Synaptic Mechanisms Regulating Mood State Transitions in Depression.

Depression is an episodic form of mental illness characterized by mood state transitions with poorly understood neurobiological mechanisms. Antidepressants reverse the effects of stress and depression on synapse function, enhancing neurotransmission, increasing plasticity, and generating new synapses in stress-sensitive brain regions. These properties are shared to varying degrees by all known antidepressants, suggesting that synaptic remodeling could play a key role in depression pathophysiology and antidepressant function. Still, it is unclear whether and precisely how synaptogenesis contributes to mood state transitions. Here, we review evidence supporting an emerging model in which depression is defined by a distinct brain state distributed across multiple stress-sensitive circuits, with neurons assuming altered functional properties, synapse configurations, and, importantly, a reduced capacity for plasticity and adaptation. Antidepressants act initially by facilitating plasticity and enabling a functional reconfiguration of this brain state. Subsequently, synaptogenesis plays a specific role in sustaining these changes over time.

Postnatal persistence of hippocampal Cajal-Retzius cells has a crucial role in the establishment of the hippocampal circuit.

Cajal-Retzius (CR) cells are a transient neuron type that populate the postnatal hippocampus. To understand how the persistence of CR cells influences the maturation of hippocampal circuits, we combined a specific transgenic mouse line with viral vector injection to selectively ablate CR cells from the postnatal hippocampus. We observed layer-specific changes in the dendritic complexity and spine density of CA1 pyramidal cells. In addition, transcriptomic analysis highlighted significant changes in the expression of synapse-related genes across development. Finally, we were able to identify significant changes in the expression levels of latrophilin 2, a postsynaptic guidance molecule known for its role in the entorhinal-hippocampal connectivity. These findings were supported by changes in the synaptic proteomic content in CA1 stratum lacunosum-moleculare. Our results reveal a crucial role for CR cells in the establishment of the hippocampal network.

Altered integration of excitatory inputs onto the basal dendrites of layer 5 pyramidal neurons in a mouse model of Fragile X syndrome.

Layer 5 (L5) pyramidal neurons receive predictive and sensory inputs in a compartmentalized manner at their apical and basal dendrites, respectively. To uncover how integration of sensory inputs is affected in autism spectrum disorders (ASD), we used two-photon glutamate uncaging to activate spines in the basal dendrites of L5 pyramidal neurons from a mouse model of Fragile X syndrome (FXS), the most common genetic cause of ASD. While subthreshold excitatory inputs integrate linearly in wild-type animals, surprisingly those with FXS summate sublinearly, contradicting what would be expected of sensory hypersensitivity classically associated with ASD. We next investigated the mechanism underlying this sublinearity by performing knockdown of the regulatory ß4 subunit of BK channels, which rescued the synaptic integration, a result that was corroborated with numerical simulations. Taken together, these findings suggest that there is a differential impairment in the integration of feedforward sensory and feedback predictive inputs in L5 pyramidal neurons in FXS and potentially other forms of ASD, as a result of specifically localized subcellular channelopathies. These results challenge the traditional view that FXS and other ASD are characterized by sensory hypersensitivity, proposing instead a hyposensitivity of sensory inputs and hypersensitivity of predictive inputs onto cortical neurons.

Conditional Astrocyte Rac1KO Attenuates Hyperreflexia after Spinal Cord Injury.

