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Frontiers in Cellular Neuroscience 2024Intracellular Ca-signaling in astrocytes is instrumental for their brain "housekeeping" role and astroglial control of synaptic plasticity. An important source for...
Intracellular Ca-signaling in astrocytes is instrumental for their brain "housekeeping" role and astroglial control of synaptic plasticity. An important source for elevating the cytosolic Ca level in astrocytes is a release from endoplasmic reticulum which can be triggered via two fundamental pathways: IP3 receptors and calcium-induced calcium release (CICR) mediated by Ca-sensitive ryanodine receptors (RyRs). While the physiological role for glial IP3 became a focus of intensive research and debate, ryanodine receptors received much less attention. We explored the role for ryanodine receptors in the modulation of cytosolic Ca-signaling in the cortical and hippocampal astrocytes, astrocyte-neuron communication and astroglia modulation of synaptic plasticity. Our data show that RyR-mediated Ca-induced Ca-release from ER brings substantial contribution into signaling in the functional microdomains hippocampal and neocortical astrocytes. Furthermore, RyR-mediated CICR activated the release of ATP and glutamate from hippocampal and neocortical astrocytes which, in turn, elicited transient purinergic and tonic glutamatergic currents in the neighboring pyramidal neurons. The CICR-facilitated release of ATP and glutamate was inhibited after intracellular perfusion of astrocytes with ryanodine and BAPTA and in the transgenic dnSNARE mice with impaired astroglial exocytosis. We also found out that RyR-mediated amplification of astrocytic Ca-signaling enhanced the long-term synaptic potentiation in the hippocampus and neocortex of aged mice. Combined, our data demonstrate that ryanodine receptors are essential for astrocytic Ca-signaling and efficient astrocyte-neuron communications. The RyR-mediated CICR contributes to astrocytic control of synaptic plasticity and can underlie, at least partially, neuroprotective and cognitive effects of caffein.
PubMed: 38812795
DOI: 10.3389/fncel.2024.1382010 -
Cell Reports May 2024Affective empathy enables social mammals to learn and transfer emotion to conspecifics, but an understanding of the neural circuitry and genetics underlying affective...
Affective empathy enables social mammals to learn and transfer emotion to conspecifics, but an understanding of the neural circuitry and genetics underlying affective empathy is still very limited. Here, using the naive observational fear between cagemates as a paradigm similar to human affective empathy and chemo/optogenetic neuroactivity manipulation in mouse brain, we investigate the roles of multiple brain regions in mouse affective empathy. Remarkably, two neural circuits originating from the ventral hippocampus, previously unknown to function in empathy, are revealed to regulate naive observational fear. One is from ventral hippocampal pyramidal neurons to lateral septum GABAergic neurons, and the other is from ventral hippocampus pyramidal neurons to nucleus accumbens dopamine-receptor-expressing neurons. Furthermore, we identify the naive observational-fear-encoding neurons in the ventral hippocampus. Our findings highlight the potentially diverse regulatory pathways of empathy in social animals, shedding light on the mechanisms underlying empathy circuity and its disorders.
PubMed: 38805397
DOI: 10.1016/j.celrep.2024.114277 -
Communications Biology May 2024Alterations in the experience-dependent and autonomous elaboration of neural circuits are assumed to underlie autism spectrum disorder (ASD), though it is unclear what...
Alterations in the experience-dependent and autonomous elaboration of neural circuits are assumed to underlie autism spectrum disorder (ASD), though it is unclear what synaptic traits are responsible. Here, utilizing a valproic acid-induced ASD marmoset model, which shares common molecular features with idiopathic ASD, we investigate changes in the structural dynamics of tuft dendrites of upper-layer pyramidal neurons and adjacent axons in the dorsomedial prefrontal cortex through two-photon microscopy. In model marmosets, dendritic spine turnover is upregulated, and spines are generated in clusters and survived more often than in control marmosets. Presynaptic boutons in local axons, but not in commissural long-range axons, demonstrate hyperdynamic turnover in model marmosets, suggesting alterations in projection-specific plasticity. Intriguingly, nasal oxytocin administration attenuates clustered spine emergence in model marmosets. Enhanced clustered spine generation, possibly unique to certain presynaptic partners, may be associated with ASD and be a potential therapeutic target.
Topics: Animals; Oxytocin; Callithrix; Disease Models, Animal; Neuronal Plasticity; Male; Synapses; Dendritic Spines; Autism Spectrum Disorder; Autistic Disorder; Prefrontal Cortex; Pyramidal Cells; Valproic Acid; Presynaptic Terminals; Female; Axons
PubMed: 38802535
DOI: 10.1038/s42003-024-06345-9 -
Cell Reports May 2024Anxiety plays a key role in guiding behavior in response to potential threats. Anxiety is mediated by the activation of pyramidal neurons in the ventral hippocampus...
