Search

We examine the development of amblyopia and the effectiveness of conventional and emerging therapies through the lens of the Bienenstock, Cooper, and Munro (BCM) theory of synaptic modification.The BCM theory posits metaplastic adjustment in the threshold for synaptic potentiation, governed by prior neuronal activity. Viewing established clinical principles of amblyopia treatment from the perspective of the BCM theory, occlusion, blur, or release of interocular suppression reduce visual cortical activity in the amblyopic state to lower the modification threshold and enable amblyopic eye strengthening. Although efficacy of these treatment approaches declines with age, significant loss of vision in the fellow eye by damage or disease can trigger visual acuity improvements in the amblyopic eye of adults. Likewise, reversible retinal inactivation stimulates recovery of amblyopic eye visual function in adult mice and cats.Conventional and emerging amblyopia treatment responses abide by the framework of BCM theory. Preclinical studies support that the dramatic reduction in cortical activity accompanying temporary retinal silencing can promote recovery from amblyopia even in adulthood, highlighting a promising therapeutic avenue.

The visual cliff assay (VCA) has been used in multiple animal models including humans to assess stereopsis, the pinnacle percept of binocular function that is markedly disrupted in amblyopia. Amblyopia is a neurodevelopmental disorder of the visual system caused by refractive error, strabismus, or obscuration of the visual axis during infancy and early childhood. While the current standard of care can improve visual acuity in the amblyopic eye, gains are infrequently associated with improvements in stereoscopic depth perception and typically only achieved when treatment is initiated in early childhood. The mouse model of amblyopia induced by monocular deprivation (MD) is a powerful tool to study the mechanistic pathophysiology of this disorder and test novel therapeutics. However, to date, only one study has used the VCA to assess the effects of MD in mice in a limited capacity. Advantages of the VCA include no need for operant conditioning or training, completion in minutes, and minimal equipment. We comprehensively characterize and validate fundamental aspects of the VCA including test-retest reliability and contributions of binocularity using multiple monocular and binocular manipulations with clinically relevant paradigms. After long-term (3 weeks) MD, mice exhibit reduced predilection for the safe side, decreased latency to cross to the cliff side, and more crosses to the cliff side compared to sham littermate controls. Our data demonstrate that the VCA can detect binocular deficits in amblyopia but with important limitations that guide how the VCA should be applied to read out binocular function in both mechanistic and therapeutic studies in mice.

PurposeThe effectiveness of traditional amblyopia therapies is largely restricted to childhood. However, recovery in adulthood is possible following removal or vision-limiting disease of the fellow eye. Study of this phenomenon is currently limited to isolated case reports and a few case series, with reported incidence ranging from 19-77%1–5. We set out to accomplish two distinct goals: (1) define the incidence of clinically meaningful recovery and (2) elucidate the clinical features associated with greater amblyopic eye gains.MethodsA systematic review of 3 literature databases yielded 23 reports containing 109 cases of patients ≥18 years old with unilateral amblyopia and vision-limiting fellow eye pathology.ResultsStudy 1 revealed 25/42 (59.5%) of adult patients gained ≥2 logMAR lines in the amblyopia eye after FE vision loss. The overall degree of improvement is clinically meaningful (median 2.6 logMAR lines). Study 2 showed that for cases with amblyopic eye visual acuity improvement, recovery occurs within 12 months of initial loss of fellow eye vision. Regression analysis revealed that younger age, worse baseline acuity in the amblyopic eye, and worse vision in the fellow eye independently conferred greater gains in amblyopic eye visual acuity. Recovery occurs across amblyopia types and fellow eye pathologies, although disease entities affecting fellow eye retinal ganglion cells demonstrate shorter latencies to recovery.ConclusionsAmblyopia recovery after fellow eye injury demonstrates that the adult brain harbors the neuroplastic capacity for clinically meaningful recovery, which could potentially be harnessed by novel approaches to treat adults with amblyopia.

Recovery from amblyopia in adulthood after fellow eye (FE) vision loss is a well-known phenomenon. Incidence of recovery varies widely following different FE pathologies, and the rate of recovery after FE ischemic optic neuropathy (ION) has not been examined. We aimed to determine the frequency and degree of improvement in amblyopic eye (AE) visual function after ION in the FE.We performed a retrospective chart review of patients between 2007 and 2021 confirmed to have amblyopia and ischemic optic neuropathy in different eyes. Patients with unstable ocular pathology potentially limiting vision were excluded. We compared the best-corrected visual acuity (VA) in each eye before and after FE ION over time. For patients with available data, we examined change in perimetric performance over time.Among the 12 patients who met the inclusion criteria (mean age 67 ± 8 years), 9 (75%) improved ≥1 line and 2 (17%) improved ≥3 lines. The median time from ION symptom onset to maximal improvement was 6 months (range: 2-101 months). Reliable perimetric data were available for 6 patients. Mean sensitivity improved in the AE for all patients, with mean improvement of 1.9 ± 1.1 dB. There was no correspondence between foci of ION-related field loss and gains in field sensitivity in the AE.A high proportion of patients with amblyopia and contralateral ION experience improvement in AEVA. Modest gains in perimetric sensitivity in the AE may accompany FE ION. These findings support the view that residual plasticity in the adult visual cortex can be tapped to support functional improvement in amblyopia.

