Dendritic Length Research Articles

Optogenetics stimulates nerve reorganization in the contralesional anterolateral primary motor cortex in a mouse model of ischemic stroke.

The anterolateral motor cortex of rodents is an important motor auxiliary area, and its function is similar to that of the premotor area in humans. Activation and inhibition of the contralesional anterolateral motor cortex (cALM) have been shown to have direct effects on motor behavior. However, the significance of cALM activation and inhibition in the treatment of stroke remains unclear. This study investigated the role of optogenetic cALM stimulation in a mouse model of cerebral stroke. The results showed that 21-day optogenetic cALM inhibition, but not activation, improved neurological function. In addition, optogenetic cALM stimulation substantially altered dendritic structural reorganization and dendritic spine plasticity, as optogenetic cALM inhibition resulted in increased dendritic length, number of dendritic spines, and number of perforated synapses, whereas optogenetic activation led to an increase in the number of multiple synapse boutons and the number of dendritic intersections. Furthermore, RNA-seq analysis showed that multiple biological processes regulated by the cALM were upregulated immediately after optogenetic cALM inhibition, and that several immediate-early genes (including cFOS, Erg1, and Sema3f) were expressed at higher levels after optogenetic inhibition than after optogenetic activation. These results were confirmed by quantitative reverse transcription-polymerase chain reaction. Finally, immunofluorescence analysis showed that the c-FOS signal in layer V of the primary motor cortex in the ischemic hemisphere was higher after optogenetic cALM activation than it was after optogenetic cALM inhibition. Taken together, these findings suggest that optogenetic cALM stimulation promotes neural reorganization in the primary motor cortex of the ischemic hemisphere, and that optogenetic cALM inhibition and activation have different effects on neural plasticity. The study was approved by the Experimental Animal Ethics Committee of Fudan University (approval No. 201802173S) on March 3, 2018.

Dendritic and behavioral changes in rats neonatally treated with homocysteine; A proposal as an animal model to study the attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHAD) is a neurobehavioral disorder that affects children and adolescents with a high prevalence. Despite its prevalence and an unclear etiology, previous reports suggest that it is closely related to homocysteine metabolism. Male Sprague Dawley rats were administered with homocysteine from postnatal day (PD) 2 to PD 16. Locomotor activity was evaluated at 35 PD (prepuberal age) and 60 PD (adult age) before and after amphetamine administration. In rats evaluated at both ages, homocysteine induced hyperactivity, and the amphetamine administration reduced hyperactivity significantly at 35 PD, but not at 60 PD. In the social interaction test, homocysteine reduced the number of contacts and increased the latency to the first contact only in rats at 35 PD. Homocysteine also had an effect on short term memory at 35D and 60 PD and long-term memory at 60 PD. Morphological changes were found mainly in the shape of dendritic spines in the prefrontal cortex (PFC-3), dorsal hippocampus (CA1), dentate gyrus (DG) and nucleus accumbens (NAcc), in rats administered neonatally with homocysteine at both ages studied. In prepuberal and adult rats, there was an increase in dendritic length in DG and NAcc, respectively. The dendritic spine morphology also was altered at both ages, mainly decreasing the number of mushroom spines in NAcc and CA1 at 30 PD and in all the areas studied at 60 PD rats. Those areas are associated with the processes of attention, learning and memory that were studied, and those alterations are possibly related to changes observed in the behavioral tests. These behavioral and morphological changes in rats at 35 PD administered with homocysteine could be similar to changes found in children diagnosed with ADHD. Moreover, half to two thirds of children diagnosed with ADHD reach adulthood with this disorder. In this study we found similarities with ADHD, finding alterations in both rats at 35 PD and 60 PD. So, this may be proposed as an animal model to study this disorder present in children, adolescents and adults.

Rapid Golgi Stain for Dendritic Spine Visualization in Hippocampus and Prefrontal Cortex.

Golgi impregnation, using the Golgi staining kit with minor adaptations, is used to impregnate dendritic spines in the rat hippocampus and medial prefrontal cortex. This technique is a marked improvement over previous methods of Golgi impregnation because the premixed chemicals are safer to use, neurons are consistently well impregnated, there is far less background debris, and for a given region, there are extremely small deviations in spine density between experiments. Moreover, brains can be accumulated after a certain point and kept frozen until further processing. Using this method any brain region of interest can be studied. Once stained and cover slipped, dendritic spine density is determined by counting the number of spines for a length of dendrite and expressed as spine density per 10 µm dendrite.