Anxiety plays a key role in guiding behavior in response to potential threats. Anxiety is mediated by the activation of pyramidal neurons in the ventral hippocampus (vH), whose activity is controlled by GABAergic inhibitory interneurons. However, how different vH interneurons might contribute to anxiety-related processes is unclear. Here, we investigate the role of vH parvalbumin (PV)-expressing interneurons while mice transition from safe to more anxiogenic compartments of the elevated plus maze (EPM). We find that vH PV interneurons increase their activity in anxiogenic EPM compartments concomitant with dynamic changes in inhibitory interactions between PV interneurons and pyramidal neurons. By optogenetically inhibiting PV interneurons, we induce an increase in the activity of vH pyramidal neurons and persistent anxiety. Collectively, our results suggest that vH inhibitory microcircuits may act as a trigger for enduring anxiety states.
PubMed: 38796850
DOI: 10.1016/j.celrep.2024.114295 -
International Journal of Molecular... May 2024Human evolution is characterized by rapid brain enlargement and the emergence of unique cognitive abilities. Besides its distinctive cytoarchitectural organization and... (Review)
Review
Human evolution is characterized by rapid brain enlargement and the emergence of unique cognitive abilities. Besides its distinctive cytoarchitectural organization and extensive inter-neuronal connectivity, the human brain is also defined by high rates of synaptic, mainly glutamatergic, transmission, and energy utilization. While these adaptations' origins remain elusive, evolutionary changes occurred in synaptic glutamate metabolism in the common ancestor of humans and apes via the emergence of , a gene encoding the human glutamate dehydrogenase 2 (hGDH2) isoenzyme. Driven by positive selection, hGDH2 became adapted to function upon intense excitatory firing, a process central to the long-term strengthening of synaptic connections. It also gained expression in brain astrocytes and cortical pyramidal neurons, including the CA1-CA3 hippocampal cells, neurons crucial to cognition. In mice transgenic for , theta-burst-evoked long-term potentiation (LTP) is markedly enhanced in hippocampal CA3-CA1 synapses, with patch-clamp recordings from CA1 pyramidal neurons revealing increased sNMDA receptor currents. D-lactate blocked LTP enhancement, implying that glutamate metabolism via hGDH2 potentiates L-lactate-dependent glia-neuron interaction, a process essential to memory consolidation. The transgenic (Tg) mice exhibited increased dendritic spine density/synaptogenesis in the hippocampus and improved complex cognitive functions. Hence, enhancement of neuron-glia communication, via evolution, likely contributed to human cognitive advancement by potentiating synaptic plasticity and inter-neuronal connectivity.
Topics: Animals; Humans; Neuronal Plasticity; Glutamic Acid; Cognition; Glutamate Dehydrogenase; Mice; Lactic Acid; Long-Term Potentiation; Mice, Transgenic; Pyramidal Cells; Hippocampus; Evolution, Molecular; Synapses
PubMed: 38791334
DOI: 10.3390/ijms25105297 -
Brain Sciences Apr 2024Psychostimulants alter cellular morphology and activate neuroimmune signaling in a number of brain regions, yet few prior studies have investigated their persistence...
Methamphetamine and the Synthetic Cathinone 3,4-Methylenedioxypyrovalerone (MDPV) Produce Persistent Effects on Prefrontal and Striatal Microglial Morphology and Neuroimmune Signaling Following Repeated Binge-like Intake in Male and Female Rats.
Psychostimulants alter cellular morphology and activate neuroimmune signaling in a number of brain regions, yet few prior studies have investigated their persistence beyond acute abstinence or following high levels of voluntary drug intake. In this study, we examined the effects of the repeated binge-like self-administration (96 h/week for 3 weeks) of methamphetamine (METH) and 21 days of abstinence in female and male rats on changes in cell density, morphology, and cytokine levels in two addiction-related brain regions-the prefrontal cortex (PFC) and dorsal striatum (DStr). We also examined the effects of similar patterns of intake of the cocaine-like synthetic cathinone derivative 3,4-methylenedioxypyrovalerone (MDPV) or saline as a control. Robust levels of METH and MDPV intake (~500-1000 infusions per 96 h period) were observed in both sexes. We observed no changes in astrocyte or neuron density in either region, but decreases in dendritic spine densities were observed in PFC pyramidal and DStr medium spiny neurons. The microglial cell density was decreased in the PFC of METH self-administering animals, accompanied by evidence of microglial apoptosis. Changes in microglial morphology (e.g., decreased territorial volume and ramification and increased cell soma volume) were also observed, indicative of an inflammatory-like state. Multiplex analyses of PFC and DStr cytokine content revealed elevated levels of various interleukins and chemokines only in METH self-administering animals, with region- and sex-dependent effects. Our findings suggest that voluntary binge-like METH or MDPV intake induces similar cellular perturbations in the brain, but they are divergent neuroimmune responses that persist beyond the initial abstinence phase.
