Spine Density In Pyramidal Neurons Research Articles

Neurodevelopment effects of early life bisphenol-A exposure on visual memory: Insights into recovery dynamics

Bisphenol A (BPA), a ubiquitous endocrine disruptor, is implicated in the cognitive deficits observed in both children and animals. Especially, BPA-induced spatial memory deterioration during the whole development phase of rodents has been well delineated. However, whether BPA exposure on the different development phases exerts similar effects on the prefrontal cortex (PFC) dependent visual memory is still elusive. Here, we chose two exposure windows, the whole gestation and lactation phases (E0∼P21) and the whole juvenile and adolescent phases (P22∼P60), for exposing rats to BPA. The visual memory of those rats was accessed by object recognition testing in the open field after BPA exposure and a constant recovery interval. The results revealed a substantial decline of visual memory under both exposure conditions, accompanied by an increase in anxiety-like behavior in BPA-exposed rats. Notably, after a 20-day recovery period, those behavioral changes induced by BPA exposure during P22∼60, not E0∼P21, were reversed compared to the control rats. According to morphological analysis of those rats after recovery, we found that the spine density of pyramidal neurons in the PFC were significant decreased in rats with BPA exposure during E0∼P21 and there was no difference between rats with or without BPA exposure during P22∼P60. Additionally, a similar change trend in excitatory receptors expression was observed under both exposure conditions. After an additional 20 days of recovery, the behavioral changes in rats with perinatal BPA exposure reverted to the normal status. Our present findings illuminate the dynamic effects of BPA on PFC-dependent functions across two crucial early developmental stages of life.

The antipsychotic olanzapine reduces memory deficits and neuronal abnormalities in a male rat model of Autism

The prevalence of autism spectrum disorder (ASD), a neurodevelopmental condition that impacts social interaction and sensory processing, is rising. Valproic acid (VPA) exposure during pregnancy causes autistic-like traits in offspring. Olanzapine (OLZ), an atypical antipsychotic, is used to treat ASD. We assessed the impact of OLZ on behavior, neuromorphology, and nitric oxide (NO) levels in the hippocampus using prenatal VPA treatment in rats. It is commonly known that ASD patients exhibit sensory abnormalities. As such, we utilized the tail flick test to validate the ASD model. In the novel object recognition test (NORT), VPA exposure reduces the discrimination index (DI) in the first introduction to the novel object. Moreover, OLZ and vehicle-treated rats perform differently in the second exposition to the DI of the novel object, suggesting that OLZ reverses VPA-induced deficits in recognition memory. The latency to find the hidden platform in the Morris water maze test of memory and learning improves in VPA-exposed rats after OLZ administration, indicating that OLZ improves spatial memory in these rats. Administration of prenatal VPA induces neuronal hypotrophy and reduces spine density in pyramidal neurons of the CA1 region of the hippocampus. Treatment with OLZ corrects the neuromorphological changes brought on by VPA. In the CA1 region of the hippocampus, VPA treatment increases the number of neurons, which normalizes with OLZ treatment. OLZ increases the NO levels in the dorsal hippocampus in control rats. In rats exposed to VPA, the second-generation antipsychotic OLZ reduces memory-related and neuroplastic alterations. The current findings support the use of OLZ in this illness and further validate the use of prenatal VPA as a model of ASD.

Dehydroepiandrosterone Attenuates Astroglial Activation, Neuronal Loss and Dendritic Degeneration in Iron-Induced Post-Traumatic Epilepsy