Perillaldehyde improves cognitive function in vivo and in vitro by inhibiting neuronal damage via blocking TRPM2/NMDAR pathway

BackgroundVascular cognitive dysfunction in patients with vascular dementia (VD) is a kind of severe cognitive dysfunction syndrome caused by cerebrovascular diseases. At present, effective drugs to improve the cognitive function of VD patients still need to be explored. Transient Receptor Potential Melastatin 2 (TRPM2) channel is a nonspecific cation channel that plays a key role in the toxic death of neurons. Perillaldehyde (PAE) has the protective effect of epilepsy and insomnia and other central nervous system diseases. The aim of this study is to explore whether PAE improves cognitive function in VD rats and to investigate the potential mechanisms in vivo and vitro.MethodsVD rats were induced by bilateral common carotid arteries occlusion (2-vessel occlusion [2VO]) and treated with PAE for 4 weeks. The neuroprotective effects of PAE was subsequently assessed by the Morris water maze, hematoxylin–eosin (HE) staining, Golgi staining, electron microscopy, Neuron-specific nuclear protein (Neu N) staining, and TdT-mediated dUTP nick end labeling (TUNEL) staining. After primary hippocampal neurons were isolated, cell viability was detected by MTT assay and intracellular Ca2+ concentration was detected by calcium imaging assay. The content of Nitriteoxide (NO), Malondialdehyde (MDA) and Superoxide dismutase (SOD) activity in serum of rats were observed by Enzyme Linked Immunosorbent Assay (ELISA). Immunohistochemistry, Western blot, and Confocal laser scanning were used to detect the expression levels of N-methyl-d-asprtate receptor-2B (NR2B) and TRPM2.ResultsThe results showed that PAE can improve the number and activity of neurons, increase the length and number of dendrites in hippocampus, decrease the Vv value and PE value of neuronal nucleus and mitochondrial structure significantly, increase the s value and L value in nucleus structure, decrease the s value and L value in mitochondrial structure, and improve the learning and memory ability of rats significantly. And PAE can strengthen the ability of antioxidant stress confirmed by increasing the activity of SOD and reducing the production of MDA. The results of western blot, immunohistochemistry and immunofluorescence showed that PAE could reduce the level of TRPM2 and increase the expression of NR2B.ConclusionsTaken together, our findings provide evidence that the neuroprotective effects of PAE in VD rats maybe through TRPM2 inhibition and subsequent activation of NMDAR signaling pathway.

A Kalirin missense mutation enhances dendritic RhoA signaling and leads to regression of cortical dendritic arbors across development

Normally, dendritic size is established prior to adolescence and then remains relatively constant into adulthood due to a homeostatic balance between growth and retraction pathways. However, schizophrenia is characterized by accelerated reductions of cerebral cortex gray matter volume and onset of clinical symptoms during adolescence, with reductions in layer 3 pyramidal neuron dendritic length, complexity, and spine density identified in multiple cortical regions postmortem. Nogo receptor 1 (NGR1) activation of the GTPase RhoA is a major pathway restricting dendritic growth in the cerebral cortex. We show that the NGR1 pathway is stimulated by OMGp and requires the Rho guanine nucleotide exchange factor Kalirin-9 (KAL9). Using a genetically encoded RhoA sensor, we demonstrate that a naturally occurring missense mutation in Kalrn, KAL-PT, that was identified in a schizophrenia cohort, confers enhanced RhoA activitation in neuronal dendrites compared to wild-type KAL. In mice containing this missense mutation at the endogenous locus, there is an adolescent-onset reduction in dendritic length and complexity of layer 3 pyramidal neurons in the primary auditory cortex. Spine density per unit length of dendrite is unaffected. Early adult mice with these structural deficits exhibited impaired detection of short gap durations. These findings provide a neuropsychiatric model of disease capturing how a mild genetic vulnerability may interact with normal developmental processes such that pathology only emerges around adolescence. This interplay between genetic susceptibility and normal adolescent development, both of which possess inherent individual variability, may contribute to heterogeneity seen in phenotypes in human neuropsychiatric disease.