In mouse primary visual cortex (V1), familiar stimuli evoke significantly altered responses when compared to novel stimuli. This stimulus-selective response plasticity (SRP) was described originally as an increase in the magnitude of visual evoked potentials (VEPs) elicited in layer (L) 4 by familiar phase-reversing grating stimuli. SRP is dependent on NMDA receptors (NMDAR) and has been hypothesized to reflect potentiation of thalamocortical synapses in L4. However, recent evidence indicates that the synaptic modifications that manifest as SRP do not occur on L4 principal cells. To shed light on where and how SRP is induced and expressed, the present study had three related aims: (1) to confirm that NMDAR are required specifically in glutamatergic principal neurons of V1, (2) to investigate the consequences of deleting NMDAR specifically in L6, and (3) to use translaminar electrophysiological recordings to characterize SRP expression in different layers of V1. We find that knockout of NMDAR in L6 principal neurons disrupts SRP. Current-source density analysis of the VEP depth profile shows augmentation of short latency current sinks in layers 3, 4 and 6 in response to phase reversals of familiar stimuli. Multiunit recordings demonstrate that increased peak firing occurs to in response to phase reversals of familiar stimuli across all layers, but that activity between phase reversals is suppressed. Together, these data reveal important aspects of the underlying phenomenology of SRP and generate new hypotheses for the expression of experience-dependent plasticity in V1.Significance StatementRepeated exposure to stimuli that portend neither reward nor punishment leads to behavioral habituation, enabling organisms to dedicate attention to novel or otherwise significant features of the environment. The neural basis of this process, which is so often dysregulated in neurological and psychiatric disorders, remains poorly understood. Learning and memory of stimulus familiarity can be studied in mouse visual cortex by measuring electrophysiological responses to simple phase-reversing grating stimuli. The current study advances knowledge of this process by documenting changes in visual evoked potentials, neuronal spiking activity, and oscillations in the local field potentials across all layers of mouse visual cortex. In addition, we identify a key contribution of a specific population of neurons in layer 6 of visual cortex.

During a critical period of postnatal life, monocular deprivation (MD) of kittens by eyelid closure reduces the size of neurons in layers of the dorsal lateral geniculate nucleus (dLGN) connected to the deprived eye, and shifts cortical ocular dominance in favor of the non-deprived eye, modeling deprivation amblyopia in humans. Following long-term MD, temporary retinal inactivation of the non-deprived eye with microinjection of tetrodotoxin can promote superior recovery from MD, and at older ages, in comparison to conventional occlusion therapy. This suggests that monocular inactivation (MI) is a more potent approach to producing neural plasticity than occlusion. In the current study we assessed the modification of neuron size in the dLGN as a means of measuring the impact of a brief period of MI imposed at different ages during postnatal development. The biggest impact of inactivation was observed when it occurred at the peak of the critical period for ocular dominance plasticity. The effect of MI was evident in both the binocular and monocular segments of the dLGN, distinguishing it from MD that produces changes only within the binocular segment. With increasing age, the capacity for inactivation to alter postsynaptic cell size diminished but was still significant beyond the classic critical period. In comparison to MD, inactivation consistently produced effects that were about double in magnitude, and inactivation exhibited efficacy to produce neural modifications at older ages than MD. Notwithstanding the large neural alterations precipitated by inactivation, its anatomical effects were remediated with a short period of binocular visual experience, and vision through the previously inactivated eye fully recovered after washout of TTX. Our results demonstrate that MI is a potent means of modifying the visual pathway, and does so beyond the age at which occlusion is effective. The magnitude and longevity of inactivation to evoke neural modification highlights its potential to ameliorate disorders of the visual system such as amblyopia.

Learning to recognize and filter familiar, irrelevant sensory stimuli eases the computational burden on the cerebral cortex. Inhibition is a candidate mechanism in this filtration process, and oscillations in the cortical local field potential (LFP) serve as markers of the engagement of different inhibitory neurons. We show here that LFP oscillatory activity in visual cortex is profoundly altered as male and female mice learn to recognize an oriented grating stimulus—low frequency (∼15 Hz peak) power sharply increases while high frequency (∼65 Hz peak) power decreases. These changes report recognition of the familiar pattern, as they disappear when the stimulus is rotated to a novel orientation. Two-photon imaging of neuronal activity reveals that parvalbumin-expressing inhibitory neurons disengage with familiar stimuli and reactivate to novelty, whereas somatostatin-expressing inhibitory neurons show opposing activity patterns. We propose a model in which the balance of two interacting interneuron circuits shifts as novel stimuli become familiar.Significance StatementHabituation, familiarity and novelty detection are fundamental cognitive processes that enable organisms to adaptively filter meaningless stimuli and focus attention on potentially important elements of their environment. We have shown that this process can be studied fruitfully in the mouse primary visual cortex by using simple grating stimuli for which novelty and familiarity are defined by orientation, and by measuring stimulus-evoked and continuous local field potentials. Altered event-related and spontaneous potentials, and deficient habituation, are well-documented features of several neurodevelopmental psychiatric disorders. The paradigm described here will be valuable to interrogate the origins of these signals and the meaning of their disruption more deeply.