Iron-induced experimental epilepsy in rodents reproduces features of post-traumatic epilepsy (PTE) in humans. The neural network of the brain seems to be highly affected during the course of epileptogenesis and determines the occurrence of sudden and recurrent seizures. The aim of the current study was to evaluate astroglial and neuronal response as well as dendritic arborization, and the spine density of pyramidal neurons in the cortex and hippocampus of epileptic rats. We also evaluated the effect of exogenous administration of a neuroactive steroid, dehydroepiandrosterone (DHEA), in epileptic rats. To induce epilepsy, male Wistar rats were given an intracortical injection of 100 mM solution (5 µL) of iron chloride (FeCl3). After 20 days, DHEA was administered intraperitoneally for 21 consecutive days. Results showed epileptic seizures and hippocampal Mossy Fibers (MFs) sprouting in epileptic rats, while DHEA treatment significantly reduced the MFs' sprouting. Astroglial activation and neuronal loss were subdued in rats that received DHEA compared to epileptic rats. Dendritic arborization and spine density of pyramidal neurons was diminished in epileptic rats, while DHEA treatment partially restored their normal morphology in the cortex and hippocampus regions of the brain. Overall, these findings suggest that DHEA's antiepileptic effects may contribute to alleviating astroglial activation and neuronal loss along with enhancing dendritic arborization and spine density in PTE.

Ikzf1 as a novel regulator of microglial homeostasis in inflammation and neurodegeneration

In the last two decades, microglia have emerged as key contributors to disease progression in many neurological disorders, not only by exerting their classical immunological functions but also as extremely dynamic cells with the ability to modulate synaptic and neural activity. This dynamic behavior, together with their heterogeneous roles and response to diverse perturbations in the brain parenchyma has raised the idea that microglia activation is more diverse than anticipated and that understanding the molecular mechanisms underlying microglial states is essential to unravel their role in health and disease from development to aging. The Ikzf1 (a.k.a. Ikaros) gene plays crucial roles in modulating the function and maturation of circulating monocytes and lymphocytes, but whether it regulates microglial functions and states is unknown. Using genetic tools, here we describe that Ikzf1 is specifically expressed in the adult microglia in brain regions such as cortex and hippocampus. By characterizing the Ikzf1 deficient mice, we observed that these mice displayed spatial learning deficits, impaired hippocampal CA3-CA1 long-term potentiation, and decreased spine density in pyramidal neurons of the CA1, which correlates with an increased expression of synaptic markers within microglia. Additionally, these Ikzf1 deficient microglia exhibited a severe abnormal morphology in the hippocampus, which is accompanied by astrogliosis, an aberrant composition of the inflammasome, and an altered expression of disease-associated microglia molecules. Interestingly, the lack of Ikzf1 induced changes on histone 3 acetylation and methylation levels in the hippocampus. Since the lack of Ikzf1 in mice appears to induce the internalization of synaptic markers within microglia, and severe gliosis we then analyzed hippocampal Ikzf1 levels in several models of neurological disorders. Ikzf1 levels were increased in the hippocampus of these neurological models, as well as in postmortem hippocampal samples from Alzheimer’s disease patients. Finally, over-expressing Ikzf1 in cultured microglia made these cells hyporeactive upon treatment with lipopolysaccharide, and less phagocytic compared to control microglia. Altogether, these results suggest that altered Ikzf1 levels in the adult hippocampus are sufficient to induce synaptic plasticity and memory deficits via altering microglial state and function.

Effects of chronic stress on nectin1 levels in the mouse primary somatosensory cortex

Chronic exposure to stressful experiences impairs synaptic plasticity. Previous studies have shown that the spine densities of pyramidal neurons, the turnover of mushroom-type spines, and the excitatory–inhibitory balance in the primary somatosensory cortex (S1) are modulated by stress. Trans-synaptic cell adhesion molecules (CAMs) are implicated in stress-induced synaptic deficits. However, it remains unknown whether stress dysregulates CAMs in S1 and thereby impairs synaptic plasticity. In this study, we applied the early-life stress (ELS), chronic social defeat stress (CSDS), and chronic restraint stress paradigms and measured the mRNA levels of <i>nectin1</i> in S1 of wild-type and conditional forebrain corticotropin-releasing hormone receptor 1 type (CRHR1) conditional knockout mice. We found that ELS increased <i>nectin1</i> mRNA levels in S1 in adult but not adolescent mice. Moreover, CSDS increased the <i>nectin1</i> mRNA levels in S1 in adult mice via the CRH-CRHR1 system. Our findings suggest that S1 is vulnerable to repeated stress exposures at some life stages, and dysregulated <i>nectin1</i> expression may underlie stress-induced structural and functional abnormalities in S1.

