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Cell Reports. Medicine Dec 2023De novo mutations in STXBP1 are among the most prevalent causes of neurodevelopmental disorders and lead to haploinsufficiency, cortical hyperexcitability, epilepsy, and...
De novo mutations in STXBP1 are among the most prevalent causes of neurodevelopmental disorders and lead to haploinsufficiency, cortical hyperexcitability, epilepsy, and other symptoms in people with mutations. Given that Munc18-1, the protein encoded by STXBP1, is essential for excitatory and inhibitory synaptic transmission, it is currently not understood why mutations cause hyperexcitability. We find that overall inhibition in canonical feedforward microcircuits is defective in a P15-22 mouse model for Stxbp1 haploinsufficiency. Unexpectedly, we find that inhibitory synapses formed by parvalbumin-positive interneurons were largely unaffected. Instead, excitatory synapses fail to recruit inhibitory interneurons. Modeling confirms that defects in the recruitment of inhibitory neurons cause hyperexcitation. CX516, an ampakine that enhances excitatory synapses, restores interneuron recruitment and prevents hyperexcitability. These findings establish deficits in excitatory synapses in microcircuits as a key underlying mechanism for cortical hyperexcitability in a mouse model of Stxbp1 disorder and identify compounds enhancing excitation as a direction for therapy.
Topics: Animals; Humans; Mice; Brain Diseases; Munc18 Proteins; Mutation; Neurons; Synapses; Synaptic Transmission
PubMed: 38086378
DOI: 10.1016/j.xcrm.2023.101308 -
Frontiers in Molecular Neuroscience 2023Astrocytes are specialized non-neuronal glial cells of the central nervous system, contributing to neuronal excitability and synaptic transmission (gliotransmission).... (Review)
Review
Astrocytes are specialized non-neuronal glial cells of the central nervous system, contributing to neuronal excitability and synaptic transmission (gliotransmission). Astrocytes play a key roles in epileptogenesis and seizure generation. Epilepsy, as a chronic disorder characterized by neuronal hyperexcitation and hypersynchronization, is accompanied by substantial disturbances of glial cells and impairment of astrocytic functions and neuronal signaling. Anti-seizure drugs that provide symptomatic control of seizures primarily target neural activity. In epileptic patients with inadequate control of seizures with available anti-seizure drugs, novel therapeutic candidates are needed. These candidates should treat epilepsy with anti-epileptogenic and disease-modifying effects. Evidence from human and animal studies shows that astrocytes have value for developing new anti-seizure and anti-epileptogenic drugs. In this review, we present the key functions of astrocytes contributing to neuronal hyperexcitability and synaptic activity following an etiology-based approach. We analyze the role of astrocytes in both development (epileptogenesis) and generation of seizures (ictogenesis). Several promising new strategies that attempted to modify astroglial functions for treating epilepsy are being developed: (1) selective targeting of glia-related molecular mechanisms of glutamate transport; (2) modulation of tonic GABA release from astrocytes; (3) gliotransmission; (4) targeting the astrocytic Kir4.1-BDNF system; (5) astrocytic Na/K/ATPase activity; (6) targeting DNA hypo- or hypermethylation of candidate genes in astrocytes; (7) targeting astrocytic gap junction regulators; (8) targeting astrocytic adenosine kinase (the major adenosine-metabolizing enzyme); and (9) targeting microglia-astrocyte communication and inflammatory pathways. Novel disease-modifying therapeutic strategies have now been developed, such as astroglia-targeted gene therapy with a broad spectrum of genetic constructs to target astroglial cells.
PubMed: 37583518
DOI: 10.3389/fnmol.2023.1183775 -
The Journal of Neuroscience : the... Nov 2023Neuroligins (NLGNs) are postsynaptic cell adhesion molecules that are involved in synapse assembly and function. The NLGN gene family consists of 5 genes (, , and )....
Neuroligins (NLGNs) are postsynaptic cell adhesion molecules that are involved in synapse assembly and function. The NLGN gene family consists of 5 genes (, , and ). NLGN3 forms heterodimers with other NLGNs and is expressed at both excitatory and inhibitory synapses, although the distinct role at different synapses is not fully understood. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase that targets various neuronal substrates to impact neuronal migration, neurite outgrowth, synaptic transmission, and plasticity. Both NLGNs and their presynaptic binding partners neurexins are highly associated with neurodevelopmental disorders. The NLGN3 gene is on the X chromosome and variants in NLGN3 have been linked to the pathophysiology in neurodevelopmental disorders. To better understand the endogenous modulation of NLGN3, we generated an HA-tagged knock-in mouse. We found that Cdk5 associates with NLGN3 and phosphorylates NLGN3 on serine 725 (S725) in the knock-in mouse of either sex. The phosphorylation affects the NLGN3 association with Kalirin-7, a postsynaptic guanine nucleotide exchange factors for Rho GTPase family proteins. We further observed that the phosphorylation modulates NLGN3 surface expression and NLGN3-mediated synaptic currents in cultured rat neurons. Thus, we characterized NLGN3 as a novel Cdk5 substrate and revealed the functional consequences of NLGN3 S725 phosphorylation in neurons. Our study provides a novel molecular mechanism underlying Cdk5-mediated regulation of postsynaptic cell adhesion molecules. NLGN3 is involved in synapse assembly and function at both excitatory and inhibitory synapses and has been associated with the pathophysiology of neurodevelopmental disorders. Cdk5 has brain-specific activity and is involved in neuronal transmission, synapse function, and plasticity. Here, we characterize NLGN3 as a Cdk5 substrate for the first time and show that Cdk5-mediated phosphorylation regulates NLGN3 function. We demonstrate that NLGN3 S725 is a Cdk5 phosphorylation site, and reveal that the site is important for NLGN3 association with Kalirin-7, NLGN3 surface expression, and NLGN3-mediated synaptic transmission.