BackgroundRecovery from amblyopia in adulthood following fellow eye (FE) vision loss is a well-known phenomenon. Incidence of recovery varies widely following different FE pathologies and rate of recovery following FE ischemic optic neuropathy (ION) has not been examined. We aimed to determine frequency and degree of improvement in amblyopic eye (AE) visual function following ION in the FE.MethodsWe performed a retrospective chart review of patients between 2007-2021 confirmed to have amblyopia and ischemic optic neuropathy in different eyes. Patients with unstable ocular pathology potentially limiting vision were excluded. We compared best-corrected visual acuity (VA) in each eye before and after FE ION over time. For patients with available data, we examined change in perimetric performance over time.ResultsAmong the 12 patients who met inclusion criteria (mean age 67±8 years), 9 (75%) improved ≥1 line and 2 (17%) improved ≥3 lines. Median time from ION symptom onset to maximal improvement was 6 months (range: 2-101 months). Reliable perimetric data were available for 6 patients. Mean sensitivity improved in the amblyopic eye for all patients, with a mean improvement of 1.9±1.1 dB. There was no correspondence between foci of ION-related field loss and gains in field sensitivity in the AE.ConclusionA high proportion of patients with amblyopia and contralateral ION experience improvement in their amblyopic eye. Modest gains in perimetric sensitivity in the AE may accompany FE ION. These findings support the view that residual plasticity in the adult visual cortex can be tapped to support functional improvement in amblyopia.

Stimulus-selective response plasticity (SRP) is a robust and lasting modification of primary visual cortex (V1) that occurs in response to exposure to novel visual stimuli. It is readily observed as a pronounced increase in the magnitude of visual evoked potentials (VEPs) recorded in response to phase-reversing grating stimuli in neocortical layer 4. The expression of SRP at the individual neuron level is equally robust, but the qualities vary depending on the neuronal type and how activity is measured. This form of plasticity is highly selective for stimulus features such as stimulus orientation, spatial frequency, and contrast. Several key insights into the significance and underlying mechanisms of SRP have recently been made. First, it occurs concomitantly and shares core mechanisms with behavioral habituation, indicating that SRP reflects the formation of long-term familiarity that can support recognition of innocuous stimuli. Second, SRP does not manifest within a recording session but only emerges after an off-line period of several hours that includes sleep. Third, SRP requires not only canonical molecular mechanisms of Hebbian synaptic plasticity within V1, but also the opposing engagement of two key subclasses of cortical inhibitory neuron: the parvalbumin- and somatostatin-expressing GABAergic interneurons. Fourth, pronounced shifts in the power of cortical oscillations from high frequency (gamma) to low frequency (alpha/beta) oscillations provide respective readouts of the engagement of these inhibitory neuronal subtypes following familiarization. In this article we will discuss the implications of these findings and the outstanding questions that remain to gain a deeper understanding of this striking form of experience-dependent plasticity.

Fragile X syndrome (FXS) is caused by silencing of the human FMR1 gene and is the leading monogenic cause of intellectual disability and autism. Abundant preclinical data indicated that negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5) might be efficacious in treating FXS in humans. Initial attempts to translate these findings in clinical trials have failed, but these failures provide the opportunity for new discoveries that will improve future trials. The emergence of acquired treatment resistance (“tolerance”) after chronic administration of mGluR5 NAMs is a potential factor in the lack of success. Here we confirm that FXS model mice display acquired treatment resistance after chronic treatment with the mGluR5 NAM CTEP in three assays commonly examined in the mouse model of FXS: (1) audiogenic seizure susceptibility, (2) sensory cortex hyperexcitability, and (3) hippocampal protein synthesis. Cross-tolerance experiments suggest that the mechanism of treatment resistance likely occurs at signaling nodes downstream of glycogen synthase kinase 3α (GSK3α), but upstream of protein synthesis. The rapid emergence of tolerance to CTEP begs the question of how previous studies showed an improvement in inhibitory avoidance (IA) cognitive performance after chronic treatment. We show here that this observation was likely explained by timely inhibition of mGluR5 during a critical period, as brief CTEP treatment in juvenile mice is sufficient to provide a persistent improvement of IA behavior measured many weeks later. These data will be important to consider when designing future fragile X clinical trials using compounds that target the mGluR5-to-protein synthesis signaling cascade.