Dendritic synapse geometry optimizes binaural computation in a sound localization circuit.

Clustering of synapses allows neurons to overcome attenuation of electrical signals at dendrites. However, we show in avian binaural coincidence detectors computing interaural time difference for sound localization that clustering of synapses rather promotes the dendritic attenuation but augments the intensity tolerance of the binaural computations. Using glutamate uncaging, we found in the neurons that synapses were clustered at distal dendritic branches. Modeling revealed that this strengthened sublinear integration within a dendritic tree but enabled the integration of signals from different trees when inputs grow stronger, preventing monoaural output and maintaining the dynamic range of binaural computation. The extent of this clustering differed according to dendritic length and frequency tuning of neurons, being most prominent for long dendrites and low-frequency tuning. This ensures binaural spatial hearing for wide intensity and frequency ranges, highlighting the importance of coupling of synapse geometry with dendritic morphology and input frequency in sensory signal processing.

Andrographolide promotes hippocampal neurogenesis and spatial memory in the APPswe/PS1\u0394E9 mouse model of Alzheimer\u2019s disease

In Alzheimer´s disease (AD) there is a reduction in hippocampal neurogenesis that has been associated to cognitive deficits. Previously we showed that Andrographolide (ANDRO), the main bioactive component of Andrographis paniculate, induces proliferation in the hippocampus of the APPswe/PSEN1ΔE9 (APP/PS1) mouse model of AD as assessed by staining with the mitotic marker Ki67. Here, we further characterized the effect of ANDRO on hippocampal neurogenesis in APP/PS1 mice and evaluated the contribution of this process to the cognitive effect of ANDRO. Treatment of 8-month-old APP/PS1 mice with ANDRO for 4 weeks increased proliferation in the dentate gyrus as evaluated by BrdU incorporation. Although ANDRO had no effect on neuronal differentiation of newborn cells, it strongly increased neural progenitors, neuroblasts and newborn immature neurons, cell populations that were decreased in APP/PS1 mice compared to age-matched wild-type mice. ANDRO had no effect on migration or in total dendritic length, arborization and orientation of immature neurons, suggesting no effects on early morphological development of newborn neurons. Finally, ANDRO treatment improved the performance of APP/PS1 mice in the object location memory task. This effect was not completely prevented by co-treatment with the anti-mitotic drug TMZ, suggesting that other effects of ANDRO in addition to the increase in neurogenesis might underlie the observed cognitive improvement. Altogether, our data indicate that in APP/PS1 mice ANDRO stimulates neurogenesis in the hippocampus by inducing proliferation of neural precursor cells and improves spatial memory performance.

Histone Deacetylase 2 Knockdown Ameliorates Morphological Abnormalities of Dendritic Branches and Spines to Improve Synaptic Plasticity in an APP/PS1 Transgenic Mouse Model.

Disease-modifying therapies, such as neuroprotective and neurorestorative interventions, are strongly desired for Alzheimer’s disease (AD) treatment. Several studies have suggested that histone deacetylase 2 (HDAC2) inhibition can exhibit disease-modifying effects in AD patients. However, whether HDAC2 inhibition shows neuroprotective and neurorestorative effects under neuropathic conditions, such as amyloid β (Aβ)-elevated states, remains poorly understood. Here, we performed HDAC2-specific knockdown in CA1 pyramidal cells and showed that HDAC2 knockdown increased the length of dendrites and the number of mushroom-like spines of CA1 basal dendrites in APP/PS1 transgenic mouse model. Furthermore, HDAC2 knockdown also ameliorated the deficits in hippocampal CA1 long-term potentiation and memory impairment in contextual fear conditioning tests. Taken together, our results support the notion that specific inhibition of HDAC2 has the potential to slow the disease progression of AD through ameliorating Aβ-induced neuronal impairments.