Spasticity is a hyperexcitability disorder that adversely impacts functional recovery and rehabilitative efforts after spinal cord injury (SCI). The loss of evoked rate-dependent depression (RDD) of the monosynaptic H-reflex is indicative of hyperreflexia, a physiological sign of spasticity. Given the intimate relationship between astrocytes and neurons, that is, the tripartite synapse, we hypothesized that astrocytes might have a significant role in post-injury hyperreflexia and plasticity of neighboring neuronal synaptic dendritic spines. Here, we investigated the effect of selective Rac1KO in astrocytes (i.e., adult male and female mice, transgenic cre-flox system) on SCI-induced spasticity. Three weeks after a mild contusion SCI, control Rac1wt animals displayed a loss of H-reflex RDD, that is, hyperreflexia. In contrast, transgenic animals with astrocytic Rac1KO demonstrated near-normal H-reflex RDD similar to pre-injury levels. Reduced hyperreflexia in astrocytic Rac1KO animals was accompanied by a loss of thin-shaped dendritic spine density on α-motor neurons in the ventral horn. In SCI-Rac1wt animals, as expected, we observed the development of dendritic spine dysgenesis on α-motor neurons associated with spasticity. As compared with WT animals, SCI animals with astrocytic Rac1KO expressed increased levels of the glial-specific glutamate transporter, glutamate transporter-1 in the ventral spinal cord, potentially enhancing glutamate clearance from the synaptic cleft and reducing hyperreflexia in astrocytic Rac1KO animals. Taken together, our findings show for the first time that Rac1 activity in astrocytes can contribute to hyperreflexia underlying spasticity following SCI. These results reveal an opportunity to target cell-specific molecular regulators of H-reflex excitability to manage spasticity after SCI.Significance Statement Spinal cord injury leads to stretch reflex hyperexcitability, which underlies the clinical symptom of spasticity. This study shows for the first time that astrocytic Rac1 contributes to the development of hyperreflexia after SCI. Specifically, astrocytic Rac1KO reduced SCI-related H-reflex hyperexcitability, decreased dendritic spine dysgenesis on α-motor neurons, and elevated the expression of the astrocytic glutamate transporter-1 (GLT-1). Overall, this study supports a distinct role for astrocytic Rac1 signaling within the spinal reflex circuit and the development of SCI-related spasticity.

Trans-synaptic Association of Vesicular Zinc Transporter 3 and Shank3 Supports Synapse-Specific Dendritic Spine Structure and Function in the Mouse Auditory Cortex.

Shank3 is a synaptic scaffolding protein that assists in tethering and organizing structural proteins and glutamatergic receptors in the postsynaptic density of excitatory synapses. The localization of Shank3 at excitatory synapses and the formation of stable Shank3 complexes is regulated by the binding of zinc to the C-terminal sterile-alpha-motif (SAM) domain of Shank3. Mutations in the SAM domain of Shank3 result in altered synaptic function and morphology, and disruption of zinc in synapses that express Shank3 leads to a reduction of postsynaptic proteins important for synaptic structure and function. This suggests that zinc supports the localization of postsynaptic proteins via Shank3. Many regions of the brain are highly enriched with free zinc inside glutamatergic vesicles at presynaptic terminals. At these synapses, zinc transporter 3 (ZnT3) moves zinc into vesicles where it is co-released with glutamate. Alterations in ZnT3 are implicated in multiple neurodevelopmental disorders, and ZnT3 knock-out (KO) mice-which lack synaptic zinc-show behavioral deficits associated with autism spectrum disorder and schizophrenia. Here we show that male and female ZnT3 KO mice have smaller dendritic spines and miniature excitatory postsynaptic current amplitudes than wildtype (WT) mice in the auditory cortex. Additionally, spine size deficits in ZnT3 KO mice are restricted to synapses that express Shank3. In WT mice, synapses that express both Shank3 and ZnT3 have larger spines compared to synapses that express Shank3 but not ZnT3. Together these findings suggest a mechanism whereby presynaptic ZnT3-dependent zinc supports postsynaptic structure and function via Shank3 in a synapse-specific manner.

G272V and P301L Mutations Induce Isoform Specific Tau Mislocalization to Dendritic Spines and Synaptic Dysfunctions in Cellular Models of 3R and 4R Tau Frontotemporal Dementia.

Tau pathologies are detected in the brains of some of the most common neurodegenerative diseases including Alzheimer's disease (AD), Lewy body dementia (LBD), chronic traumatic encephalopathy (CTE), and frontotemporal dementia (FTD). Tau proteins are expressed in six isoforms with either three or four microtubule-binding repeats (3R tau or 4R tau) due to alternative RNA splicing. AD, LBD, and CTE brains contain pathological deposits of both 3R and 4R tau. FTD patients can exhibit either 4R tau pathologies in most cases or 3R tau pathologies less commonly in Pick's disease, which is a subfamily of FTD. Here, we report the isoform-specific roles of tau in FTD. The P301L mutation, linked to familial 4R tau FTD, induces mislocalization of 4R tau to dendritic spines in primary hippocampal cultures that were prepared from neonatal rat pups of both sexes. Contrastingly, the G272V mutation, linked to familial Pick's disease, induces phosphorylation-dependent mislocalization of 3R tau but not 4R tau proteins to dendritic spines. The overexpression of G272V 3R tau but not 4R tau proteins leads to the reduction of dendritic spine density and suppression of mEPSCs in 5-week-old primary rat hippocampal cultures. The decrease in mEPSC amplitude caused by G272V 3R tau is dynamin-dependent whereas that caused by P301L 4R tau is dynamin-independent, indicating that the two tau isoforms activate different signaling pathways responsible for excitatory synaptic dysfunction. Our 3R and 4R tau studies here will shed new light on diverse mechanisms underlying FTD, AD, LBD, and CTE.

