Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning

Benthall, Katelyn N.; Cording, Katherine R.; Wong, Corinna D.; Chen, Emily Y.; Bateup, Helen S.

doi:10.1016/j.celrep.2022.110563

Cited by 3 publications

(2 citation statements)

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“…The mTOR pathway plays critical functions in various physiological and behavioral processes, and its aberrant hyperactivation has been linked to different pathological conditions, including epilepsy. Cell type‐specific loss of the mTOR inhibition in cerebellar, dopaminergic, serotonergic, or striatal neurons induces different cognitive and behavioral deficits in the absence of epilepsy, 29–34 suggesting that distinct cell types and circuits are responsible for specific neuropsychiatric manifestations. Here, we showed that Depdc5 deletion in a subset of forebrain excitatory neurons was sufficient to cause epilepsy and SUDEP.…”

Section: Discussionmentioning

confidence: 99%

“…28 The mTOR pathway plays critical functions in various physiological and behavioral processes, and its aberrant hyperactivation has been linked to different pathological conditions, including epilepsy. Cell type-specific loss of the mTOR inhibition in cerebellar, dopaminergic, serotonergic, or striatal neurons induces different cognitive and behavioral deficits in the absence of epilepsy, [29][30][31][32][33][34] suggesting that distinct cell types For example, mice with Tsc1 deletion in PV+ or SST+ INs did not develop spontaneous seizures and grew normally into adulthood. 35 Mice conditionally expressing the constitutively active Pik3ca p.H1047R pathogenic variant in MGE-derived interneurons (Nkx2.1-Cre), 36 or more specifically in PV+ INs (Pvalb-Cre), 37 did not develop spontaneous seizures.…”

Section: Discussionmentioning

confidence: 99%

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Sudden Unexpected Death in Epilepsy and Respiratory Defects in a Mouse Model of DEPDC5‐Related Epilepsy

Kao,

Yao,

Yang

et al. 2023

Annals of Neurology

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ObjectivesDEPDC5 is a common causative gene in familial focal epilepsy with or without malformations of cortical development. Its pathogenic variants also confer a significantly higher risk for sudden unexpected death in epilepsy (SUDEP), providing opportunities to investigate the pathophysiology intersecting neurodevelopment, epilepsy, and cardiorespiratory function. There is an urgent need to gain a mechanistic understanding of DEPDC5‐related epilepsy and SUDEP, identify biomarkers for patients at high risk, and develop preventive interventions.MethodsDepdc5 was specifically deleted in excitatory or inhibitory neurons in the mouse brain to determine neuronal subtypes that drive epileptogenesis and SUDEP. EEG, cardiac, and respiratory recordings were performed to determine cardiorespiratory phenotypes associated with SUDEP. Baseline respiratory function and the response to hypoxia challenge were also studied in these mice.ResultsDepdc5 deletion in excitatory neurons in cortical layer 5 and dentate gyrus caused frequent generalized tonic–clonic seizures and SUDEP in young adult mice, but Depdc5 deletion in cortical interneurons did not. EEG suppression immediately following ictal offset was observed in fatal and non‐fatal seizures, but low amplitude rhythmic theta frequency activity was lost only in fatal seizures. In addition, these animals developed baseline respiratory dysfunction prior to SUDEP, during which ictal apnea occurred long before terminal cardiac asystole.InterpretationDepdc5 deletion in excitatory neurons is sufficient to cause DEPDC5‐related epilepsy and SUDEP. Ictal apnea and respiratory dysregulation play critical roles in SUDEP. Our study also provides a novel mouse model to investigate the underlying mechanisms of DEPDC5‐related epilepsy and SUDEP.This article is protected by copyright. All rights reserved.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Sudden Unexpected Death in Epilepsy and Respiratory Defects in a Mouse Model of DEPDC5‐Related Epilepsy

Kao,

Yao,

Yang

et al. 2023

Annals of Neurology

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Effect of chronic upregulation of endocannabinoid signalingin vivowith JZL184 on striatal synaptic plasticity and motor learning in YAC128 Huntington disease mice

Sepers,

Woodard,

Ramandi

et al. 2024

Preprint

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Synaptic dysfunction underlies early sensorimotor and cognitive deficits, and precedes neurodegeneration in a variety of disorders, including Alzheimer, Parkinson and Huntington disease (HD). A monogenic inherited disorder, HD manifests with cognitive, motor and mood disorders associated with progressive degeneration of striatal spiny projection neurons and cortical pyramidal neurons. Cortico-basal ganglia-thalamic loops regulate movement selection and motor learning, which are impaired early in HD. Skilled motor learning is mediated in part by plasticity at cortico-striatal synapses, including endocannabinoid-mediated, high-frequency stimulation induced long-term depression (HFS-LTD). Previously, we found impaired HFS-LTD in brain slice recordings from pre-manifest HD mouse models, which was corrected by JZL184, an inhibitor of endocannabinoid 2-arachidonoyl glycerol (2-AG) degradation. Here, we tested the effects of JZL184 administered in vivo to YAC128 HD model and wild-type (WT) littermate mice. JZL184, given orally daily over a 3-week period, significantly increased levels of 2-AG in striatal tissue. While JZL184 treatment had no impact on open field behavior which was similar for the two genotypes, the treatment improved motor learning on the rotarod task in YAC128 mice to the level observed in WT mice. Moreover, HFS-induced striatal plasticity measured by field potential recording in acute brain slice from YAC128 mice was normalized to WT levels after JZL184 treatment. These results suggest a novel target for mitigating early symptoms of HD, and support the need for clinical trials to test the efficacy of modulating the endocannabinoid system in treatment of HD.

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A non-canonical striatopallidal “Go” pathway that supports motor control

Labouesse

Torres-Herraez

Chohan

et al. 2023

Preprint

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In the classical model of the basal ganglia, direct pathway striatal projection neurons (dSPNs) send projections to the substantia nigra (SNr) and entopeduncular nucleus to regulate motor function. Recent studies have re-established that dSPNs also possess “bridging” collaterals within the globus pallidus (GPe), yet the significance of these collaterals for behavior is unknown. Here we use in vivo optical and chemogenetic tools combined with deep learning approaches to dissect the roles of bridging collaterals in motor function. We find that dSPNs projecting to the SNr send synchronous motor-related information to the GPe via axon collaterals. Inhibition of native activity in dSPN GPe terminals impairs motor activity and function via regulation of pallidostriatal Npas1 neurons. We propose a model by which dSPN GPe collaterals (“striatopallidal Go pathway”) act in concert with the canonical terminals in the SNr to support motor control by inhibiting Npas1 signals going back to the striatum.

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Loss of Tsc1 from striatal direct pathway neurons impairs endocannabinoid-LTD and enhances motor routine learning

Cited by 3 publications

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Sudden Unexpected Death in Epilepsy and Respiratory Defects in a Mouse Model of DEPDC5‐Related Epilepsy

Sudden Unexpected Death in Epilepsy and Respiratory Defects in a Mouse Model of DEPDC5‐Related Epilepsy

Effect of chronic upregulation of endocannabinoid signalingin vivowith JZL184 on striatal synaptic plasticity and motor learning in YAC128 Huntington disease mice

A non-canonical striatopallidal “Go” pathway that supports motor control

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