Sevoflurane Exposure in the Developing Brain Induces Hyperactivity, Anxiety-Free, and Enhancement of Memory Consolidation in Mice.

BackgroundSevoflurane exposure at brain developmental stages has been reported to induce neurotoxicity and, subsequently, results in learning deficits at the juvenile age. In this study, we aimed to investigate the effects of prior early-age sevoflurane exposure on locomotor activity, anxiety, CA1-dependent learning, and spatial memory, as well as synapse changes in mice.MethodsTotally, 3% sevoflurane was given to neonatal mice at postnatal day 7 for 4 h. These sevoflurane-treated mice were later subjected to open field and Morris water maze tests at their adult age (postnatal days 60–90) to assess their motor activity and spatial learning ability, respectively. The brain slices of sevoflurane-treated and control mice were examined for dendritic spine density and long-term potentiation (LTP) features following behavior tests (postnatal day 60). Protein levels of N-methyl-D-aspartate (NMDA) receptor subtypes and PSD95 in brain lysate were measured by using immunoblotting at the same age (postnatal day 60).ResultsPrior early-age sevoflurane exposure increased the overall moving distance, prolonged the central-area lingering time, and increased the central-area entries of adult mice. Sevoflurane-treated mice spent more time in the target quadrant during the probe test. An increase of the spine density of pyramidal neurons in the CA1 region was observed in sevoflurane-treated mice. NMDA receptor GluN2A subunit, but not the GluN2B or PSD95, was increased in the brain lysate of sevoflurane-treated mice compared with that of control mice. LTP in the hippocampus did not significantly differ between sevoflurane-treated and control mice.ConclusionExposure to sevoflurane for mice during an early brain developmental stage (P7) induces later-on hyperactivity, anxiety-free, and enhancement of memory retention. These observations shed light on future investigations on the underlying mechanisms of sevoflurane’s effect on neuronal development.

Deletion of Schizophrenia Susceptibility Gene Ulk4 Leads to Abnormal Cognitive Behaviors via Akt-GSK-3 Signaling Pathway in Mice.

Despite of strenuous research in the past decades, the etiology of schizophrenia (SCZ) still remains incredibly controversial. Previous genetic analysis has uncovered a close association of Unc-51 like kinase 4 (ULK4), a family member of Unc-51-like serine/threonine kinase, with SCZ. However, animal behavior data which may connect Ulk4 deficiency with psychiatric disorders, particularly SCZ are still missing. We generated Emx1-Cre:Ulk4flox/flox conditional knockout (CKO) mice, in which Ulk4 was deleted in the excitatory neurons of cerebral cortex and hippocampus. The cerebral cellular architecture was maintained but the spine density of pyramidal neurons was reduced in Ulk4 CKO mice. CKO mice showed deficits in the spatial and working memories and sensorimotor gating. Levels of p-Akt and p-GSK-3α/β were markedly reduced in the CKO mice indicating an elevation of GSK-3 signaling. Mechanistically, Ulk4 may regulate the GSK-3 signaling via putative protein complex comprising of two phosphatases, protein phosphatase 2A (PP2A) and 1α (PP1α). Indeed, the reduction of p-Akt and p-GSK-3α/β was rescued by administration of inhibitor acting on PP2A and PP1α in CKO mice. Our data identified potential downstream signaling pathway of Ulk4, which plays important roles in the cognitive functions and when defective, may promote SCZ-like pathogenesis and behavioral phenotypes in mice.

Neonatal Tactile Stimulation Downregulates Dendritic Spines in Layer V Pyramidal Neurons of the WAG/Rij Rat Somatosensory Cortex.