Improved DiOlistic labelling technique for neurons in situ: Detailed visualisation of dendritic spines and concurrent histochemical-detection in fixed tissue.

DiOlistic labelling is a robust, unbiased ballistic method that utilises lipophilic dyes to morphologically label neurons. While its efficacy on freshly dissected tissue specimens is well-documented, applying DiOlistic labelling to stored, fixed brain tissue and its use in polychromatic multi-marker studies poses significant technical challenges. Here, we present an improved, step-by-step protocol for DiOlistic labelling of dendrites and dendritic spines in fixed mouse tissue. Our protocol encompasses the five key stages: Tissue Preparation, Dye Bullet Preparation, DiOlistic Labelling, Confocal Imaging, and Image Analysis. This method ensures reliable and consistent labelling of dendritic spines in fixed mouse tissue, combined with increased throughput of samples and multi-parameter staining and visualisation of tissue, thereby offering a valuable approach for neuroscientific research.

Key morphological features of human pyramidal neurons.

The basic building block of the cerebral cortex, the pyramidal cell, has been shown to be characterized by a markedly different dendritic structure among layers, cortical areas, and species. Functionally, differences in the structure of their dendrites and axons are critical in determining how neurons integrate information. However, within the human cortex, these neurons have not been quantified in detail. In the present work, we performed intracellular injections of Lucifer Yellow and 3D reconstructed over 200 pyramidal neurons, including apical and basal dendritic and local axonal arbors and dendritic spines, from human occipital primary visual area and associative temporal cortex. We found that human pyramidal neurons from temporal cortex were larger, displayed more complex apical and basal structural organization, and had more spines compared to those in primary sensory cortex. Moreover, these human neocortical neurons displayed specific shared and distinct characteristics in comparison to previously published human hippocampal pyramidal neurons. Additionally, we identified distinct morphological features in human neurons that set them apart from mouse neurons. Lastly, we observed certain consistent organizational patterns shared across species. This study emphasizes the existing diversity within pyramidal cell structures across different cortical areas and species, suggesting substantial species-specific variations in their computational properties.

Role and mechanism of EphB3 in epileptic seizures and epileptogenesis through Kalirin.

BACKGROUND: The EphB receptor tyrosine kinase family participates in intricate signaling pathways that orchestrate neural networks, guide neuronal axon development, and modulate synaptic plasticity through interactions with surface-bound ephrinB ligands. Additionally, Kalirin, a Rho guanine nucleotide exchange factor, is notably expressed in the postsynaptic membrane of excitatory neurons and plays a role in synaptic morphogenesis. This study postulates that Kalirin may act as a downstream effector of EphB3 in epilepsy. This investigation focuses on understanding the link between EphB3 and epilepsy. MATERIALS AND METHODS: Chronic seizure models using LiCl-pilocarpine (LiCl/Pilo) and pentylenetetrazol were developed in rats. Neuronal excitability was gauged through whole-cell patch clamp recordings on rat hippocampal slices. Real-time PCR determined Kalirin's mRNA expression, and Western blotting was employed to quantify EphB3 and Kalirin protein levels. Moreover, dendritic spine density in epileptic rats was evaluated using Golgi staining. RESULTS: Modulation of EphB3 functionality influenced acute seizure severity, latency duration, and frequency of spontaneous recurrent seizures. Golgi staining disclosed an EphB3-driven alteration in dendritic spine density within the hippocampus of epileptic rats, underscoring its pivotal role in the reconfiguration of hippocampal neural circuits. Furthermore, our data propose Kalirin as a prospective downstream mediator of the EphB3 receptor. CONCLUSIONS: Our findings elucidate that EphB3 impacts the action potential dynamics in isolated rat hippocampal slices and alters dendritic spine density in the inner molecular layer of epileptic rat hippocampi, likely through Kalirin-mediated pathways. This hints at EphB3's significant role in shaping excitatory circuit loops and recurrent seizure activity via Kalirin.