Experience-dependent plasticity in early stations of sensory processing in mature brains: effects of environmental enrichment on dendrite measures in trigeminal nuclei

Nervous systems respond with structural changes to environmental changes even in adulthood. In recent years, experience-dependent structural plasticity was shown not to be restricted to the cerebral cortex, as it also occurs at subcortical and even peripheral levels. We have previously shown that two populations of trigeminal nuclei neurons, trigeminothalamic barrelette neurons of the principal nucleus (Pr5), and intersubnuclear neurons in the caudal division of the spinal trigeminal nucleus (Sp5C) that project to Pr5 underwent morphometric and topological changes in their dendritic trees after a prolonged total or partial loss of afferent input from the vibrissae. Here we examined whether and what structural alterations could be elicited in the dendritic trees of the same cell populations in young adult rats after being exposed for 2 months to an enriched environment (EE), and how these changes evolved when animals were returned to standard housing for an additional 2 months. Neurons were retrogradely labeled with BDA delivered to, respectively, the ventral posteromedial thalamic nucleus or Pr5. Fully labeled cells were digitally reconstructed with Neurolucida and analyzed with NeuroExplorer. EE gave rise to increases in dendritic length, number of trees and branching nodes, spatial expansion of the trees, and dendritic spines, which were less pronounced in Sp5C than in Pr5 and differed between sides. In Pr5, these parameters returned, but only partially, to control values after EE withdrawal. These results underscore a ubiquity of experience-dependent changes that should not be overlooked when interpreting neuroplasticity and developing plasticity-based therapeutic strategies.

Dendritic Architecture Predicts in vivo Firing Pattern in Mouse Ventral Tegmental Area and Substantia Nigra Dopaminergic Neurons.

The firing activity of ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) dopaminergic (DA) neurons is an important factor in shaping DA release and its role in motivated behavior. Dendrites in DA neurons are the main postsynaptic compartment and, along with cell body and axon initial segment, contribute to action potential generation and firing pattern. In this study, the organization of the dendritic domain in individual VTA and SNc DA neurons of adult male mice, and their relationship to in vivo spontaneous firing, are described. In comparison with dorsal VTA DA neurons, ventrally located VTA neurons (as measured by cell body location) possess a shorter total dendritic length and simpler dendritic architecture, and exhibit the most irregular in vivo firing patterns among DA neurons. In contrast, for DA neurons in the SNc, the higher irregularity of firing was related to a smaller dendritic domain, as measured by convex hull volumes. However, firing properties were also related to the specific regional distribution of the dendritic tree. Thus, VTA DA neurons with a larger extension of their dendritic tree within the parabrachial pigmented (PBP) nucleus fired more regularly compared with those with relatively more dendrites extending outside the PBP. For DA neurons in the SNc, enhanced firing irregularity was associated with a smaller proportion of dendrites penetrating the substantia nigra pars reticulata. These results suggest that differences in dendritic morphology contribute to the in vivo firing properties of individual DA neurons, and that the existence of region-specific synaptic connectivity rules that shape firing diversity.

Comparative study of doxycycline, sancycline, and 4-dedimethylamino sancycline (CMT-3) on epidermal melanogenesis.

Melanogenesis is regulated by melanocytes, which synthesize the pigment melanin inside melanosomes; these melanosomes are exported through dendritic extensions to adjacent keratinocytes and result in skin coloration. Chemically modified tetracyclines (CMTs) are nonantimicrobial tetracyclines that retain the capacity to inhibit matrix metalloproteinases (MMPs) and have shown several biological benefits; in particular, CMT-3 [(4-dedimethylamino sancycline (SAN)] has emerged as a candidate for therapeutic benefits in our previous studies. However, to date, studies of the effects of CMT-3 or SAN on melanogenesis are lacking. We have previously reported the anti-melanogenic activity of CMT-308 (the 9-amino derivative of CMT-3). Herein, we have compared the three tetracycline analogs, doxycycline (DOX), SAN, and CMT-3, for their effects on melanogenesis using B16F10 mouse melanoma cells and have validated results in primary human melanocytes (HEMn-DP). DOX did not show any significant effects on intracellular melanin or melanosome export in DP cells while SAN was cytotoxic at high doses but without effects on melanogenesis at lower doses. However, CMT-3 showed a robust suppression of dendricity parameters (dendrite number, dendrite length, and proportion of dendritic cells) in DP cells which was associated, at least in part, with a significant reduction of intracellular tyrosinase activity. In spite of its inhibition of tyrosinase activity, CMT-3 had no significant effects on intracellular melanin levels, suggesting that it selectively targets melanosome export. Our results demonstrate a unique structure-activity relationship (SAR) for the effects of these compounds on melanogenesis and support the conclusion that removal of the 4-dimethylamino moiety confers the selective capacity to suppress melanosome export. Collectively, these results indicate that CMT-3 might be a candidate for diminishing hyperpigmentation skin disorders.