Objective The aim of our study is to examine the effects of neonatal tactile stimulations on the brain structures that previously defined as the focus of epilepsy in the Wistar-Albino-Glaxo from Rijswijk (WAG/Rij) rat brain with genetic absence epilepsy. Methods In the present research, morphology and density of dendritic spines were analyzed in layer V pyramidal neurons of the somatosensory cortex (SoCx) of WAG/Rij rats (nonstimulated control, tactile-stimulated, and maternal separated rats) and healthy Wistar (nonepileptic) rats. To achieve this, a Golgi-Cox method was used. Results Dendritic spine number in layer V of the SoCx has been detected significantly higher in adult WAG/Rij rats at postnatal day 150 in comparison to nonepileptic adult control Wistar rats (p < 0.001). Moreover, quantitative analyses of dendrite structure in adult WAG/Rij rats showed a decrease in dendrite spine density of pyramidal neurons of SoCx which occurred in early neonatal exposure to maternal separation (MS) and tactile stimulation (TS) (p < 0.001). Conclusions Our findings provide the first evidence that tactile stimulations during the early postnatal period have a long-term impact on dendrite structure in WAG/Rij rat's brain and demonstrate that neonatal tactile stimulation can regulate dendritic spines in layer V in pyramidal neurons of SoCx in epileptic brains.

Anti-PTSD Effects of Hypidone Hydrochloride (YL-0919): A Novel Combined Selective 5-HT Reuptake Inhibitor/5-HT1A Receptor Partial Agonist/5-HT6 Receptor Full Agonist.

Posttraumatic stress disorder (PTSD) is a debilitating trauma and stressor-related disorder that has become a major neuropsychiatric problem, leading to substantial disruptions in individual health and societal costs. Our previous studies have demonstrated that hypidone hydrochloride (YL-0919), a novel combined selective 5-HT reuptake inhibitor/5-HT1A receptor partial agonist/5-HT6 receptor full agonist, exerts notable antidepressant- and anxiolytic-like as well as procognitive effects. However, whether YL-0919 exerts anti-PTSD effects and its underlying mechanisms are still unclear. In the present study, we showed that repeated treatment with YL-0919 caused significant suppression of contextual fear, enhanced anxiety and cognitive dysfunction induced by the time-dependent sensitization (TDS) procedure in rats and by inescapable electric foot-shock in a mouse model of PTSD. Furthermore, we found that repeated treatment with YL-0919 significantly reversed the accompanying decreased expression of the brain-derived neurotrophic factor (BDNF) and the synaptic proteins (synapsin1 and GluA1), and ameliorated the neuroplasticity disruption in the prefrontal cortex (PFC), including the dendritic complexity and spine density of pyramidal neurons. Taken together, the current study indicated that YL-0919 exerts clear anti-PTSD effects, which might be partially mediated by ameliorating the structural neuroplasticity by increasing the expression of BDNF and the formation of synaptic proteins in the PFC.

The C-terminal fragment of the heavy chain of the tetanus toxin (Hc-TeTx) improves motor activity and neuronal morphology in the limbic system of aged mice.

In the aging process, the brain presents biochemical and morphological alterations. The neurons of the limbic system show reduced size dendrites, in addition to the loss of dendritic spines. These disturbances trigger a decrease in motor and cognitive function. Likewise, it is reported that during aging, in the brain, there is a significant decrease in neurotrophic factors, which are essential in promoting the survival and plasticity of neurons. The carboxyl-terminal fragment of the heavy chain of the tetanus toxin (Hc-TeTx) acts similarly to neurotrophic factors, inducing neuroprotection in different models of neuronal damage. The aim here, was to evaluate the effect of Hc-TeTx on the motor processes of elderly mice (18months old), and its impact on the dendritic morphology and density of dendritic spines of neurons in the limbic system. The morphological analysis in the dendrites was evaluated employing Golgi-Cox staining. Hc-TeTx was administered (0.5mg/kg) intraperitoneally for three days in 18-month-old mice. Locomotor activity was evaluated in a novel environment 30days after the last administration of Hc-TeTx. Mice treated with Hc-TeTx showed significant changes in their motor behavior, and an increased dendritic spine density of pyramidal neurons in layers 3 and 5 of the prefrontal cortex in the hippocampus, and medium spiny neurons of the nucleus accumbens (NAcc). In conclusion, the Hc-TeTx improves the plasticity of the brain regions of the limbic system of aged mice. Therefore, it is proposed as a pharmacological alternative to prevent or delay brain damage during aging.

Df(h15q13)/+ Mouse Model Reveals Loss of Astrocytes and Synaptic-Related Changes of the Excitatory and Inhibitory Circuits in the Medial Prefrontal Cortex.