Cross-Platform Synaptic Network Analysis of Human Entorhinal Cortex Identifies TWF2 as a Modulator of Dendritic Spine Length.

Proteomic studies using postmortem human brain tissue samples have yielded robust assessments of the aging and neurodegenerative disease(s) proteomes. While these analyses provide lists of molecular alterations in human conditions, like Alzheimer's disease (AD), identifying individual proteins that affect biological processes remains a challenge. To complicate matters, protein targets may be highly understudied and have limited information on their function. To address these hurdles, we sought to establish a blueprint to aid selection and functional validation of targets from proteomic datasets. A cross-platform pipeline was engineered to focus on synaptic processes in the entorhinal cortex (EC) of human patients, including controls, preclinical AD, and AD cases. Label-free quantification mass spectrometry (MS) data (n = 2260 proteins) was generated on synaptosome fractionated tissue from Brodmann area 28 (BA28; n = 58 samples). In parallel, dendritic spine density and morphology was measured in the same individuals. Weighted gene co-expression network analysis was used to construct a network of protein co-expression modules that were correlated with dendritic spine metrics. Module-trait correlations were used to guide unbiased selection of Twinfilin-2 (TWF2), which was the top hub protein of a module that positively correlated with thin spine length. Using CRISPR-dCas9 activation strategies, we demonstrated that boosting endogenous TWF2 protein levels in primary hippocampal neurons increased thin spine length, thus providing experimental validation for the human network analysis. Collectively, this study describes alterations in dendritic spine density and morphology as well as synaptic proteins and phosphorylated tau from the entorhinal cortex of preclinical and advanced stage AD patients.SIGNIFICANCE STATEMENT Proteomic studies can yield vast lists of molecules that are altered under various experimental or disease conditions. Here, we provide a blueprint to facilitate mechanistic validation of protein targets from human brain proteomic datasets. We conducted a proteomic analysis of human entorhinal cortex (EC) samples spanning cognitively normal and Alzheimer's disease (AD) cases with a comparison of dendritic spine morphology in the same samples. Network integration of proteomics with dendritic spine measurements allowed for unbiased discovery of Twinfilin-2 (TWF2) as a regulator of dendritic spine length. A proof-of-concept experiment in cultured neurons demonstrated that altering Twinfilin-2 protein level induced corresponding changes in dendritic spine length, thus providing experimental validation for the computational framework.

Stabilizing Immature Dendritic Spines in the Auditory Cortex: A Key Mechanism for mTORC1-Mediated Enhancement of Long-Term Fear Memories.

Mammalian target of rapamycin (mTOR) pathway has emerged as a key molecular mechanism underlying memory processes. Although mTOR inhibition is known to block memory processes, it remains elusive whether and how an enhancement of mTOR signaling may improve memory processes. Here we found in male mice that the administration of VO-OHpic, an inhibitor of the phosphatase and tensin homolog (PTEN) that negatively modulates AKT-mTOR pathway, enhanced auditory fear memory for days and weeks, while it left short-term memory unchanged. Memory enhancement was associated with a long-lasting increase in immature-type dendritic spines of pyramidal neurons into the auditory cortex. The persistence of spine remodeling over time arose by the interplay between PTEN inhibition and memory processes, as VO-OHpic induced only a transient immature spine growth in the somatosensory cortex, a region not involved in long-term auditory memory. Both the potentiation of fear memories and increase in immature spines were hampered by rapamycin, a selective inhibitor of mTORC1. These data revealed that memory can be potentiated over time by the administration of a selective PTEN inhibitor. In addition to disclosing new information on the cellular mechanisms underlying long-term memory maintenance, our study provides new insights on the molecular processes that aid enhancing memories over time.SIGNIFICANCE STATEMENT The neuronal mechanisms that may help improve the maintenance of long-term memories are still elusive. The inhibition of mammalian-target of rapamycin (mTOR) signaling shows that this pathway plays a crucial role in synaptic plasticity and memory formation. However, whether its activation may strengthen long-term memory storage is unclear. We assessed the consequences of positive modulation of AKT-mTOR pathway obtained by VO-OHpic administration, a phosphatase and tensin homolog inhibitor, on memory retention and underlying synaptic modifications. We found that mTOR activation greatly enhanced memory maintenance for weeks by producing a long-lasting increase of immature-type dendritic spines in pyramidal neurons of the auditory cortex. These results offer new insights on the cellular and molecular mechanisms that can aid enhancing memories over time.

