived neurotrophic factor (BDNF) and atypical PKC (PKCζ/PKMζ), two factors controlling stabilization of synaptic potentiation. It appears that not only nonvisual sensory activity and exercise but also cortical activation induced by rTMS has the potential to alleviate the effects of DR on cortical development, most likely due to stimulation of BDNF synthesis and release. As we showed previously, iTBS reduced the expression of parvalbumin in inhibitory cortical interneurons, indicating that modulation of the activity of fast‐spiking interneurons contributes to the observed effects of iTBS. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 19–33, 2016     

Tactile stimulation during artificial rearing influences adult function and morphology in a sexually dimorphic neuromuscular system

Maternal licking of rat pups affects the development of the spinal nucleus of the bulbocavernosus (SNB), a sexually dimorphic motor nucleus that controls penile reflexes involved with copulation. Maternal licking influences SNB motoneurons, with reductions in licking producing decreased SNB number, size, and dendritic length in adulthood. Reduced maternal licking also produces deficits in adult male copulatory behavior. In this experiment, we used an artificial rearing paradigm to assess the potential role of tactile stimulation in mediating the effects of maternal licking on the SNB neuromuscular system. During artificial rearing, pups were stroked with a paintbrush to mimic maternal licking, receiving low, medium, or high levels of daily stimulation. In adulthood, ex copula penile reflex behavior was tested and the morphology of SNB motoneurons assessed. SNB motoneurons were retrogradely labeled with cholera toxin-conjugated HRP and dendritic arbor was reconstructed in three dimensions. Animals that received low levels of stimulation showed deficits in penile reflexes relative to maternally reared controls, including a longer latency to erection, fewer cup erections, and fewer erection clusters. SNB dendritic morphology was also shaped by stimulation condition, with animals that received low or medium levels of stimulation showing an average 27% reduction in dendritic length. In addition, several reflex behaviors were significantly correlated with dendritic length, including latency to first erection, percent of cup erections, and number of erection clusters. These results suggest that tactile stimulation provided by maternal licking mediates some of the effects of maternal care on the development of male copulatory behavior.     

Regulation of rho GTPases by crosstalk and neuronal activity in vivo

Proper development of neurons depends on synaptic activity, but the mechanisms of activity-dependent neuronal growth are not well understood. The small GTPases, RhoA, Rac, and Cdc42, regulate neuronal morphogenesis by controlling the assembly and stability of the actin cytoskeleton. We report an in situ method to determine endogenous Rho GTPase activity in intact Xenopus brain. We use this method to provide evidence for crosstalk between Rho GTPases in optic tectal cells. Moreover, crosstalk between the Rho GTPases appears to affect dendritic arbor development in vivo. Finally, we demonstrate that optic nerve stimulation regulates Rho GTPase activity in a glutamate receptor-dependent manner. These data suggest a link between glutamate receptor function, Rho GTPase activity, and dendritic arbor growth in the intact animal.     

Experience-Driven Axon Retraction in the Pharmacologically Inactivated Visual Cortex Does Not Require Synaptic Transmission

Background

Experience during early postnatal development plays an important role in the refinement of specific neural connections in the brain. In the mammalian visual system, altered visual experiences induce plastic adaptation of visual cortical responses and guide rearrangements of afferent axons from the lateral geniculate nucleus. Previous studies using visual deprivation demonstrated that the afferents serving an open eye significantly retract when cortical neurons are pharmacologically inhibited by applying a γ-aminobutyric acid type A receptor agonist, muscimol, whereas those serving a deprived eye are rescued from retraction, suggesting that presynaptic activity can lead to the retraction of geniculocortical axons in the absence of postsynaptic activity. Because muscimol application suppresses the spike activity of cortical neurons leaving transmitter release intact at geniculocortical synapses, local synaptic interaction may underlie the retraction of active axons in the inhibited cortex.

Method and Findings

New studies reported here determined whether experience-driven axon retraction can occur in the visual cortex inactivated by blocking synaptic inputs. We inactivated the primary visual cortex of kittens by suppressing synaptic transmission with cortical injections of botulinum neurotoxin type E, which cleaves a synaptic protein, SNAP-25, and blocks transmitter release, and examined the geniculocortical axon morphology in the animals with normal vision and those deprived of vision binocularly. We found that afferent axons in the animals with normal vision showed a significant retraction in the inactivated cortex, as similarly observed in the muscimol-treated cortex, whereas the axons in the binocularly deprived animals were preserved.

Conclusions

Therefore, the experience-driven axon retraction in the inactivated cortex can proceed in the absence of synaptic transmission. These results suggest that presynaptic mechanisms play an important role in the experience-driven refinement of geniculocortical axons.     