The 15q13.3 deletion is associated with multiple neurodevelopmental disorders including epilepsy, schizophrenia, and autism. The Df(h15q13)/+ mouse model was recently generated that recapitulates several phenotypic features of the human 15q13.3 deletion syndrome (DS). However, the biological substrates underlying these phenotypes in Df(h15q13)/+ mice have not yet been fully characterized. RNA sequencing followed by real-time quantitative PCR, western blotting, liquid chromatography-mass spectrometry, and stereological analysis were employed to dissect the molecular, structural, and neurochemical phenotypes of the medial prefrontal cortex (mPFC) circuits in Df(h15q13)/+ mouse model. Transcriptomic profiling revealed enrichment for astrocyte-specific genes among differentially expressed genes, translated by a decrease in the number of glial fibrillary acidic protein positive cells in mPFC of Df(h15q13)/+ mice compared with wild-type mice. mPFC in Df(h15q13)/+ mice also showed a deficit of the inhibitory presynaptic marker GAD65, in addition to a reduction in dendritic arborization and spine density of pyramidal neurons from layers II/III. mPFC levels of GABA and glutamate neurotransmitters were not different between genotypes. Our results suggest that the 15q13.3 deletion modulates nonneuronal circuits in mPFC and confers molecular and morphometric alterations in the inhibitory and excitatory neurocircuits, respectively. These alterations potentially contribute to the phenotypes accompanied with the 15q13.3DS.

7, 8-Dihydroxy-4-methylcoumarin reverses depression model-induced depression-like behaviors and alteration of dendritic spines in the mood circuits

Major depressive disorder (MDD) is a common mental disorder characterized by a persistent feeling of sadness, slow thought, impaired focus and loss of interest but the underlying mechanisms are largely unknown. Dendritic spines play an important role in the formation and maintenance of emotional circuits in the brain. Abnormalities in this process can lead to psychiatric diseases. 7,8-Dihydroxy-4-methylcoumarin (Dhmc), a precursor in the synthesis of derivatives of 4-methyl coumarin, plays an important role in protecting the nervous system from developing diseases and its most distinctive feature is safety. The aim of this study was to investigate whether Dhmc alleviates chronic unpredictable mild stress (CUMS)-induced depression-like behaviors and reverses CUMS-induced alterations in dendritic spines of principal neurons in brain areas of the emotional circuits including the hippocampus, medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and basolateral amygdala (BLA) in male rats. Our results showed that CUMS-induced depression-like behaviors were accompanied by a decrease in spine density in pyramidal neurons of both the hippocampal CA3 area and the mPFC, and an increase in spine density in both the neurons of BLA and the medium spiny neurons (MSNs) of the NAc, as well as a decrease in the levels of the AMPA receptor subunit GluA1 and Kalirin-7 in the hippocampus compared with the control group. Intraperitoneal injection (i.p.) of Dhmc to the CUMS-exposed rats ameliorated CUMS-induced depression-like behaviors and reversed CUMS-mediated alterations in spine density and the levels of both GluA1 and Kalirin-7. Our results show an important role of Dhmc in reversing CUMS-induced depression-like behaviors and CUMS-mediated alterations in spine density.

Amygdalar Plasticity in Airway Disease

Asthma is one of the most common immunological diseases among humans. Chronic airway inflammation drives asthma pathophysiology. While much effort has focused on understanding the airway intrinsic effects of inflammation, chronic inflammation also activates stress‐responsive brain regions, including the amygdala. This is important because greater amygdala activity exaggerates inflammatory responses, and greater amygdala activation in asthmatic patients correlates with reduced bronchodilator responses. Within the amygdala, pyramidal neurons of the basolateral amygdala (BLA) encode aversive stimuli. These neurons are characterized by spiny dendrites, are excitatory (e.g., glutamatergic), and exhibit unique cellular and structural plasticity in response to aversive stimuli that is mechanistically linked to BLA function. Thus, pyramidal neurons might be key targets of inflammation that further drive asthma pathology. Here we test the central hypothesis that pyramidal neurons of the BLA encode airway inflammation and exacerbate asthma pathophysiology. Our preliminary data suggest that an acute asthma exacerbation increases activity of the murine BLA, as evidenced by c‐fos expression and manganese‐enhanced MRI. Further, we show that global pharmacological disruption of glutamatergic signaling mitigates airway disease features, including airway hyperreactivity and mucus hypersecretion. Finally, we show that airway inflammation increases dendritic spine density in pyramidal neurons of the BLA. These results identify novel therapeutic targets for asthma, and possibly other airway diseases.