PubMed: 38790414
DOI: 10.3390/brainsci14050435 -
Disease Models & Mechanisms Jun 2024Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, which encodes methyl-CpG-binding protein 2, a transcriptional regulator of many genes,...
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, which encodes methyl-CpG-binding protein 2, a transcriptional regulator of many genes, including brain-derived neurotrophic factor (BDNF). BDNF levels are lower in multiple brain regions of Mecp2-deficient mice, and experimentally increasing BDNF levels improve atypical phenotypes in Mecp2 mutant mice. Due to the low blood-brain barrier permeability of BDNF itself, we tested the effects of LM22A-4, a brain-penetrant, small-molecule ligand of the BDNF receptor TrkB (encoded by Ntrk2), on dendritic spine density and form in hippocampal pyramidal neurons and on behavioral phenotypes in female Mecp2 heterozygous (HET) mice. A 4-week systemic treatment of Mecp2 HET mice with LM22A-4 restored spine volume in MeCP2-expressing neurons to wild-type (WT) levels, whereas spine volume in MeCP2-lacking neurons remained comparable to that in neurons from female WT mice. Female Mecp2 HET mice engaged in aggressive behaviors more than WT mice, the levels of which were reduced to WT levels by the 4-week LM22A-4 treatment. These data provide additional support to the potential usefulness of novel therapies not only for RTT but also to other BDNF-related disorders.
Topics: Animals; Rett Syndrome; Dendritic Spines; Female; Phenotype; Receptor, trkB; Methyl-CpG-Binding Protein 2; Behavior, Animal; Ligands; Pyramidal Cells; Mice; Brain-Derived Neurotrophic Factor; Hippocampus; Heterozygote; Mice, Inbred C57BL; Disease Models, Animal; Benzamides
PubMed: 38785269
DOI: 10.1242/dmm.050612 -
Cell & Bioscience May 2024Human patients often experience an episode of serious seizure activity, such as status epilepticus (SE), prior to the onset of temporal lobe epilepsy (TLE), suggesting...
BACKGROUND
Human patients often experience an episode of serious seizure activity, such as status epilepticus (SE), prior to the onset of temporal lobe epilepsy (TLE), suggesting that SE can trigger the development of epilepsy. Yet, the underlying mechanisms are not fully understood. The low-density lipoprotein receptor related protein (Lrp4), a receptor for proteoglycan-agrin, has been indicated to modulate seizure susceptibility. However, whether agrin-Lrp4 pathway also plays a role in the development of SE-induced TLE is not clear.
METHODS
Lrp4 mice were crossed with hGFAP-Cre and Nex-Cre mice to generate brain conditional Lrp4 knockout mice (hGFAP-Lrp4) and pyramidal neuron specific knockout mice (Nex-Lrp4). Lrp4 was specifically knocked down in hippocampal astrocytes by injecting AAV virus carrying hGFAP-Cre into the hippocampus. The effects of agrin-Lrp4 pathway on the development of SE-induced TLE were evaluated on the chronic seizure model generated by injecting kainic acid (KA) into the amygdala. The spontaneous recurrent seizures (SRS) in mice were video monitored.
RESULTS
We found that Lrp4 deletion from the brain but not from the pyramidal neurons elevated the seizure threshold and reduced SRS numbers, with no change in the stage or duration of SRS. More importantly, knockdown of Lrp4 in the hippocampal astrocytes after SE induction decreased SRS numbers. In accord, direct injection of agrin into the lateral ventricle of control mice but not mice with Lrp4 deletion in hippocampal astrocytes also increased the SRS numbers. These results indicate a promoting effect of agrin-Lrp4 signaling in hippocampal astrocytes on the development of SE-induced TLE. Last, we observed that knockdown of Lrp4 in hippocampal astrocytes increased the extracellular adenosine levels in the hippocampus 2 weeks after SE induction. Blockade of adenosine A1 receptor in the hippocampus by DPCPX after SE induction diminished the effects of Lrp4 on the development of SE-induced TLE.