Fragile X syndrome (FXS) is caused by silencing of the human FMR1 gene and is the leading monogenic cause of intellectual disability and autism. Abundant preclinical data indicated that negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5) might be efficacious in treating FXS in humans. Initial attempts to translate these findings in clinical trials have failed, but these failures provide the opportunity for new discoveries that will improve future trials. The emergence of acquired treatment resistance (“tolerance”) after chronic administration of mGluR5 NAMs is a potential factor in the lack of success. Here we confirm that FXS model mice display acquired treatment resistance after chronic treatment with the mGluR5 NAM CTEP in three assays commonly examined in the mouse model of FXS: (1) audiogenic seizure susceptibility, (2) sensory cortex hyperexcitability, and (3) hippocampal protein synthesis. Cross-tolerance experiments suggest that the mechanism of treatment resistance likely occurs at signaling nodes downstream of glycogen synthase kinase 3α (GSK3α), but upstream of protein synthesis. The rapid emergence of tolerance to CTEP begs the question of how previous studies showed an improvement in inhibitory avoidance (IA) cognitive performance after chronic treatment. We show here that this observation was likely explained by timely inhibition of mGluR5 during a critical period, as brief CTEP treatment in juvenile mice is sufficient to provide a persistent improvement of IA behavior measured many weeks later. These data will be important to consider when designing future fragile X clinical trials using compounds that target the mGluR5-to-protein synthesis signaling cascade.

Monocular deprivation early in development causes amblyopia, a severe visual impairment. Prognosis is poor if therapy is initiated after an early critical period. However, clinical observations have shown that recovery from amblyopia can occur later in life when the non-deprived (fellow) eye is removed. The traditional interpretation of this finding is that vision is improved simply by the elimination of interocular suppression in primary visual cortex, revealing responses to previously subthreshold input. However, an alternative explanation is that silencing activity in the fellow eye establishes conditions in visual cortex that enable the weak connections from the amblyopic eye to gain strength, in which case the recovery would persist even if vision is restored in the fellow eye. Consistent with this idea, we show here in cats and mice that temporary inactivation of the fellow eye is sufficient to promote a full and enduring recovery from amblyopia at ages when conventional treatments fail. Thus, connections serving the amblyopic eye are capable of substantial plasticity beyond the critical period, and this potential is unleashed by reversibly silencing the fellow eye.

The hippocampus and neocortex are theorized to be crucial partners in the formation of long-term memories. Here, we assess hippocampal involvement in two related forms of experience-dependent plasticity in the primary visual cortex (V1) of mice. Like control animals, those with hippocampal lesions exhibit potentiation of visually evoked potentials following passive daily exposure to a phase reversing oriented grating stimulus, which is accompanied by long-term habituation of a reflexive behavioral response. Thus, low-level recognition memory is formed independently of the hippocampus. However, response potentiation resulting from daily exposure to a fixed sequence of four oriented gratings is severely impaired in mice with hippocampal damage. A feature of sequence plasticity in V1 of controls, but absent in lesioned mice, is generation of predictive responses to an anticipated stimulus element when it is withheld or delayed. Thus, hippocampus is involved in encoding temporally structured experience, even in primary sensory cortex.

© 2020 The Author(s) In order to analyze how a signal transduction network converts cellular inputs into cellular outputs, ideally one would measure the dynamics of many signals within the network simultaneously. We found that, by fusing a fluorescent reporter to a pair of self-assembling peptides, it could be stably clustered within cells at random points, distant enough to be resolved by a microscope but close enough to spatially sample the relevant biology. Because such clusters, which we call signaling reporter islands (SiRIs), can be modularly designed, they permit a set of fluorescent reporters to be efficiently adapted for simultaneous measurement of multiple nodes of a signal transduction network within single cells. We created SiRIs for indicators of second messengers and kinases and used them, in hippocampal neurons in culture and intact brain slices, to discover relationships between the speed of calcium signaling, and the amplitude of PKA signaling, upon receiving a cAMP-driving stimulus.

Methods for one-photon fluorescent imaging of calcium dynamics in vivo are popular due to their ability to simultaneously capture the dynamics of hundreds of neurons across large fields of view, at a low equipment complexity and cost. In contrast to two-photon methods, however, one-photon methods suffer from higher levels of crosstalk between cell bodies and the surrounding neuropil, resulting in decreased signal-to-noise and artifactual correlations of neural activity. Here, we address this problem by engineering cell body-targeted variants of the fluorescent calcium indicator GCaMP6f. We screened fusions of GCaMP6f to both natural as well as engineered peptides, and identified fusions that localized GCaMP6f to within approximately 50 microns of the cell body of neurons in live mice and larval zebrafish. One-photon imaging of soma-targeted GCaMP6f in dense neural circuits reported fewer artifactual spikes from neuropil, increased signal-to-noise ratio, and decreased artifactual correlation across neurons. Thus, soma-targeting of fluorescent calcium indicators increases neuronal signal fidelity and may facilitate even greater usage of simple, powerful, one-photon methods of population imaging of neural calcium dynamics.

