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Synaptic homeostasis transiently leverages Hebbian mechanisms for a multiphasic response to inactivity

Sun, Simón E D; Levenstein, Daniel; Li, Boxing; Mandelberg, Nataniel; Chenouard, Nicolas; Suutari, Benjamin S; Sanchez, Sandrine; Tian, Guoling; Rinzel, John; Buzsáki, György; Tsien, Richard W
Homeostatic regulation of synapses is vital for nervous system function and key to understanding a range of neurological conditions. Synaptic homeostasis is proposed to operate over hours to counteract the destabilizing influence of long-term potentiation (LTP) and long-term depression (LTD). The prevailing view holds that synaptic scaling is a slow first-order process that regulates postsynaptic glutamate receptors and fundamentally differs from LTP or LTD. Surprisingly, we find that the dynamics of scaling induced by neuronal inactivity are not exponential or monotonic, and the mechanism requires calcineurin and CaMKII, molecules dominant in LTD and LTP. Our quantitative model of these enzymes reconstructs the unexpected dynamics of homeostatic scaling and reveals how synapses can efficiently safeguard future capacity for synaptic plasticity. This mechanism of synaptic adaptation supports a broader set of homeostatic changes, including action potential autoregulation, and invites further inquiry into how such a mechanism varies in health and disease.
PMID: 38507409
ISSN: 2211-1247
CID: 5640592

A dedicated hypothalamic oxytocin circuit controls aversive social learning

Osakada, Takuya; Yan, Rongzhen; Jiang, Yiwen; Wei, Dongyu; Tabuchi, Rina; Dai, Bing; Wang, Xiaohan; Zhao, Gavin; Wang, Clara Xi; Liu, Jing-Jing; Tsien, Richard W; Mar, Adam C; Lin, Dayu
To survive in a complex social group, one needs to know who to approach and, more importantly, who to avoid. In mice, a single defeat causes the losing mouse to stay away from the winner for weeks1. Here through a series of functional manipulation and recording experiments, we identify oxytocin neurons in the retrochiasmatic supraoptic nucleus (SOROXT) and oxytocin-receptor-expressing cells in the anterior subdivision of the ventromedial hypothalamus, ventrolateral part (aVMHvlOXTR) as a key circuit motif for defeat-induced social avoidance. Before defeat, aVMHvlOXTR cells minimally respond to aggressor cues. During defeat, aVMHvlOXTR cells are highly activated and, with the help of an exclusive oxytocin supply from the SOR, potentiate their responses to aggressor cues. After defeat, strong aggressor-induced aVMHvlOXTR cell activation drives the animal to avoid the aggressor and minimizes future defeat. Our study uncovers a neural process that supports rapid social learning caused by defeat and highlights the importance of the brain oxytocin system in social plasticity.
PMID: 38267576
ISSN: 1476-4687
CID: 5625042

A dedicated hypothalamic oxytocin circuit controls aversive social learning

Osakada, Takuya; Yan, Rongzhen; Jiang, Yiwen; Wei, Dongyu; Tabuchi, Rina; Dai, Bing; Wang, Xiaohan; Zhao, Gavin; Wang, Clara Xi; Liu, Jing Jing; Tsien, Richard W.; Mar, Adam C.; Lin, Dayu
To survive in a complex social group, one needs to know who to approach and, more importantly, who to avoid. In mice, a single defeat causes the losing mouse to stay away from the winner for weeks1. Here through a series of functional manipulation and recording experiments, we identify oxytocin neurons in the retrochiasmatic supraoptic nucleus (SOROXT) and oxytocin-receptor-expressing cells in the anterior subdivision of the ventromedial hypothalamus, ventrolateral part (aVMHvlOXTR) as a key circuit motif for defeat-induced social avoidance. Before defeat, aVMHvlOXTR cells minimally respond to aggressor cues. During defeat, aVMHvlOXTR cells are highly activated and, with the help of an exclusive oxytocin supply from the SOR, potentiate their responses to aggressor cues. After defeat, strong aggressor-induced aVMHvlOXTR cell activation drives the animal to avoid the aggressor and minimizes future defeat. Our study uncovers a neural process that supports rapid social learning caused by defeat and highlights the importance of the brain oxytocin system in social plasticity.
SCOPUS:85182997082
ISSN: 0028-0836
CID: 5629362