Topics: Animals; Mice; Rats; Cell Adhesion Molecules; Cyclin-Dependent Kinase 5; Phosphorylation; Rho Guanine Nucleotide Exchange Factors; Serine; Synapses; Synaptic Transmission
PubMed: 37699715
DOI: 10.1523/JNEUROSCI.2309-22.2023 -
The Journal of Cell Biology Nov 2023Sexually dimorphic behaviors are ubiquitous throughout the animal kingdom. Although both sex-specific and sex-shared neurons have been functionally implicated in these...
Sexually dimorphic behaviors are ubiquitous throughout the animal kingdom. Although both sex-specific and sex-shared neurons have been functionally implicated in these diverse behaviors, less is known about the roles of sex-shared neurons. Here, we discovered sexually dimorphic cholinergic synaptic transmission in C. elegans occurring at neuromuscular junctions (NMJs), with males exhibiting increased release frequencies, which result in sexually dimorphic locomotion behaviors. Scanning electron microscopy revealed that males have significantly more synaptic vesicles (SVs) at their cholinergic synapses than hermaphrodites. Analysis of previously published transcriptome identified the male-enriched transcripts and focused our attention on UNC-43/CaMKII. We ultimately show that differential accumulation of UNC-43 at cholinergic neurons controls axonal SV abundance and synaptic transmission. Finally, we demonstrate that sex reversal of all neurons in hermaphrodites generates male-like cholinergic transmission and locomotion behaviors. Thus, beyond demonstrating UNC-43/CaMKII as an essential mediator of sex-specific synaptic transmission, our study provides molecular and cellular insights into how sex-shared neurons can generate sexually dimorphic locomotion behaviors.
Topics: Animals; Female; Male; Caenorhabditis elegans; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Neuromuscular Junction; Neurons; Synaptic Transmission; Caenorhabditis elegans Proteins
PubMed: 37624117
DOI: 10.1083/jcb.202301117 -
Neuropsychopharmacology : Official... Dec 2023Mistuning of synaptic transmission has been proposed to underlie many psychiatric disorders, with decreased reuptake of the excitatory neurotransmitter glutamate as one...
Mistuning of synaptic transmission has been proposed to underlie many psychiatric disorders, with decreased reuptake of the excitatory neurotransmitter glutamate as one contributing factor. Synaptic tuning occurs through several diverging and converging forms of plasticity. By recording evoked field postsynaptic potentials in the CA1 area in hippocampal slices, we found that inhibiting glutamate transporters using DL-TBOA causes retuning of synaptic transmission, resulting in a new steady state with reduced synaptic strength and a lower threshold for inducing long-term synaptic potentiation (LTP). Moreover, a similar reduced threshold for LTP was observed in a rat model of depression with decreased levels of glutamate transporters. Most importantly, we found that the antidepressant ketamine counteracts the effects of increased glutamate on the various steps involved in synaptic retuning. We, therefore, propose that ketamine's mechanism of action as an antidepressant is to restore adequate synaptic tuning.
Topics: Humans; Rats; Animals; Ketamine; Hippocampus; Long-Term Potentiation; Synaptic Transmission; Antidepressive Agents; Glutamates; Synapses
PubMed: 37301901
DOI: 10.1038/s41386-023-01617-0 -
Biomolecules Apr 2024This article examines the involvement of the brain-derived neurotrophic factor (BDNF) in the control of nociception and pain. BDNF, a neurotrophin known for its... (Review)
Review
This article examines the involvement of the brain-derived neurotrophic factor (BDNF) in the control of nociception and pain. BDNF, a neurotrophin known for its essential role in neuronal survival and plasticity, has garnered significant attention for its potential implications as a modulator of synaptic transmission. This comprehensive review aims to provide insights into the multifaceted interactions between BDNF and pain pathways, encompassing both physiological and pathological pain conditions. I delve into the molecular mechanisms underlying BDNF's involvement in pain processing and discuss potential therapeutic applications of BDNF and its mimetics in managing pain. Furthermore, I highlight recent advancements and challenges in translating BDNF-related research into clinical practice.