Protein 4.1N Plays a Cell Type-Specific Role in Hippocampal Glutamatergic Synapse Regulation.

Many glutamatergic synapse proteins contain a 4.1N protein binding domain. However, a role for 4.1N in the regulation of glutamatergic neurotransmission has been controversial. Here, we observe significantly higher expression of protein 4.1N in granule neurons of the dentate gyrus (DG granule neurons) compared with other hippocampal regions. We discover that reducing 4.1N expression in rat DG granule neurons of either sex results in a significant reduction in glutamatergic synapse function that is caused by a decrease in the number of glutamatergic synapses. By contrast, we find reduction of 4.1N expression in hippocampal CA1 pyramidal neurons has no impact on basal glutamatergic neurotransmission. We also find 4.1N's C-terminal domain (CTD) to be nonessential to its role in the regulation of glutamatergic synapses of DG granule neurons. Instead, we show that 4.1N's four-point-one, ezrin, radixin, and moesin (FERM) domain is essential for supporting synaptic AMPA receptor (AMPAR) function in these neurons. Altogether, this work demonstrates a novel, cell type-specific role for protein 4.1N in governing glutamatergic synapse function.SIGNIFICANCE STATEMENT Glutamatergic synapses exhibit immense molecular diversity. In comparison to heavily studied Schaffer collateral, CA1 glutamatergic synapses, significantly less is known about perforant path-dentate gyrus (DG) synapses. Our data demonstrate that compromising 4.1N function in CA1 pyramidal neurons produces no alteration in basal glutamatergic synaptic transmission. However, in DG granule neurons, compromising 4.1N function leads to a significant decrease in the strength of glutamatergic neurotransmission at perforant pathway synapses. Together, our data identifies 4.1N as a cell type-specific regulator of synaptic transmission within the hippocampus and reveals a unique molecular program that governs perforant pathway synapse function.

Circadian-Dependent Intermittent Fasting Influences Ischemic Tolerance and Dendritic Spine Remodeling.

BACKGROUND: Preconditioning by intermittent fasting is linked to improved cognition and motor function, and enhanced recovery after stroke. Although the duration of fasting was shown to elicit different levels of neuroprotection after ischemic stroke, the impact of time of fasting with respect to the circadian cycles remains unexplored. METHODS: Cohorts of mice were subjected to a daily 16-hour fast, either during the dark phase (active-phase intermittent fasting) or the light phase (inactive-phase intermittent fasting) or were fed ad libitum. Following a 6-week dietary regimen, mice were subjected to transient focal cerebral ischemia and underwent behavioral functional assessment. Brain samples were collected for RNA sequencing and histopathologic analyses. RESULTS: Active-phase intermittent fasting cohort exhibited better poststroke motor and cognitive recovery as well as reduced infarction, in contrast to inactive-phase intermittent fasting cohort, when compared with ad libitum cohort. In addition, protection of dendritic spine density/morphology and increased expression of postsynaptic density protein-95 were observed in the active-phase intermittent fasting. CONCLUSIONS: These findings indicate that the time of daily fasting is an important factor in inducing ischemic tolerance by intermittent fasting.

Morphological heterogeneity of neurons in the human central amygdaloid nucleus.

The central amygdaloid nucleus (CeA) has an ancient phylogenetic development and functions relevant for animal survival. Local cells receive intrinsic amygdaloidal information that codes emotional stimuli of fear, integrate them, and send cortical and subcortical output projections that prompt rapid visceral and social behavior responses. We aimed to describe the morphology of the neurons that compose the human CeA (N = 8 adult men). Cells within CeA coronal borders were identified using the thionine staining and were further analyzed using the "single-section" Golgi method followed by open-source software procedures for two-dimensional and three-dimensional image reconstructions. Our results evidenced varied neuronal cell body features, number and thickness of primary shafts, dendritic branching patterns, and density and shape of dendritic spines. Based on these criteria, we propose the existence of 12 morphologically different spiny neurons in the human CeA and discuss the variability in the dendritic architecture within cellular types, including likely interneurons. Some dendritic shafts were long and straight, displayed few collaterals, and had planar radiation within the coronal neuropil volume. Most of the sampled neurons showed a few to moderate density of small stubby/wide spines. Long spines (thin and mushroom) were observed occasionally. These novel data address the synaptic processing and plasticity in the human CeA. Our morphological description can be combined with further transcriptomic, immunohistochemical, and electrophysiological/connectional approaches. It serves also to investigate how neurons are altered in neurological and psychiatric disorders with hindered emotional perception, in anxiety, following atrophy in schizophrenia, and along different stages of Alzheimer's disease.