Compartmental spiking neuron model for pattern classification

One of the directions of development within the framework of the neuromorphic approach is the development of anatomically similar models of brain networks, taking into account the structurally complex structure of neurons and the adaptation of connections between them, as well as the development of learning algorithms for such models. In this work, we use the previously presented compartmental spike model of a neuron, which describes the structure (dendritic tree, soma, synapses) and behaviour (temporal and spatial signal summation, generation of action potential, stimulation and suppression of electrical activity) of a biological neuron. An algorithm for the structural organization of neuron models into a spike neural network is proposed for recognizing an arbitrary impulse pattern by introducing inhibitory synapses between trained neuron models. The dynamically adapting neuron models used are trained according to a previously proposed algorithm that automatically selects parameters such as soma size, dendrite length, and the number of synapses on each of the dendrites in order to induce a temporal response at the output depending on the input pattern encoded using a time window and temporal delays in the vector of single spikes arriving at a separate dendrite of a neuron. The developed algorithms are evaluated on the Iris dataset classification problem with four training examples from each class. As a result of the classification, separate disjoint clusters are formed, which demonstrates the applicability of the proposed spike neural network with a dynamically changing structure of elements in the problem of pattern recognition and classification.

Repeated ethanol exposure following avoidance conditioning impairs avoidance extinction and modifies conditioning-associated prefrontal dendritic changes in a mouse model of post-traumatic stress disorder.

Treatment of post-traumatic stress disorder is complicated by the presence of alcohol use disorder comorbidity. Little is known about the underlying brain mechanisms. We have recently shown, in mice, that the post-traumatic stress disorder-like phenotype is characterised by the increase and decrease in total dendritic number and length in the prelimbic and infralimbic areas of the medial prefrontal cortex, respectively. Here, we examined whether repeated ethanol exposure would exacerbate these changes and whether this would be associated with difficulty to extinguish passive avoidance behaviour, as an indicator of treatment resistance. We also analysed whether other known trauma-associated changes, like increased or decreased corticosterone and decreased brain-derived neurotrophic factor levels, would also be exacerbated. Male mice underwent trauma exposure (1.5-mA footshock), followed, 8 days later, by a conditioned place preference training with ethanol. Tests for fear sensitization, passive avoidance, anxiety-like behaviour, extinction acquisition and relapse susceptibility were used to assess behaviour changes. Plasma corticosterone and brain-derived neurotrophic factor levels and prefrontal dendritic changes were subsequently measured. Trauma-susceptible mice exposed to ethanol acquired a strong place preference and behaved differently from those not exposed to ethanol, with delayed avoidance extinction and higher avoidance relapse vulnerability. Ethanol potentiated trauma-associated dendritic changes in the prelimbic area and suppressed trauma-associated dendritic changes in the infralimbic area. However, ethanol had no effect on trauma-induced increased corticosterone and decreased brain-derived neurotrophic factor levels. These data suggest that the modification of prefrontal trauma-related changes, due to alcohol use, can characterise, and probably support, treatment-resistant post-traumatic stress disorder.

The effects of melatonin on the striatum

Objective: Some of the neurological diseases cause morphologic changes in the striatal neurons. Medial forebrain bundle (MFB)lesion is a commonly used method to produce a Parkinsonian model rat. Melatonin is a hormone which exerts a neuroprotectiveeffect on the neurons. The aim of this study is to investigate the effect of melatonin on the dendritic morphology of striatal mediumspiny neurons (MSNs) in rats with MFB lesion.Materials and Methods: Twelve male Wistar albino rats were given saline injections into the MFB and divided into sedentary andtreatment groups. The treatment group was administered a 10 mg/kg dose of melatonin intraperitoneally for 30 days. The lesionwas confirmed histologically by Nissl staining. Golgi staining technique was applied to observe neuronal morphology. Neuronalstructures were analysed from three-dimensional images by Neurolucida (MBF Bioscience) software.Results: The MFB lesion caused a reduction in the total dendritic length and in the number of dendritic endings. The melatoninenhanced the number of dendritic endings compared to the sedentary group. The melatonin led to an increase in the total spinedensity, spine densities of thin and mushroom types.Conclusion: Melatonin improved the dendritic degeneration due to MFB lesion.