Postnatal nectin-3 knockdown induces structural abnormalities of hippocampal principal neurons and memory deficits in adult mice.

The early postnatal stage is a critical period of hippocampal neurodevelopment and also a period of high vulnerability to adverse life experiences. Recent evidence suggests that nectin‐3, a cell adhesion molecule, mediates memory dysfunction and dendritic alterations in the adult hippocampus induced by postnatal stress. But it is unknown whether postnatal nectin‐3 reduction alone is sufficient to alter hippocampal structure and function in adulthood. Here, we down regulated hippocampal expression of nectin‐3 and its heterophilic adhesion partner nectin‐1, respectively, from early postnatal stage by injecting adeno‐associated virus (AAV) into the cerebral lateral ventricles of neonatal mice (postnatal day 2). We found that suppression of nectin‐3, but not nectin‐1, expression from the early postnatal stage impaired hippocampus‐dependent novel object recognition and spatial object recognition in adult mice. Moreover, AAV‐mediated nectin‐3 knockdown significantly reduced dendritic complexity and spine density of pyramidal neurons throughout the hippocampus, whereas nectin‐1 knockdown only induced the loss of stubby spines in CA3. Our data provide direct evidence that nectins, especially nectin‐3, are necessary for postnatal hippocampal development of memory functions and structural integrity.

Obesity Impairs Mobility and Adult Hippocampal Neurogenesis.

Currently, it is controversially discussed whether a relationship between obesity and cognition exists. We here analyzed a mouse model of obesity (leptin-deficient mice) to study the effects of obesity on the morphology of the hippocampus (a brain structure involved in mechanisms related to learning and memory) and on behavior. Mice aged 4 to 6 months were analyzed. At this age, the obese mice have nearly double the body weight as controls, but display smaller brains (brain volume is about 10% smaller) as control animals of the same age. Adult hippocampal neurogenesis, a process that is linked to learning and memory, might be disturbed in the obese mice and contribute to the smaller brain volume. Adult hippocampal neurogenesis was examined using specific markers for cell proliferation (phosphohistone H3), neuronal differentiation (doublecortin), and apoptosis (caspase 3). The number of phosphohistone H3 and doublecortin-positive cells was markedly reduced in leptin-deficient mice, but not the number of apoptotic cells, indicating that adult hippocampal neurogenesis on the level of cell proliferation was affected. In addition, dendritic spine densities of pyramidal neurons in the hippocampal area CA1 were analyzed using Golgi impregnation. However, no significant change in dendritic spine densities was noted in the obese mice. Moreover, the performance of the mice was analyzed in the open field as well as in the Morris water maze. In the open field test, obese mice showed reduced locomotor activity, but in the Morris water maze they showed similar performance compared with control animals.

Bisphenol A exposure remodels cognition of male rats attributable to excitatory alterations in the hippocampus and visual cortex