CONCLUSION
These results demonstrate a promoting role of agrin-Lrp4 signaling in hippocampal astrocytes in the development of SE-induced development of epilepsy through elevating adenosine levels. Targeting agrin-Lrp4 signaling may serve as a potential therapeutic intervention strategy to treat TLE.
PubMed: 38783336
DOI: 10.1186/s13578-024-01241-5 -
Scientific Reports May 2024The development of neurons is regulated by several spatiotemporally changing factors, which are crucial to give the ability of neurons to form functional networks. While...
The development of neurons is regulated by several spatiotemporally changing factors, which are crucial to give the ability of neurons to form functional networks. While external physical stimuli may impact the early developmental stages of neurons, the medium and long-term consequences of these influences have yet to be thoroughly examined. Using an animal model, this study focuses on the morphological and transcriptome changes of the hippocampus that may occur as a consequence of fetal ultrasound examination. We selectively labeled CA1 neurons of the hippocampus with in-utero electroporation to analyze their morphological features. Furthermore, certain samples also went through RNA sequencing after repetitive ultrasound exposure. US exposure significantly changed several morphological properties of the basal dendritic tree. A notable increase was also observed in the density of spines on the basal dendrites, accompanied by various alterations in individual spine morphology. Transcriptome analysis revealed several up or downregulated genes, which may explain the molecular background of these alterations. Our results suggest that US-derived changes in the dendritic trees of CA1 pyramidal cells might be connected to modification of the transcriptome of the hippocampus and may lead to an increased dendritic input.
Topics: Animals; CA1 Region, Hippocampal; Transcriptome; Dendrites; Female; Pregnancy; Pyramidal Cells; Mice; Hippocampus; Gene Expression Profiling; Dendritic Spines; Ultrasonography, Prenatal
PubMed: 38778177
DOI: 10.1038/s41598-024-62621-y -
JAMA Psychiatry May 2024The risk of mental disorders is consistently associated with variants in CACNA1C (L-type calcium channel Cav1.2) but it is not known why these channels are critical to...
IMPORTANCE
The risk of mental disorders is consistently associated with variants in CACNA1C (L-type calcium channel Cav1.2) but it is not known why these channels are critical to cognition, and whether they affect the layer III pyramidal cells in the dorsolateral prefrontal cortex that are especially vulnerable in cognitive disorders.
OBJECTIVE
To examine the molecular mechanisms expressed in layer III pyramidal cells in primate dorsolateral prefrontal cortices.
DESIGN, SETTING, AND PARTICIPANTS
The design included transcriptomic analyses from human and macaque dorsolateral prefrontal cortex, and connectivity, protein expression, physiology, and cognitive behavior in macaques. The research was performed in academic laboratories at Yale, Harvard, Princeton, and the University of Pittsburgh. As dorsolateral prefrontal cortex only exists in primates, the work evaluated humans and macaques.
MAIN OUTCOMES AND MEASURES
Outcome measures included transcriptomic signatures of human and macaque pyramidal cells, protein expression and interactions in layer III macaque pyramidal cells using light and electron microscopy, changes in neuronal firing during spatial working memory, and working memory performance following pharmacological treatments.
RESULTS
Layer III pyramidal cells in dorsolateral prefrontal cortex coexpress a constellation of calcium-related proteins, delineated by CALB1 (calbindin), and high levels of CACNA1C (Cav1.2), GRIN2B (NMDA receptor GluN2B), and KCNN3 (SK3 potassium channel), concentrated in dendritic spines near the calcium-storing smooth endoplasmic reticulum. L-type calcium channels influenced neuronal firing needed for working memory, where either blockade or increased drive by β1-adrenoceptors, reduced neuronal firing by a mean (SD) 37.3% (5.5%) or 40% (6.3%), respectively, the latter via SK potassium channel opening. An L-type calcium channel blocker or β1-adrenoceptor antagonist protected working memory from stress.
CONCLUSIONS AND RELEVANCE
The layer III pyramidal cells in the dorsolateral prefrontal cortex especially vulnerable in cognitive disorders differentially express calbindin and a constellation of calcium-related proteins including L-type calcium channels Cav1.2 (CACNA1C), GluN2B-NMDA receptors (GRIN2B), and SK3 potassium channels (KCNN3), which influence memory-related neuronal firing. The finding that either inadequate or excessive L-type calcium channel activation reduced neuronal firing explains why either loss- or gain-of-function variants in CACNA1C were associated with increased risk of cognitive disorders. The selective expression of calbindin in these pyramidal cells highlights the importance of regulatory mechanisms in neurons with high calcium signaling, consistent with Alzheimer tau pathology emerging when calbindin is lost with age and/or inflammation.
PubMed: 38776078
DOI: 10.1001/jamapsychiatry.2024.1112