Copyright © 2020 The Authors, some rights reserved. Fragile X syndrome is caused by FMR1 gene silencing and loss of the encoded fragile X mental retardation protein (FMRP), which binds to mRNA and regulates translation. Studies in the Fmr1-/y mouse model of fragile X syndrome indicate that aberrant cerebral protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5) signaling contributes to disease pathogenesis, but clinical trials using mGluR5 inhibitors were not successful. Animal studies suggested that treatment with lithium might be an alternative approach. Targets of lithium include paralogs of glycogen synthase kinase 3 (GSK3), and nonselective small-molecule inhibitors of these enzymes improved disease phenotypes in a fragile X syndrome mouse model. However, the potential therapeutic use of GSK3 inhibitors has been hampered by toxicity arising from inhibition of both α and β paralogs. Recently, we developed GSK3 inhibitors with sufficient paralog selectivity to avoid a known toxic consequence of dual inhibition, that is, increased β-catenin stabilization. We show here that inhibition of GSK3α, but not GSK3β, corrected aberrant protein synthesis, audiogenic seizures, and sensory cortex hyperexcitability in Fmr1-/y mice. Although inhibiting either paralog prevented induction of NMDA receptor–dependent long-term depression (LTD) in the hippocampus, only inhibition of GSK3α impaired mGluR5-dependent and protein synthesis–dependent LTD. Inhibition of GSK3α additionally corrected deficits in learning and memory in Fmr1-/y mice; unlike mGluR5 inhibitors, there was no evidence of tachyphylaxis or enhanced psychotomimetic-induced hyperlocomotion. GSK3α selective inhibitors may have potential as a therapeutic approach for treating fragile X syndrome.

Primary visual cortex (V1) is the locus of numerous forms of experience-dependent plasticity. Restricting visual stimulation to one eye at a time has revealed that many such forms of plasticity are eye-specific, indicating that synaptic modification occurs prior to binocular integration of thalamocortical inputs. A common feature of these forms of plasticity is the requirement for NMDA receptor (NMDAR) activation in V1. We therefore hypothesized that NMDARs in cortical layer 4 (L4), which receives the densest thalamocortical input, would be necessary for all forms of NMDAR-dependent and input-specific V1 plasticity. We tested this hypothesis in awake mice using a genetic approach to selectively delete NMDARs from L4 principal cells. We found, unexpectedly, that both stimulus-selective response potentiation and potentiation of open-eye responses following monocular deprivation (MD) persist in the absence of L4 NMDARs. In contrast, MD-driven depression of deprived-eye responses was impaired in mice lacking L4 NMDARs, as was L4 long-term depression in V1 slices. Our findings reveal a crucial requirement for L4 NMDARs in visual cortical synaptic depression, and a surprisingly negligible role for them in cortical response potentiation. These results demonstrate that NMDARs within distinct cellular subpopulations support different forms of experience-dependent plasticity.

The immediate early geneArcis critical for maintenance of long-term memory. How Arc mediates this process remains unclear, but it has been proposed to sustain Hebbian synaptic potentiation, which is a key component of memory encoding. This form of plasticity is modelled experimentally by induction of long-term potentiation (LTP), which increases Arc mRNA and protein expression. However, mechanistic data implicates Arc in the endocytosis of AMPA-type glutamate receptors and the weakening of synapses. Here, we took a comprehensive approach to determine if Arc is necessary for hippocampal LTP. We find that Arc is not required for LTP maintenance and must regulate memory storage through alternative mechanisms.

Memory consolidation is thought to occur through protein synthesis-dependent synaptic plasticity mechanisms such as long-term potentiation (LTP). Dynamic changes in gene expression and epigenetic modifications underlie the maintenance of LTP. Similar mechanisms may mediate the storage of memory. Key plasticity genes, such as the immediate early geneArc, are induced by learning and by LTP induction. Mice that lack Arc have severe deficits in memory consolidation, and Arc has been implicated in numerous other forms of synaptic plasticity, including long-term depression and cell-to-cell signaling. Here, we take a comprehensive approach to determine if Arc is necessary for hippocampal LTP in male and female mice. Using a variety of Arc knock-out (KO) lines, we found that germline Arc KO mice show no deficits in CA1 LTP induced by high-frequency stimulation and enhanced LTP induced by theta-burst stimulation. Temporally restricting the removal of Arc to adult animals and spatially restricting it to the CA1 using Arc conditional KO mice did not have an effect on any form of LTP. Similarly, acute application of Arc antisense oligodeoxynucleotides had no effect on hippocampal CA1 LTP. Finally, the maintenance ofin vivoLTP in the dentate gyrus of Arc KO mice was normal. We conclude that Arc is not necessary for hippocampal LTP and may mediate memory consolidation through alternative mechanisms.SIGNIFICANCE STATEMENTThe immediate early gene Arc is critical for maintenance of long-term memory. How Arc mediates this process remains unclear, but it has been proposed to sustain Hebbian synaptic potentiation, which is a key component of memory encoding. This form of plasticity is modeled experimentally by induction of LTP, which increases Arc mRNA and protein expression. However, mechanistic data implicates Arc in the endocytosis of AMPA-type glutamate receptors and the weakening of synapses. Here, we took a comprehensive approach to determine if Arc is necessary for hippocampal LTP. We find that Arc is not required for LTP maintenance and may regulate memory storage through alternative mechanisms.