Bisphenol A, an environmental xenoestrogen, has been shown sex-specific adverse effects on cognitive function of rodents. However, the specific mechanisms underlying these outcomes remain elusive, limiting our understanding the differences in behavioral impairments due to BPA exposure between genders in humans. The present study chose the juvenile stage (with a stable estrogen level) as the exposure window to explore BPA effects on cognitive behaviors of male and female Sprague-Dawley (SD) rats and related mechanisms. Three dosages of BPA (0.04, 0.4 and 4 mg/kg/day) were chose to make BPA-exposed models. Especially, the mid-dose for rats was close to the current reference daily limit for human exposure given by the U.S. Environmental Protection Agency. Our results showed that male but not female juvenile rats had a marked decline in spatial memory after 0.4 mg/kg/day BPA exposure, which accompanied with downregulation of glutamate receptor (NR2) expression in their hippocampus and primary visual cortex (V1). In the high-dose BPA exposed groups (4 mg/kg/day), there was not only a deficit of spatial memory, but also an anxiety-like behavior of male rats. Additionally, those rats had a significant decline in spine density of pyramidal neurons and a decreased expression of glutamate receptor subtypes (NR2 and GluR1) in the hippocampus. Importantly, such impairments in the hippocampus of male rats were associated with a decrease of glutamate receptor (NR2) expression in the V1, which could perturb the visual information inputs. To some extent, altered ERβ expression within their hypothalamus could contribute to the anxiety-like behavior after high-dose BPA exposure. However, the low-dose BPA exposed juvenile rats didn’t present any structural and behavioral changes in our present study. Those results suggests that BPA exerts dose dependent and gender-specific effects on the cognition of juvenile animals. Our findings shed light on mechanisms underlying BPA effects on the juvenile animals.

Cdk5 Is Essential for Amphetamine to Increase Dendritic Spine Density in Hippocampal Pyramidal Neurons.

Psychostimulant drugs of abuse increase dendritic spine density in reward centers of the brain. However, little is known about their effects in the hippocampus, where activity-dependent changes in the density of dendritic spine are associated with learning and memory. Recent reports suggest that Cdk5 plays an important role in drug addiction, but its role in psychostimulant’s effects on dendritic spines in hippocampus remain unknown. We used in vivo and in vitro approaches to demonstrate that amphetamine increases dendritic spine density in pyramidal neurons of the hippocampus. Primary cultures and organotypic slice cultures were used for cellular, molecular, pharmacological and biochemical analyses of the role of Cdk5/p25 in amphetamine-induced dendritic spine formation. Amphetamine (two-injection protocol) increased dendritic spine density in hippocampal neurons of thy1-green fluorescent protein (GFP) mice, as well as in hippocampal cultured neurons and organotypic slice cultures. Either genetic or pharmacological inhibition of Cdk5 activity prevented the amphetamine–induced increase in dendritic spine density. Amphetamine also increased spine density in neurons overexpressing the strong Cdk5 activator p25. Finally, inhibition of calpain, the protease necessary for the conversion of p35 to p25, prevented amphetamine’s effect on dendritic spine density. We demonstrate, for the first time, that amphetamine increases the density of dendritic spine in hippocampal pyramidal neurons in vivo and in vitro. Moreover, we show that the Cdk5/p25 signaling and calpain activity are both necessary for the effect of amphetamine on dendritic spine density. The identification of molecular mechanisms underlying psychostimulant effects provides novel and promising therapeutic approaches for the treatment of drug addiction.

Effects of prenatal binge-like ethanol exposure and maternal stress on postnatal morphological development of hippocampal neurons in rats

BackgroundAlcohol is one of the most commonly used drugs of abuse negatively affecting human health and it is known as a potent teratogen responsible for fetal alcohol syndrome (FAS), which is characterized by cognitive deficits especially pronounced in juveniles but ameliorating in adults. Searching for the potential morphological correlates of these effects, in this study, we compared the course of developmental changes in the morphology of principal hippocampal neurons in fetal-alcohol (A group), intubated control (IC group), and intact control male rats (C group) over a protracted period of the first two postnatal months. MethodsEthanol was administered to the pregnant Wistar dams intragastrically, throughout gestation days (GD) 7–20, at a total dose of 6g/kg/day resulting in the mean blood alcohol concentration (BAC) of 246.6±40.9mg/dl. Ten morphometric parameters of Golgi-stained hippocampal neurons (pyramidal and granule) from CA1, CA3, and DG areas were examined at critical postnatal days (PD): at birth (PD1), at the end of the brain growth spurt period (PD10), in juveniles (PD30), and in young adults (PD60). ResultsDuring postnatal development, the temporal pattern of morphometric changes was shown to be region-dependent with most significant alterations observed between PD1-30 in the CA region and between PD10-30 in the DG region. It was also parameter-dependent with the soma size (except for CA3 pyramids), number of primary dendrites, dendrite diameter, dendritic tortuosity and the branch angle demonstrating little changes, while the total dendritic field area, dendritic length, number of dendritic bifurcations, and spine density being highly increased in all hippocampal regions during the first postnatal month. Moderate ethanol intoxication and the maternal intubation stress during gestation, showed similar, transient effects on the neuron development manifested as a smaller soma size in granule cells, reduced dendritic parameters and lower spine density in pyramidal neurons at PD1. Full recovery from these effects took place within the first 10 postnatal days. ConclusionsThis study showed regional and temporal differences in the development of different morphometric features of principal hippocampal neurons in intact subjects over a protracted 2-months postnatal period. It also demonstrated an overlap in the effects of a moderate fetal ethanol intoxication and a mild maternal stress produced by the intragastric intubation, a commonly used method of ethanol administration to the pregnant dams. Fast recovery from the adverse effects on the soma size, dendritic arborization and spines density observed at birth indicates towards the fetal ethanol/stress induced developmental retardation.