The translatome of neuronal cell bodies, dendrites, and axons

To form synaptic connections and store information, neurons continuously remodel their proteomes. The impressive length of dendrites and axons imposes logistical challenges to maintain synaptic proteins at locations remote from the transcription source (the nucleus). The discovery of thousands of messenger RNAs (mRNAs) near synapses suggested that neurons overcome distance and gain autonomy by producing proteins locally. It is not generally known, however, if, how, and when localized mRNAs are translated into protein. To investigate the translational landscape in neuronal subregions, we performed simultaneous RNA sequencing (RNA-seq) and ribosome sequencing (Ribo-seq) from microdissected rodent brain slices to identify and quantify the transcriptome and translatome in cell bodies (somata) as well as dendrites and axons (neuropil). Thousands of transcripts were differentially translated between somatic and synaptic regions, with many scaffold and signaling molecules displaying increased translation levels in the neuropil. Most translational changes between compartments could be accounted for by differences in RNA abundance. Pervasive translational regulation was observed in both somata and neuropil influenced by specific mRNA features (e.g., untranslated region [UTR] length, RNA-binding protein [RBP] motifs, and upstream open reading frames [uORFs]). For over 800 mRNAs, the dominant source of translation was the neuropil. We constructed a searchable and interactive database for exploring mRNA transcripts and their translation levels in the somata and neuropil [MPI Brain Research, The mRNA translation landscape in the synaptic neuropil. https://public.brain.mpg.de/dashapps/localseq/ Accessed 5 October 2021]. Overall, our findings emphasize the substantial contribution of local translation to maintaining synaptic protein levels and indicate that on-site translational control is an important mechanism to control synaptic strength.

Neuroprotective role of Ginkgobiloba and Rosuvastatin in CA1 region of Hippocampus against high fat diet induced neurotoxicity

Diet rich in fat is one of the main risk factor for the development of Alzheimer’s disease. Studies have shown that diet rich in fat disrupts memory and learning. The present study evaluates the ameliorative role of Ginkgobiloba and Rosuvastatin against high fat diet induced neurotoxicity in CA1 (Corona Ammonis) region of hippocampus. Animals were randomly divided into six groups. Group I received normal diet, Group II received high fat diet, Group III & IV were treated with Ginkgobiloba 50mg/kg and 100mg/kg body weight, and Group V & VI were treated with Rosuvastatin 10mg/kg and 20 mg/kg body weight. All the rats were subjected to spatial learning (Morris water maze). Subsequently, rats were sacrificed and brains were removed. Golgi staining was done and CA1 neurons of hippocampus were traced using camera lucida. Dendritic branching points and dendritic intersections were quantified. Lipid profile and Super oxide (SOD) was also estimated.There was enhancement of spatial learning in treatment group rats. Furthermore, a significant increase in dendritic length and branching points was observed in CA1 region along with significant decrease in the Superoxide dismutase in rats treated with higher dose of Ginkgobiloba and Rosuvastatin. Present study concludes that Ginkgobiloba and Rosuvastatin in higher dose have protective role against high fat diet induced neurotoxicity in CA1 region.

Testing Fmr1 KO Phenotypes in Response to GSK3 Inhibitors: SB216763 versus AFC03127.