Cannabidiol modulates excitatory-inhibitory ratio to counter hippocampal hyperactivity

Rosenberg, Evan C; Chamberland, Simon; Bazelot, Michael; Nebet, Erica R; Wang, Xiaohan; McKenzie, Sam; Jain, Swati; Greenhill, Stuart; Wilson, Max; Marley, Nicole; Salah, Alejandro; Bailey, Shanice; Patra, Pabitra Hriday; Rose, Rebecca; Chenouard, Nicolas; Sun, Simón E D; Jones, Drew; Buzsáki, György; Devinsky, Orrin; Woodhall, Gavin; Scharfman, Helen E; Whalley, Benjamin J; Tsien, Richard W
Cannabidiol (CBD), a non-euphoric component of cannabis, reduces seizures in multiple forms of pediatric epilepsies, but the mechanism(s) of anti-seizure action remain unclear. In one leading model, CBD acts at glutamatergic axon terminals, blocking the pro-excitatory actions of an endogenous membrane phospholipid, lysophosphatidylinositol (LPI), at the G-protein-coupled receptor GPR55. However, the impact of LPI-GPR55 signaling at inhibitory synapses and in epileptogenesis remains underexplored. We found that LPI transiently increased hippocampal CA3-CA1 excitatory presynaptic release probability and evoked synaptic strength in WT mice, while attenuating inhibitory postsynaptic strength by decreasing GABAA2 and gephyrin puncta. LPI effects at excitatory and inhibitory synapses were eliminated by CBD pre-treatment and absent after GPR55 deletion. Acute pentylenetrazole-induced seizures elevated GPR55 and LPI levels, and chronic lithium-pilocarpine-induced epileptogenesis potentiated LPI's pro-excitatory effects. We propose that CBD exerts potential anti-seizure effects by blocking LPI's synaptic effects and dampening hyperexcitability.
PMID: 36787750
ISSN: 1097-4199
CID: 5432102

Brief synaptic inhibition persistently interrupts firing of fast-spiking interneurons

Chamberland, Simon; Nebet, Erica R; Valero, Manuel; Hanani, Monica; Egger, Robert; Larsen, Samantha B; Eyring, Katherine W; Buzsáki, György; Tsien, Richard W
Neurons perform input-output operations that integrate synaptic inputs with intrinsic electrical properties; these operations are generally constrained by the brevity of synaptic events. Here, we report that sustained firing of CA1 hippocampal fast-spiking parvalbumin-expressing interneurons (PV-INs) can be persistently interrupted for several hundred milliseconds following brief GABAAR-mediated inhibition in vitro and in vivo. A single presynaptic neuron could interrupt PV-IN firing, occasionally with a single action potential (AP), and reliably with AP bursts. Experiments and computational modeling reveal that the persistent interruption of firing maintains neurons in a depolarized, quiescent state through a cell-autonomous mechanism. Interrupted PV-INs are strikingly responsive to Schaffer collateral inputs. The persistent interruption of firing provides a disinhibitory circuit mechanism favoring spike generation in CA1 pyramidal cells. Overall, our results demonstrate that neuronal silencing can far outlast brief synaptic inhibition owing to the well-tuned interplay between neurotransmitter release and postsynaptic membrane dynamics, a phenomenon impacting microcircuit function.
PMID: 36787751
ISSN: 1097-4199
CID: 5432112

Oxytocin-Modulated Ion Channel Ensemble Controls Depolarization, Integration and Burst Firing in CA2 Pyramidal Neurons