Bisphenol A Impairs Synaptic Plasticity by Both Pre- and Postsynaptic Mechanisms.

Bisphenol A (BPA), an environmental xenoestrogen, has been reported to induce learning and memory impairments in rodent animals. However, effects of BPA exposure on synaptic plasticity and the underlying physiological mechanisms remain elusive. Our behavioral and electrophysiological analyses show that BPA obviously perturbs hippocampal spatial memory of juvenile Sprague–Dawley rats after four weeks exposure, with significantly impaired long‐term potentiation (LTP) in the hippocampus. These effects involve decreased spine density of pyramidal neurons, especially the apical dendritic spine. Further presynaptic findings show an overt inhibition of pulse‐paired facilitation during electrophysiological recording, which suggest the decrease of presynaptic transmitter release and is consistent with reduced production of presynaptic glutamate after BPA exposure. Meanwhile, LTP‐related glutamate receptors, NMDA receptor 2A (NR2A) and AMPA receptor 1 (GluR1), are significantly downregulated in BPA‐exposed rats. Excitatory postsynaptic currents (EPSCs) results also show that EPSCNMDA, but not EPSCAMPA, is declined by 40% compared to the baseline in BPA‐perfused brain slices. Taken together, these findings reveal that juvenile BPA exposure has negative effects on synaptic plasticity, which result from decreases in dendritic spine density and excitatory synaptic transmission. Importantly, this study also provides new insights into the dynamics of BPA‐induced memory deterioration during the whole life of rats.

Cerebrolysin improves memory and ameliorates neuronal atrophy in spontaneously hypertensive, aged rats.

The spontaneously hypertensive (SH) rat has been used as an animal model of vascular dementia (VD). Our previous report showed that, SH rats exhibited dendritic atrophy of pyramidal neurons of the CA1 dorsal hippocampus and layers 3 and 5 of the prefrontal cortex (PFC) at 8 months of age. In addition, we showed that cerebrolysin (Cbl), a neurotrophic peptide mixture, reduces the dendritic atrophy in aged animal models. This study aimed to determine whether Cbl was capable of reducing behavioral and neuronal alterations, in old female SH rats. The level of diastolic and systolic pressure was measured every month for the 6 first months and only animals with more than 160 mm Hg of systolic pressure were used. Female SH rats (6 months old) received 6 months of Cbl treatment. Immediately after the Cbl treatment, two behavioral tests were applied, the Morris water maze test for memory and learning and locomotor activity in novel environments. Immediately after the last behavioral test, dendritic morphology was studied with the Golgi-Cox stain procedure followed by a Sholl analysis. Clearly, SH rats with Cbl showed an increase in the dendritic length and dendritic spine density of pyramidal neurons in the CA1 in the dorsal hippocampus and layers 3 and 5 of the PFC. Interestingly, Cbl improved memory of the old SH rats. Our results support the possibility that Cbl may have beneficial effects on the management of brain alterations in an animal model with VD. Synapse 70:378-389, 2016. © 2016 Wiley Periodicals, Inc.