Ion-concentration gradients induced by synaptic input increase the voltage depolarization in dendritic spines.

The vast majority of excitatory synaptic connections occur on dendritic spines. Due to their extremely small volume and spatial segregation from the dendrite, even moderate synaptic currents can significantly alter ionic concentrations. This results in chemical potential gradients between the dendrite and the spine head, leading to measurable electrical currents. In modeling electric signals in spines, different formalisms were previously used. While the cable equation is fundamental for understanding the electrical potential along dendrites, it only considers electrical currents as a result of gradients in electrical potential. The Poisson-Nernst-Planck (PNP) equations offer a more accurate description for spines by incorporating both electrical and chemical potential. However, solving PNP equations is computationally complex. In this work, diffusion currents are incorporated into the cable equation, leveraging an analogy between chemical and electrical potential. For simulating electric signals based on this extension of the cable equation, a straightforward numerical solver is introduced. The study demonstrates that this set of equations can be accurately solved using an explicit finite difference scheme. Through numerical simulations, this study unveils a previously unrecognized mechanism involving diffusion currents that amplify electric signals in spines. This discovery holds crucial implications for both numerical simulations and experimental studies focused on spine neck resistance and calcium signaling in dendritic spines.

Microglia-mediated calcium-permeable AMPAR accumulation in the nucleus accumbens drives hyperlocomotion during cocaine withdrawal.

During withdrawal from cocaine, calcium permeable-AMPA receptors (CP-AMPAR) progressively accumulate in nucleus accumbens (NAc) synapses, a phenomenon linked to behavioral sensitization and drug-seeking. Recently, it has been suggested that neuroimmune alterations might promote aberrant changes in synaptic plasticity, thus contributing to substance abuse-related behaviors. Here, we investigated the role of microglia in NAc neuroadaptations after withdrawal from cocaine-induced conditioned place preference (CPP). We depleted microglia using PLX5622-supplemented diet during cocaine withdrawal, and after the place preference test, we measured dendritic spine density and the presence of CP-AMPAR in the NAc shell. Microglia depletion prevented cocaine-induced changes in dendritic spines and CP-AMPAR accumulation. Furthermore, microglia depletion prevented conditioned hyperlocomotion without affecting drug-context associative memory. Microglia displayed fewer number of branches, resulting in a reduced arborization area and microglia control domain at late withdrawal. Our results suggest that microglia are necessary for the synaptic adaptations in NAc synapses during cocaine withdrawal and therefore represent a promising therapeutic target for relapse prevention.

Differential Effects of Neonatal Ventral Hippocampus Lesion on Behavior and Corticolimbic Plasticity in Wistar-Kyoto and Spontaneously Hypertensive Rats.

Dysfunction of the corticolimbic system, particularly at the dendritic spine level, is a recognized core mechanism in neurodevelopmental disorders such as schizophrenia. Neonatal ventral hippocampus lesion (NVHL) in Sprague-Dawley rats induces both a schizophrenia-related behavioral phenotype and dendritic spine pathology (reduced total number and mature spines) in corticolimbic areas, which is mitigated by antipsychotics. However, there is limited information on the impact of rat strain on NVHL outcomes and antipsychotic effects. We compared the behavioral performance in the open field, novel object recognition (NORT), and social interaction tests, as well as structural neuroplasticity with the Golgi-Cox stain in Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) male rats with and without NVHL. Additionally, we explored the effect of the atypical antipsychotic risperidone (RISP). WKY rats with NVHL displayed motor hyperactivity without impairments in memory and social behavior, accompanied by dendritic spine pathology in the neurons of the prefrontal cortex (PFC) layer 3 and basolateral amygdala. RISP treatment reduced motor activity and had subtle and selective effects on the neuroplasticity alterations. In SH rats, NVHL increased the time spent in the border area during the open field test, impaired the short-term performance in NORT, and reduced social interaction time, deficits that were corrected after RISP administration. The NVHL caused dendritic spine pathology in the PFC layers 3 and 5 of SH rats, which RISP treatment ameliorated. Our results support the utility of the NVHL model for exploring neuroplasticity mechanisms in schizophrenia and understanding pharmacotherapy.