Low Intensity Repetitive Transcranial Magnetic Stimulation Does Not Induce Cell Survival or Regeneration in a Mouse Optic Nerve Crush Model

Low intensity repetitive Transcranial Magnetic Stimulation (LI-rTMS), a non-invasive form of brain stimulation, has been shown to induce structural and functional brain plasticity, including short distance axonal sprouting. However, the potential for LI-rTMS to promote axonal regeneration following neurotrauma has not been investigated. This study examined the effect of LI-rTMS on retinal ganglion cell (RGC) survival, axon regeneration and levels of BDNF in an optic nerve crush neurotrauma model. Adult C57Bl/6J mice received a unilateral intraorbital optic nerve crush. Mice received 10 minutes of sham (handling control without stimulation) (n=6) or LI-rTMS (n = 8) daily stimulation for 14 days to the operated eye. Immunohistochemistry was used to assess RGC survival (β-3 Tubulin) and axon regeneration across the injury (GAP43). Additionally, BDNF expression was quantified in a separate cohort by ELISA in the retina and optic nerve of injured (optic nerve crush) (sham n = 5, LI-rTMS n = 5) and non-injured mice (sham n = 5, LI-rTMS n = 5) that received daily stimulation as above for 7 days. Following 14 days of LI-rTMS there was no significant difference in mean RGC survival between sham and treated animals (p>0.05). Also, neither sham nor LI-rTMS animals showed GAP43 positive labelling in the optic nerve, indicating that regeneration did not occur. At 1 week, there was no significant difference in BDNF levels in the retina or optic nerves between sham and LI-rTMS in injured or non-injured mice (p>0.05). Although LI-rTMS has been shown to induce structural and molecular plasticity in the visual system and cerebellum, our results suggest LI-rTMS does not induce neuroprotection or regeneration following a complete optic nerve crush. These results help define the therapeutic capacity and limitations of LI-rTMS in the treatment of neurotrauma.     

Glutamate-Bound NMDARs Arising from In Vivo-like Network Activity Extend Spatio-temporal Integration in a L5 Cortical Pyramidal Cell Model

In vivo, cortical pyramidal cells are bombarded by asynchronous synaptic input arising from ongoing network activity. However, little is known about how such ‘background’ synaptic input interacts with nonlinear dendritic mechanisms. We have modified an existing model of a layer 5 (L5) pyramidal cell to explore how dendritic integration in the apical dendritic tuft could be altered by the levels of network activity observed in vivo. Here we show that asynchronous background excitatory input increases neuronal gain and extends both temporal and spatial integration of stimulus-evoked synaptic input onto the dendritic tuft. Addition of fast and slow inhibitory synaptic conductances, with properties similar to those from dendritic targeting interneurons, that provided a ‘balanced’ background configuration, partially counteracted these effects, suggesting that inhibition can tune spatio-temporal integration in the tuft. Excitatory background input lowered the threshold for NMDA receptor-mediated dendritic spikes, extended their duration and increased the probability of additional regenerative events occurring in neighbouring branches. These effects were also observed in a passive model where all the non-synaptic voltage-gated conductances were removed. Our results show that glutamate-bound NMDA receptors arising from ongoing network activity can provide a powerful spatially distributed nonlinear dendritic conductance. This may enable L5 pyramidal cells to change their integrative properties as a function of local network activity, potentially allowing both clustered and spatially distributed synaptic inputs to be integrated over extended timescales.     

ESCRT-III dysfunction causes autophagosome accumulation and neurodegeneration

Defects in the endosomal-lysosomal pathway have been implicated in a number of neurodegenerative disorders. A key step in the endocytic regulation of transmembrane proteins occurs in a subset of late-endosomal compartments known as multivesicular bodies (MVBs), whose formation is controlled by endosomal sorting complex required for transport (ESCRT). The roles of ESCRT in dendritic maintenance and neurodegeneration remain unknown. Here, we show that mSnf7-2, a key component of ESCRT-III, is highly expressed in most mammalian neurons. Loss of mSnf7-2 in mature cortical neurons caused retraction of dendrites and neuronal cell loss. mSnf7-2 binds to CHMP2B, another ESCRT-III subunit, in which a rare dominant mutation is associated with frontotemporal dementia linked to chromosome 3 (FTD3). Ectopic expression of the mutant protein CHMP2B(Intron5) also caused dendritic retraction prior to neurodegeneration. CHMP2B(Intron5) was associated more avidly than CHMP2B(WT) with mSnf7-2, resulting in sequestration of mSnf7-2 in ubiquitin-positive late-endosomal vesicles in cortical neurons. Moreover, loss of mSnf7-2 or CHMP2B(Intron5) expression caused the accumulation of autophagosomes in cortical neurons and flies. These findings indicate that ESCRT-III dysfunction is associated with the autophagy pathway, suggesting a novel neurodegeneration mechanism that may have important implications for understanding FTD and other age-dependent neurodegenerative diseases.