Liu, Jing-Jing; Eyring, Katherine W; König, Gabriele M; Kostenis, Evi; Tsien, Richard W
Oxytocin (OXT) and OXT receptor (OXTR)-mediated signaling control excitability, firing patterns, and plasticity of hippocampal CA2 pyramidal neurons, which are pivotal in generation of brain oscillations and social memory. Nonetheless, the ionic mechanisms underlying OXTR-induced effects in CA2 neurons are not fully understood. Using slice physiology in a reporter mouse line and interleaved current-clamp and voltage-clamp experiments, we systematically identified the ion channels modulated by OXT signaling in CA2 pyramidal cells (PYRs) in mice of both sexes and explored how changes in channel conductance support altered electrical activity. Activation of OXTRs inhibits an outward potassium current mediated by inward rectifier potassium channels (I Kir) and thus favoring membrane depolarization. Concomitantly, OXT signaling also diminishes inward current mediated by hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels (I h), providing a hyperpolarizing drive. The combined reduction in both I Kir and I h synergistically elevate the membrane resistance and favor dendritic integration while the membrane potential is restrained from quickly depolarizing from rest. As a result, the responsiveness of CA2 PYRs to synaptic inputs is highly sharpened during OXTR activation. Unexpectedly, OXTR signaling also strongly enhances a tetrodotoxin-resistant (TTX-R), voltage-gated sodium current that helps drive the membrane potential to spike threshold and thus promote rhythmic firing. This novel array of OXTR-stimulated ionic mechanisms operates in close coordination and underpins OXT-induced burst firing, a key step in CA2 PYRs' contribution to hippocampal information processing and broader influence on brain circuitry. Our study deepens our understanding of underpinnings of OXT-promoted social memory and general neuropeptidergic control of cognitive states.SIGNIFICANCE STATEMENT Oxytocin (OXT) plays key roles in reproduction, parenting and social and emotional behavior, and deficiency in OXT receptor (OXTR) signaling may contribute to neuropsychiatric disorders. We identified a novel array of OXTR-modulated ion channels that operate in close coordination to retune hippocampal CA2 pyramidal neurons, enhancing responsiveness to synaptic inputs and sculpting output. OXTR signaling inhibits both potassium conductance (I Kir) and mixed cation conductance (I h), engaging opposing influences on membrane potential, stabilizing it while synergistically elevating membrane resistance and electrotonic spread. OXT signaling also facilitates a tetrodotoxin-resistant (TTX-R) Na+ current, not previously described in hippocampus (HP), engaged on further depolarization. This TTX-R current lowers the spike threshold and supports rhythmic depolarization and burst firing, a potent driver of downstream circuitry.
PMID: 36414006
ISSN: 1529-2401
CID: 5365892

Hypothalamic melanin-concentrating hormone regulates hippocampus-dorsolateral septum activity

Liu, Jing-Jing; Tsien, Richard W; Pang, Zhiping P
Hypothalamic melanin-concentrating hormone (MCH) polypeptide contributes to regulating energy homeostasis, sleep and memory, although the mechanistic bases of its effects are unknown. In this study, in mice, we uncovered the physiological mechanism underlying the functional role of MCH signaling in projections to the dorsolateral septum (dLS), a region involved in routing hippocampal firing rhythms and encoding spatial memory based on such rhythms. Firing activity within the dLS in response to dorsal CA3 (dCA3) excitation is limited by strong feed-forward inhibition (FFI). We found that MCH synchronizes dLS neuronal firing with its dCA3 inputs by enhancing GABA release, which subsequently reduces the FFI and augments dCA3 excitatory input strength, both via pre-synaptic mechanisms. At the functional level, our data reveal a role for MCH signaling in the dLS in facilitating spatial memory. These findings support a model in which peptidergic signaling within the dLS modulates dorsal hippocampal output and supports memory encoding.
PMCID:8741735
PMID: 34980924
ISSN: 1546-1726
CID: 5106932

De novo mutations in childhood cases of sudden unexplained death that disrupt intracellular Ca2+ regulation