Glycogen synthase kinase 3 (GSK3) is a proline-directed serine-threonine kinase that is associated with several neurological disorders, including Alzheimer’s disease and fragile X syndrome (FXS). We tested the efficacy of a novel GSK3 inhibitor AFC03127, which was developed by Angelini Pharma, in comparison to the metabotropic glutamate receptor 5 inhibitor 2-Methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and the GSK3 inhibitor SB216763 in in vivo and in vitro assays in Fmr1KO mice, a mouse model useful for the study of FXS. The in vivo assay tested susceptibility to audiogenic-induced seizures (AGS) whereas the in vitro assays assessed biomarker expression and dendritic spine length and density in cultured primary neurons as a function of drug dose. MPEP and SB216763 attenuated AGS in Fmr1KO mice, whereas AFC03127 did not. MPEP and AFC03127 significantly reduced dendritic expression of amyloid-beta protein precursor (APP). All drugs rescued spine length and the ratio of mature dendritic spines. Spine density was not statistically different between vehicle and GSK3 inhibitor-treated cells. The drugs were tested over a wide concentration range in the in vitro assays to determine dose responses. A bell-shaped dose response decrease in APP expression was observed in response to AFC03127, which was more effective than SB216763. These findings confirm previous studies demonstrating differential effects of various GSK3 inhibitors on AGS propensity in Fmr1KO mice and confirm APP as a downstream biomarker that is responsive to GSK3 activity.

Serotonin Transporter Defect Disturbs Structure and Function of the Auditory Cortex in Mice.

Serotonin transporter (SERT) modulates the level of 5-HT and significantly affects the activity of serotonergic neurons in the central nervous system. The manipulation of SERT has lasting neurobiological and behavioral consequences, including developmental dysfunction, depression, and anxiety. Auditory disorders have been widely reported as the adverse events of these mental diseases. It is unclear how SERT impacts neuronal connections/interactions and what mechanism(s) may elicit the disruption of normal neural network functions in auditory cortex. In the present study, we report on the neuronal morphology and function of auditory cortex in SERT knockout (KO) mice. We show that the dendritic length of the fourth layer (L-IV) pyramidal neurons and the second-to-third layer (L-II/III) interneurons were reduced in the auditory cortex of the SERT KO mice. The number and density of dendritic spines of these neurons were significantly less than those of wild-type neurons. Also, the frequency-tonotopic organization of primary auditory cortex was disrupted in SERT KO mice. The auditory neurons of SERT KO mice exhibited border frequency tuning with high-intensity thresholds. These findings indicate that SERT plays a key role in development and functional maintenance of auditory cortical neurons. Auditory function should be examined when SERT is selected as a target in the treatment for psychiatric disorders.

Cellular Substrates of Functional Network Integration and Memory in Temporal Lobe Epilepsy

Temporal lobe epilepsy (TLE) patients are at risk of memory deficits, which have been linked to functional network disturbances, particularly of integration of the default mode network (DMN). However, the cellular substrates of functional network integration are unknown. We leverage a unique cross-scale dataset of drug-resistant TLE patients (n = 31), who underwent pseudo resting-state functional magnetic resonance imaging (fMRI), resting-state magnetoencephalography (MEG) and/or neuropsychological testing before neurosurgery. fMRI and MEG underwent atlas-based connectivity analyses. Functional network centrality of the lateral middle temporal gyrus, part of the DMN, was used as a measure of local network integration. Subsequently, non-pathological cortical tissue from this region was used for single cell morphological and electrophysiological patch-clamp analysis, assessing integration in terms of total dendritic length and action potential rise speed. As could be hypothesized, greater network centrality related to better memory performance. Moreover, greater network centrality correlated with more integrative properties at the cellular level across patients. We conclude that individual differences in cognitively relevant functional network integration of a DMN region are mirrored by differences in cellular integrative properties of this region in TLE patients. These findings connect previously separate scales of investigation, increasing translational insight into focal pathology and large-scale network disturbances in TLE.

A general principle of dendritic constancy: A neuron’s size- and shape-invariant excitability

Reducing neuronal size results in less membrane and therefore lower input conductance. Smaller neurons are thus more excitable, as seen in their responses to somatic current injections. However, the impact of a neuron's size and shape on its voltage responses to dendritic synaptic activation is much less understood. Here we use analytical cable theory to predict voltage responses to distributed synaptic inputs in unbranched cables, showing that these are entirely independent of dendritic length. For a given synaptic density, neuronal responses depend only on the average dendritic diameter and intrinsic conductivity. This remains valid for a wide range of morphologies irrespective of their arborization complexity. Spiking models indicate that morphology-invariant numbers of spikes approximate the percentage of active synapses. In contrast to spike rate, spike times do depend on dendrite morphology. In summary, neuronal excitability in response to distributed synaptic inputs is largely unaffected by dendrite length or complexity.