Changes in excitatory neuron and synapse structure have been recognized as a potential physical source of age-related cognitive decline. Despite the importance of inhibition to brain plasticity, little is known regarding aging-associated changes to inhibitory neurons. Here we test for age-related cellular and circuit changes to inhibitory neurons of mouse visual cortex. We find no substantial difference in inhibitory neuron number, inhibitory neuronal subtypes, or synapse numbers within the cerebral cortex of aged mice compared with younger adults. However, when comparing cortical interneuron morphological parameters, we find differences in complexity, suggesting that arbors are simplified in aged mice.In vivotwo-photon microscopy has previously shown that in contrast to pyramidal neurons, inhibitory interneurons retain a capacity for dendritic remodeling in the adult. We find that this capacity diminishes with age and is accompanied by a shift in dynamics from balanced branch additions and retractions to progressive prevalence of retractions, culminating in a dendritic arbor that is both simpler and more stable. Recording of visually evoked potentials shows that aging-related interneuron dendritic arbor simplification and reduced dynamics go hand in hand with loss of induced stimulus-selective response potentiation (SRP), a paradigm for adult visual cortical plasticity. Chronic treatment with the antidepressant fluoxetine reversed deficits in interneuron structural dynamics and restored SRP in aged animals. Our results support a structural basis for age-related impairments in sensory perception, and suggest that declines in inhibitory neuron structural plasticity during aging contribute to reduced functional plasticity.SIGNIFICANCE STATEMENTStructural alterations in neuronal morphology and synaptic connections have been proposed as a potential physical basis for age–related decline in cognitive function. Little is known regarding aging-associated changes to inhibitory neurons, despite the importance of inhibitory circuitry to adult cortical plasticity and the reorganization of cortical maps. Here we show that brain aging goes hand in hand with progressive structural simplification and reduced plasticity of inhibitory neurons, and a parallel decline in sensory map plasticity. Fluoxetine treatment can attenuate the concurrent age–related declines in interneuron structural and functional plasticity, suggesting it could provide an important therapeutic approach for mitigating sensory and cognitive deficits associated with aging.

Perineuronal nets (PNNs), components of the extracellular matrix, preferentially coat parvalbumin-positive interneurons and constrain critical-period plasticity in the adult cerebral cortex. Current strategies to remove PNN are long-lasting, invasive, and trigger neuropsychiatric symptoms. Here, we apply repeated anesthetic ketamine as a method with minimal behavioral effect. We find that this paradigm strongly reduces PNN coating in the healthy adult brain and promotes juvenile-like plasticity. Microglia are critically involved in PNN loss because they engage with parvalbumin-positive neurons in their defined cortical layer. We identify external 60-Hz light-flickering entrainment to recapitulate microglia-mediated PNN removal. Importantly, 40-Hz frequency, which is known to remove amyloid plaques, does not induce PNN loss, suggesting microglia might functionally tune to distinct brain frequencies. Thus, our 60-Hz light-entrainment strategy provides an alternative form of PNN intervention in the healthy adult brain.

Neurodevelopmental disorders such as fragile X syndrome (FXS) result in lifelong cognitive and behavioural deficits and represent a major public health burden. FXS is the most frequent monogenic form of intellectual disability and autism, and the underlying pathophysiology linked to its causal gene, FMR1, has been the focus of intense research. Key alterations in synaptic function thought to underlie this neurodevelopmental disorder have been characterized and rescued in animal models of FXS using genetic and pharmacological approaches. These robust preclinical findings have led to the implementation of the most comprehensive drug development programme undertaken thus far for a genetically defined neurodevelopmental disorder, including phase IIb trials of metabotropic glutamate receptor 5 (mGluR5) antagonists and a phase III trial of a GABAB receptor agonist. However, none of the trials has been able to unambiguously demonstrate efficacy, and they have also highlighted the extent of the knowledge gaps in drug development for FXS and other neurodevelopmental disorders. In this Review, we examine potential issues in the previous studies and future directions for preclinical and clinical trials. FXS is at the forefront of efforts to develop drugs for neurodevelopmental disorders, and lessons learned in the process will also be important for such disorders.

Brief monocular deprivation (MD) shifts ocular dominance and reduces the density of thalamic synapses in layer 4 of the mouse primary visual cortex (V1). We found that microglial lysosome content is also increased as a result of MD. Previous studies have shown that the microglial fractalkine receptor CX3CR1 is involved in synaptic development and hippocampal plasticity. We therefore tested the hypothesis that neuron-to-microglial communication via CX3CR1 is an essential component of visual cortical development and plasticity in male mice. Our data show that CX3CR1 is not required for normal development of V1 responses to visual stimulation, multiple forms of experience-dependent plasticity, or the synapse loss that accompanies MD in layer 4. By ruling out an essential role for fractalkine signaling, our study narrows the search for understanding how microglia respond to active synapse modification in the visual cortex.SIGNIFICANCE STATEMENTMicroglia in the visual cortex respond to monocular deprivation with increased lysosome content, but signaling through the fractalkine receptor CX3CR1 is not an essential component in the mechanisms of visual cortical development or experience-dependent synaptic plasticity.