Halvorsen, Matthew; Gould, Laura; Wang, Xiaohan; Grant, Gariel; Moya, Raquel; Rabin, Rachel; Ackerman, Michael J; Tester, David J; Lin, Peter T; Pappas, John G; Maurano, Matthew T; Goldstein, David B; Tsien, Richard W; Devinsky, Orrin
Sudden unexplained death in childhood (SUDC) is an understudied problem. Whole-exome sequence data from 124 "trios" (decedent child, living parents) was used to test for excessive de novo mutations (DNMs) in genes involved in cardiac arrhythmias, epilepsy, and other disorders. Among decedents, nonsynonymous DNMs were enriched in genes associated with cardiac and seizure disorders relative to controls (odds ratio = 9.76, P = 2.15 × 10-4). We also found evidence for overtransmission of loss-of-function (LoF) or previously reported pathogenic variants in these same genes from heterozygous carrier parents (11 of 14 transmitted, P = 0.03). We identified a total of 11 SUDC proband genotypes (7 de novo, 1 transmitted parental mosaic, 2 transmitted parental heterozygous, and 1 compound heterozygous) as pathogenic and likely contributory to death, a genetic finding in 8.9% of our cohort. Two genes had recurrent missense DNMs, RYR2 and CACNA1C Both RYR2 mutations are pathogenic (P = 1.7 × 10-7) and were previously studied in mouse models. Both CACNA1C mutations lie within a 104-nt exon (P = 1.0 × 10-7) and result in slowed L-type calcium channel inactivation and lower current density. In total, six pathogenic DNMs can alter calcium-related regulation of cardiomyocyte and neuronal excitability at a submembrane junction, suggesting a pathway conferring susceptibility to sudden death. There was a trend for excess LoF mutations in LoF intolerant genes, where ≥1 nonhealthy sample in denovo-db has a similar variant (odds ratio = 6.73, P = 0.02); additional uncharacterized genetic causes of sudden death in children might be discovered with larger cohorts.
PMID: 34930847
ISSN: 1091-6490
CID: 5108732

Unique dynamics and exocytosis properties of GABAergic synaptic vesicles revealed by three-dimensional single vesicle tracking

Park, Chungwon; Chen, Xingxiang; Tian, Chong-Li; Park, Gyu Nam; Chenouard, Nicolas; Lee, Hunki; Yeo, Xin Yi; Jung, Sangyong; Tsien, Richard W; Bi, Guo-Qiang; Park, Hyokeun
Maintaining the balance between neuronal excitation and inhibition is essential for proper function of the central nervous system. Inhibitory synaptic transmission plays an important role in maintaining this balance. Although inhibitory transmission has higher kinetic demands compared to excitatory transmission, its properties are poorly understood. In particular, the dynamics and exocytosis of single inhibitory vesicles have not been investigated, due largely to both technical and practical limitations. Using a combination of quantum dots (QDs) conjugated to antibodies against the luminal domain of the vesicular GABA transporter to selectively label GABAergic (i.e., predominantly inhibitory) vesicles together with dual-focus imaging optics, we tracked the real-time three-dimensional position of single GABAergic vesicles up to the moment of exocytosis (i.e., fusion). Using three-dimensional trajectories, we found that GABAergic synaptic vesicles traveled a shorter distance prior to fusion and had a shorter time to fusion compared to synaptotagmin-1 (Syt1)-labeled vesicles, which were mostly from excitatory neurons. Moreover, our analysis revealed that GABAergic synaptic vesicles move more straightly to their release sites than Syt1-labeled vesicles. Finally, we found that GABAergic vesicles have a higher prevalence of kiss-and-run fusion than Syt1-labeled vesicles. These results indicate that inhibitory synaptic vesicles have a unique set of dynamics and exocytosis properties to support rapid synaptic inhibition, thereby maintaining a tightly regulated coordination between excitation and inhibition in the central nervous system.
PMID: 33622785
ISSN: 1091-6490
CID: 4794532

Synaptic vesicle traffic is supported by transient actin filaments and regulated by PKA and NO

Chenouard, Nicolas; Xuan, Feng; Tsien, Richard W
Synaptic vesicles (SVs) can be pooled across multiple synapses, prompting questions about their dynamic allocation for neurotransmission and plasticity. We find that the axonal traffic of recycling vesicles is not supported by ubiquitous microtubule-based motility but relies on actin instead. Vesicles freed from synaptic clusters undergo ~1 µm bouts of active transport, initiated by nearby elongation of actin filaments. Long distance translocation arises when successive bouts of active transport were linked by periods of free diffusion. The availability of SVs for active transport can be promptly increased by protein kinase A, a key player in neuromodulation. Vesicle motion is in turn impeded by shutting off axonal actin polymerization, mediated by nitric oxide-cyclic GMP signaling leading to inhibition of RhoA. These findings provide a potential framework for coordinating post-and pre-synaptic strength, using retrograde regulation of axonal actin dynamics to mobilize and recruit presynaptic SV resources.
PMID: 33087709
ISSN: 2041-1723
CID: 4642352