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

Abstract

Tuberous Sclerosis Complex (TSC) is a neurodevelopmental disorder in which individualsfrequently present with autism spectrum disorder (ASD). A core diagnostic criterion for ASD is the presence of restricted, repetitive behaviors (RRBs), which may result from abnormal activity in striatal circuits that mediate motor learning, action selection and habit formation. Striatal control over motor behavior relies on the coordinated activity of two subtypes of principle neurons, direct pathway and indirect pathway spiny projection neurons (dSPNs or iSPNs, respectively), which provide the main output of the striatum. To test if altered striatal activity is sufficient to cause repetitive behaviors in the context of TSC, we conditionally deleted Tsc1 from dSPNs or iSPNs in mice and measured the consequences on synaptic function and motor behavior. We find that mice with loss of Tsc1 from dSPNs, but not iSPNs, have enhanced motor routine learning in the accelerating rotarod task. This increased motor learning is associated with an impairment in endocannabinoid-mediated long-term depression (eCB-LTD) at cortico-dSPN synapses in the dorsal striatum. Consistent with a loss of eCB-LTD, disruption of Tsc1 in dSPNs, but not iSPNs, results in a strong enhancement of corticostriatal synaptic drive. Together these findings demonstrate that within the striatum dSPNs show selective sensitivity to Tsc1 loss and indicate that enhanced activation of the striatal direct pathway is a potential contributor to RRBs in TSC.

Current Approaches and Future Directions for the Treatment of mTORopathies

“…Deletion of Tsc1 from serotonergic neu-rons using Slc6a4 (SERT)-Cre mice was also sufficient to cause ASD-like behaviors including social behavior deficits and increased repetitive behaviors [159]. Deletion of Tsc1 from one of the primary targets of dopamine neurons, striatal projection neurons, results in enhanced motor routine learning, which only occurs when Tsc1 is lost from direct pathway, but not indirect pathway, striatal projection neurons [160]. In addition, deletion of Tsc1 from thalamic neurons during mid-embryonic development leads to repetitive grooming [161].…”

Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2

“…While mTOR is present and active in all cells, distinct neuronal types show differential responses to alterations in mTOR signaling (Benthall et al, 2021;Yang et al, 2012). Midbrain dopamine (DA) neurons residing in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) are particularly sensitive to mTOR signaling status, which may be a result of their unique physiology and high metabolic demands (Matsuda et al, 2009;Pacelli et al, 2015).…”

A twin UGUA motif directs the balance between gene isoforms through CFIm and the mTORC1 signaling pathway

“…Our results demonstrate the feasibility of our approach to circumvent the cumbersome breeding process and model constitutive mTORC1 signaling, the hallmark of TSC (Salussolia et al, 2019), in desired cell populations in the mouse brain in vivo. Deletion of Tsc1 in different brain cell types in mouse generates distinct phenotypes, each capturing separate human disease features (Bateup et al, 2013;Benthall et al, 2021;Ercan et al, 2017;Jiang et al, 2016;Kosillo et al, 2019;Lebrun-Julien et al, 2014;Meikle et al, 2007;Tsai et al, 2012;Uhlmann et al, 2002;Zou et al, 2017).…”

“…Our results demonstrate the feasibility of our approach to circumvent the cumbersome breeding process and model constitutive mTORC1 signaling, the hallmark of TSC (Salussolia et al, 2019), in desired cell populations in the mouse brain in vivo . Deletion of Tsc1 in different brain cell types in mouse generates distinct phenotypes, each capturing separate human disease features (Bateup et al, 2013; Benthall et al, 2021; Ercan et al, 2017; Jiang et al, 2016; Kosillo et al, 2019; Lebrun-Julien et al, 2014; Meikle et al, 2007; Tsai et al, 2012; Uhlmann et al, 2002; Zou et al, 2017). Our results suggest that extending APA analysis to additional cell types in TSC brain with the rapidly expanding AAV toolkit (Challis et al, 2022) would facilitate identification of possible molecular defects in TSC due to APA dysregulation in addition to generating a panoramic view of APA regulation in TSC.…”