Early structural and functional plasticity alterations in a susceptibility period of DYT1 dystonia mouse striatum

Abstract

The onset of abnormal movements in DYT1 dystonia is between childhood and adolescence, although it is unclear why clinical manifestations appear during this developmental period. Plasticity at corticostriatal synapses is critically involved in motor memory. In the Tor1a+/Δgag DYT1 dystonia mouse model, long-term potentiation (LTP) appeared prematurely in a critical developmental window in striatal spiny neurons (SPNs), while long-term depression (LTD) was never recorded. Analysis of dendritic spines showed an increase of both spine width and mature mushroom spines in Tor1a+/Δgag neurons, paralleled by an enhanced AMPA receptor (AMPAR) accumulation. BDNF regulates AMPAR expression during development. Accordingly, both proBDNF and BDNF levels were significantly higher in Tor1a+/Δgag mice. Consistently, antagonism of BDNF rescued synaptic plasticity deficits and AMPA currents. Our findings demonstrate that early loss of functional and structural synaptic homeostasis represents a unique endophenotypic trait during striatal maturation, promoting the appearance of clinical manifestations in mutation carriers.

BDNF controls bidirectional endocannabinoid-plasticity at corticostriatal synapses

“…In these cases, some aberrant plasticity has been observed (Deinhardt and Chao 2014;Zlebnik and Cheer 2016;Maltese et al, 2018) in line with our results showing that an over-activation of TrkB triggers a remodeling and an enlargement of the domains of expression of Hebbian plasticity. For instance, in DYT1 dystonia, increased BDNF levels trigger an abnormal LTP (together with structural dendritic modifications) during critical developmental window in premature MSNs (Maltese et al, 2018). In conclusion our study unveils a novel synaptic mechanism by which BDNF/TrkB governs striatal functions, thus potentially paving the way to a better understanding of a range of diseases in which alteration or disruption of BDNF/TrkB signaling has been recognized as causative feature for learning and memory deficits.…”

“…In the light of our results, this reduction of BDNF account for the reduction or the loss of synaptic plasticity, as observed in Huntington disease rodent models (Kolodziejczyk et al 2014;Plotkin et al 2014;Sepers et al 2018). On the opposite, BDNF levels are increased in maladaptive disorders such as ethanol or cocaine addiction (Jeanblanc et al 2009;Im et al 2010;Lu et al 2010;Bahi and Dreyer 2013) or neurogenetic disorders, such as DYT1 dystonia (Maltese et al, 2018). In these cases, some aberrant plasticity has been observed (Deinhardt and Chao 2014;Zlebnik and Cheer 2016;Maltese et al, 2018) in line with our results showing that an over-activation of TrkB triggers a remodeling and an enlargement of the domains of expression of Hebbian plasticity.…”

“…On the opposite, BDNF levels are increased in maladaptive disorders such as ethanol or cocaine addiction (Jeanblanc et al 2009;Im et al 2010;Lu et al 2010;Bahi and Dreyer 2013) or neurogenetic disorders, such as DYT1 dystonia (Maltese et al, 2018). In these cases, some aberrant plasticity has been observed (Deinhardt and Chao 2014;Zlebnik and Cheer 2016;Maltese et al, 2018) in line with our results showing that an over-activation of TrkB triggers a remodeling and an enlargement of the domains of expression of Hebbian plasticity. For instance, in DYT1 dystonia, increased BDNF levels trigger an abnormal LTP (together with structural dendritic modifications) during critical developmental window in premature MSNs (Maltese et al, 2018).…”

TorsinB overexpression prevents abnormal twisting in DYT1 dystonia mouse models

“…This Cre field includes the motor cortex, which is a critical component of the forebrain cortico-striatal network thought to participate in the expression of dystonic symptoms [20][21][22]. Disruption of this network has been observed in several dystonia mouse models [23][24][25][26]. Emx1-Cre conditional deletion of torsinA (Emx1-CKO, Table S1, Figure 1A) reduces cortical thickness ( Figure 1D), but does not significantly alter the number of CUX1+ (marker for cortical layer II-IV) or CTIP2+ (marker for cortical layer V-VI) cortical neurons ( Figure 1E-F) [27,28].…”

Transcriptome profiles in brains of mice heterozygous for a DYT1 dystonia-associated mutation in the endogenous Tor1a gene

“…After this phase, the torsinA expression decreases rapidly during a postnatal 2-to-3-week period (Puglisi et al, 2013;Tanabe et al, 2016). This early postnatal time is the critical period during which Tor1a mutations lead to abnormalities in: synaptogenesis in the cerebellum (Vanni et al, 2015); the plasticity of synaptic transmission at the cortico-striatal synapses (Maltese et al, 2018); and the structure of the nuclear envelope and accumulation of ubiquitin in the perinuclear region (Pappas et al, 2018). However, the transcriptome profile of the DYT1 model during this critical period is unknown.…”