Daily exposure of awake mice to a phase-reversing visual grating stimulus leads to enhancement of the visual-evoked potential (VEP) in layer 4 of the primary visual cortex (V1). This stimulus-selective response potentiation (SRP) resembles and shares mechanistic requirements with canonical long-term synaptic potentiation (LTP). However, it remains to be determined how this augmentation of a population response translates into altered neuronal activity of individual V1 neurons. To address this question, we performed longitudinal calcium imaging of layer 4 excitatory neurons in V1 and tracked changes associated with the induction and expression of SRP. We found no evidence for a net change in the fraction of visually responsive neurons as the stimulus became familiar. However, endoscopic calcium imaging of layer 4 principal neurons revealed that somatic calcium transients in response to phase-reversals of the familiar visual stimulus are reduced and undergo strong within-session adaptation. Conversely, neuropil calcium responses and VEPs are enhanced during familiar stimulus viewing, and the VEPs show reduced within-session adaptation. Consistent with the exquisite selectivity of SRP, the plasticity of cellular responses to phase-reversing gratings did not translate into altered orientation selectivity to drifting gratings. Our findings suggest a model in which augmentation of fast, short-latency synaptic (dendritic) responses, manifested as enhanced layer 4 VEPs, recruits inhibition to suppress cellular activity. Reduced cellular activity to the familiar stimulus may account for the behavioral correlate of SRP, orientation-selective long-term habituation.

Fragile X Syndrome (FXS) is one of the most common monogenic forms of autism and intellectual disability. Preclinical studies in animal models have highlighted the potential of pharmaceutical intervention strategies for alleviating the symptoms of FXS. However, whether treatment strategies can be tailored to developmental time windows that define the emergence of particular phenotypes is unknown. Similarly, whether a brief, early intervention can have long-lasting beneficial effects, even after treatment cessation, is also unknown. To address these questions, we first examined the developmental profile for the acquisition of associative learning in a rat model of FXS. Associative memory was tested using a range of behavioral paradigms that rely on an animal's innate tendency to explore novelty. Fmr1 knockout (KO) rats showed a developmental delay in their acquisition of object-place recognition and did not demonstrate object-place-context recognition paradigm at any age tested (up to 23 weeks of age). Treatment of Fmr1 KO rats with lovastatin between 5 and 9 weeks of age, during the normal developmental period that this associative memory capability is established, prevents the emergence of deficits but has no effect in wild-type animals. Moreover, we observe no regression of cognitive performance in the FXS rats over several months after treatment. This restoration of the normal developmental trajectory of cognitive function is associated with the sustained rescue of both synaptic plasticity and altered protein synthesis. The findings provide proof of concept that the impaired emergence of the cognitive repertoire in neurodevelopmental disorders may be prevented by brief, early pharmacological intervention.

Many neurodevelopmental disorders are characterized by impaired functional synaptic plasticity and abnormal dendritic spine morphology, but little is known about how these are related. Previous work in the Fmr1-/y mouse model of fragile X (FX) suggests that increased constitutive dendritic protein synthesis yields exaggerated mGluR5-dependent long-term synaptic depression (LTD) in area CA1 of the hippocampus, but an effect on spine structural plasticity remains to be determined. In the current study, we used simultaneous electrophysiology and time-lapse two photon imaging to examine how spines change their structure during LTD induced by activation of mGluRs or NMDA receptors (NMDARs), and how this plasticity is altered in Fmr1-/y mice. We were surprised to find that mGluR activation causes LTD and AMPA receptor internalization, but no spine shrinkage in either wildtype or Fmr1-/y mice. In contrast, NMDAR activation caused spine shrinkage as well as LTD in both genotypes. Spine shrinkage was initiated by non-ionotropic (metabotropic) signaling through NMDARs, and in wild-type mice this structural plasticity required activation of mTORC1 and new protein synthesis. In striking contrast, NMDA-induced spine plasticity in Fmr1-/y mice was no longer dependent on acute activation of mTORC1 or de novo protein synthesis. These findings reveal that the structural consequences of mGluR and metabotropic NMDAR activation differ, and that a brake on spine structural plasticity, normally provided by mTORC1 regulation of protein synthesis, is absent in FX. Increased constitutive protein synthesis in FX appears to modify functional and structural plasticity induced through different glutamate receptors.