Role of estrogen in sex differences in memory, emotion and neuropsychiatric disorders.

Estrogen regulates a wide range of neuronal functions in the brain, such as dendritic spine formation, remodeling of synaptic plasticity, cognition, neurotransmission, and neurodevelopment. Estrogen interacts with intracellular estrogen receptors (ERs) and membrane-bound ERs to produce its effect via genomic and non-genomic pathways. Any alterations in these pathways affect the number, size, and shape of dendritic spines in neurons associated with psychiatric diseases. Increasing evidence suggests that estrogen fluctuation causes changes in dendritic spine density, morphology, and synapse numbers of excitatory and inhibitory neurons differently in males and females. In this review, we discuss the role of estrogen hormone in rodents and humans based on sex differences. First, we explain estrogen role in learning and memory and show that a high estrogen level alleviates the deficits in learning and memory. Secondly, we point out that estrogen produces a striking difference in emotional memories in men and women, which leads them to display sex-specific differences in underlying neuronal signaling. Lastly, we discuss that fluctuations in estrogen levels in men and women are related to neuropsychiatric disorders, including schizophrenia, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), bipolar disorder (BPD), major depressive disorder (MDD), substance use disorder (SUD), and anxiety disorders.

Microanatomical study of pyramidal neurons in the contralesional somatosensory cortex after experimental ischemic stroke.

At present, many studies support the notion that after stroke, remote regions connected to the infarcted area are also affected and may contribute to functional outcome. In the present study, we have analyzed possible microanatomical alterations in pyramidal neurons from the contralesional hemisphere after induced stroke. We performed intracellular injections of Lucifer yellow in pyramidal neurons from layer III in the somatosensory cortex of the contralesional hemisphere in an ischemic stroke mouse model. A detailed 3-dimensional analysis of the neuronal complexity and morphological alterations of dendritic spines was then performed. Our results demonstrate that pyramidal neurons from layer III in the somatosensory cortex of the contralesional hemisphere show selective changes in their dendritic arbors, namely, less dendritic complexity of the apical dendritic arbor-but no changes in the basal dendritic arbor. In addition, we found differences in spine morphology in both apical and basal dendrites comparing the contralesional hemisphere with the lesional hemisphere. Our results show that pyramidal neurons of remote areas connected to the infarct zone exhibit a series of selective changes in neuronal complexity and morphological distribution of dendritic spines, supporting the hypothesis that remote regions connected to the peri-infarcted area are also affected after stroke.

Altered synaptic protein expression, aberrant spine morphology, and impaired spatial memory in Dlgap2 mutant mice, a genetic model of autism spectrum disorder.

A microdeletion of approximately 2.4 Mb at the 8p23 terminal region has been identified in a Taiwanese autistic boy. Among the products transcribed/translated from genes mapped in this region, the reduction of DLGAP2, a postsynaptic scaffold protein, might be involved in the pathogenesis of autism spectrum disorder (ASD). DLGAP2 protein was detected in the hippocampus yet abolished in homozygous Dlgap2 knockout (Dlgap2 KO) mice. In this study, we characterized the hippocampal phenotypes in Dlgap2 mutant mice. Dlgap2 KO mice exhibited impaired spatial memory, indicating poor hippocampal function in the absence of DLGAP2. Aberrant expressions of postsynaptic proteins, including PSD95, SHANK3, HOMER1, GluN2A, GluR2, mGluR1, mGluR5, ßCAMKII, ERK1/2, ARC, BDNF, were noticed in Dlgap2 mutant mice. Further, the spine density was increased in Dlgap2 KO mice, while the ratio of mushroom-type spines was decreased. We also observed a thinner postsynaptic density thickness in Dlgap2 KO mice at the ultrastructural level. These structural changes found in the hippocampus of Dlgap2 KO mice might be linked to impaired hippocampus-related cognitive functions such as spatial memory. Mice with Dlgap2 deficiency, showing signs of intellectual disability, a common co-occurring condition in patients with ASD, could be a promising animal model which may advance our understanding of ASD.