Topics: Brain-Derived Neurotrophic Factor; Humans; Nociception; Pain; Animals; Neuronal Plasticity
PubMed: 38785946
DOI: 10.3390/biom14050539 -
Experimental Neurology Dec 2023Parkinson's disease is a neurological disorder characterized by degeneration of midbrain dopamine neurons, which results in numerous adaptations in basal ganglia... (Review)
Review
Parkinson's disease is a neurological disorder characterized by degeneration of midbrain dopamine neurons, which results in numerous adaptations in basal ganglia circuits. Research over the past twenty-five years has identified that midbrain dopamine neurons of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) co-release multiple other transmitters including glutamate and GABA, in addition to their canonical transmitter, dopamine. This review summarizes previous work characterizing neurotransmitter co-release from dopamine neurons, work examining potential changes in co-release dynamics that result in animal models of Parkinson's disease, and future opportunities for determining how dysfunction in co-release may contribute to circuit dysfunction in Parkinson's disease.
Topics: Animals; Parkinson Disease; Substantia Nigra; Ventral Tegmental Area; Synaptic Transmission; Dopaminergic Neurons; Neurotransmitter Agents
PubMed: 37802381
DOI: 10.1016/j.expneurol.2023.114562 -
Frontiers in Molecular Neuroscience 2024The complex nature of the retina demands well-organized signaling to uphold signal accuracy and avoid interference, a critical aspect in handling a variety of visual... (Review)
Review
The complex nature of the retina demands well-organized signaling to uphold signal accuracy and avoid interference, a critical aspect in handling a variety of visual stimuli. A-kinase anchoring proteins (AKAPs), known for binding protein kinase A (PKA), contribute to the specificity and efficiency of retinal signaling. They play multifaceted roles in various retinal cell types, influencing photoreceptor sensitivity, neurotransmitter release in bipolar cells, and the integration of visual information in ganglion cells. AKAPs like AKAP79/150 and AKAP95 exhibit distinct subcellular localizations, impacting synaptic transmission and receptor sensitivity in photoreceptors and bipolar cells. Furthermore, AKAPs are involved in neuroprotective mechanisms and axonal degeneration, particularly in retinal ganglion cells. In particular, AKAP6 coordinates stress-specific signaling and promotes neuroprotection following optic nerve injury. As our review underscores the therapeutic potential of targeting AKAP signaling complexes for retinal neuroprotection and enhancement, it acknowledges challenges in developing selective drugs that target complex protein-protein interactions. Overall, this exploration of AKAPs provides valuable insights into the intricacies of retinal signaling, offering a foundation for understanding and potentially addressing retinal disorders.
PubMed: 38813437
DOI: 10.3389/fnmol.2024.1412407 -
Proceedings of the National Academy of... Oct 2023Pre- and postsynaptic forms of long-term potentiation (LTP) are candidate synaptic mechanisms underlying learning and memory. At layer 5 pyramidal neurons, LTP increases...
Pre- and postsynaptic forms of long-term potentiation (LTP) are candidate synaptic mechanisms underlying learning and memory. At layer 5 pyramidal neurons, LTP increases the initial synaptic strength but also short-term depression during high-frequency transmission. This classical form of presynaptic LTP has been referred to as redistribution of synaptic efficacy. However, the underlying mechanisms remain unclear. We therefore performed whole-cell recordings from layer 5 pyramidal neurons in acute cortical slices of rats and analyzed presynaptic function before and after LTP induction by paired pre- and postsynaptic neuronal activity. LTP was successfully induced in about half of the synaptic connections tested and resulted in increased synaptic short-term depression during high-frequency transmission and a decelerated recovery from short-term depression due to an increased fraction of a slow recovery component. Analysis with a recently established sequential two-step vesicle priming model indicates an increase in the abundance of fully-primed and slowly-recovering vesicles. A systematic analysis of short-term plasticity and synapse-to-synapse variability of synaptic strength at various types of synapses revealed that stronger synapses generally recover more slowly from synaptic short-term depression. Finally, pharmacological stimulation of the cyclic adenosine monophosphate and diacylglycerol signaling pathways, which are both known to promote synaptic vesicle priming, mimicked LTP and slowed the recovery from short-term depression. Our data thus demonstrate that LTP at layer 5 pyramidal neurons increases synaptic strength primarily by enlarging a subpool of fully-primed slowly-recovering vesicles.
Topics: Rats; Animals; Long-Term Potentiation; Neocortex; Neurons; Synapses; Synaptic Transmission; Neuronal Plasticity; Hippocampus
PubMed: 37856547
DOI: 10.1073/pnas.2305460120 -
Frontiers in Cellular Neuroscience 2023
PubMed: 37810259
DOI: 10.3389/fncel.2023.1289874