Shortly before he died in October 2017, John Lisman submitted an invited review to Molecular Brain on ‘Criteria for identifying the molecular basis of the engram (CaMKII, PKMζ)’. John had no opportunity to read the referees’ comments, and as a mark of the regard in which he was held by the neuroscience community the Editors decided to publish his review as submitted. This obituary takes the form of a series of commentaries on Lisman’s review. At the same time we are publishing as a separate article a longer response by Todd Sacktor and André Fenton entitled ‘What does LTP tell us about the roles of CaMKII and PKMζ in memory?’ which presents the case for a rival memory molecule, PKMζ.

Much has been written about the validity of mice as a preclinical model for brain disorders. Critics cite numerous examples of apparently effective treatments in mouse models that failed in human clinical trials, raising the possibility that the two species' neurobiological differences could explain the high translational failure rate in psychiatry and neurology (neuropsychiatry). However, every stage of translation is plagued by complex problems unrelated to neurobiological conservation. Therefore, although these case studies are intriguing, they cannot alone determine whether these differences observed account for translation failures. Our analysis of the literature indicates that most neuropsychiatric treatments used in humans are at least partially effective in mouse models, suggesting that neurobiological differences are unlikely to be the main cause of neuropsychiatric translation failures.

Thema von Kapitel 19 sind Systeme, die die Rhythmen des Gehirns erzeugen: sowohl die schnellen elektrischen Rhythmen wahrend der Schlaf- und Wachphasen als auch die langsamen circadianen Rhythmen, denen die Kontrolle von Hormonen, Korpertemperatur, der Wachheit und des Stoffwechsels unterliegt. Das Vorderhirn, insbesondere die Groshirnrinde, produziert eine Reihe rascher elektrischer Rhythmen, die leicht messbar sind und eng mit interessanten Verhaltensweisen, einschlieslich Schlaf, korrelieren. Zuerst wird das Elektroenzephalogramm (EEG) diskutiert, weil es die klassische Methode ist, um Hirnrhythmen aufzuzeichnen, und weil es fur die Diskussion von Schlaf grundlegend ist. Schlaf wird ausfuhrlich behandelt, weil er so komplex und allgegenwartig ist – und weil er uns so sehr am Herzen liegt. Schlieslich wird das Wissen uber die inneren Zeitgeber zusammengefasst, die Vigilanz, Hormonausschuttung, Korpertemperatur und Stoffwechsel steuern.

In Kapitel 2 liegt der Fokus auf der Zellbiologie der Neuronen. Diese Grundlagen sind vor allem fur Studierende ohne biologische Vorkenntnisse wichtig, stellen aber erfahrungsgemas fur fortgeschrittene Studierende eine hilfreiche Wiederholung dar. Anschliesend wenden wir uns den strukturellen Eigenschaften zu, die die Nervenzellen und ihre unterstutzenden Zellen so einzigartig machen, und gehen dabei besonders auf den Zusammenhang zwischen Struktur und Funktion ein. Auserdem stellen wir einige Meisterleistungen der Gentechnik vor, mit denen Neurowissenschaftler inzwischen routinemasig die Funktionen der verschiedenen Typen von Nervenzellen erforschen.

Kapitel 25 befasst sich mit den zellularen und molekularen Grundlagen von Lern- und Gedachtnisleistungen, wobei insbesondere auf die Anderungen der synaptischen Verbindungen eingegangen wird. Die letzten Jahrzehnte haben rasche Fortschritte in diesem Bereich gebracht. Hierzu haben Untersuchungen der neuronalen Aktivitat in Regionen des Saugetiergehirns beigetragen, die mit verschiedenen Formen des Gedachtnisses assoziiert sind. Erkenntnisse aus theoretischen Analysen neuronaler Netzwerke waren ebenfalls wichtig, um die synaptischen Modifikationen zu verstehen, die an der Speicherung von Informationen beteiligt sind. Zahlreiche neue Technologien haben es ermoglicht, infrage kommende physiologische und molekulare Mechanismen zu identifizieren. Zu den interessantesten Schlussfolgerungen aus diesen Forschungen gehort, dass die Mechanismen aktivitatsabhangiger synaptischer Plastizitat und Gedachtnisbildung im adulten Gehirn vieles mit den Mechanismen gemeinsam haben, die wahrend der Entwicklung der neuronalen Schaltkreise ablaufen. Unter Neurowissenschaftlern breitet sich zunehmend Optimismus aus, dass die physiologischen Grundlagen des Gedachtnisses schon bald entschlusselt sein werden.

Kapitel 3 widmet sich der Physiologie der Nervenzellmembran. Hier werden die notwendigen chemischen, physikalischen und molekularen Eigenschaften erklart, die das Neuron zur Generierung und Weiterleitung elektrischer Signale befahigen. In diesem Kapitel beschaftigen wir uns bei der Untersuchung der neuronalen Signalubertragung zuerst mit der Frage, wie es zum Ruhepotenzial an der Membran kommt. Es ist sehr wichtig, das Ruhepotenzial verstanden zu haben, da es die Grundlage fur die ubrige Neurophysiologie bildet. Die Kenntnis dieser basalen physiologischen Mechanismen ist von zentraler Bedeutung, um die Fahigkeiten und Grenzen der Gehirnfunktion zu erfassen.