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Purkinje cell dendrite and spine morphology in vitro. Purified Purkinje cells were cocultured with purified granule cells for 14 DIV in serum-free medium and immunostained with antibodies to calbindin-D 28k. A, B, Control cells (untreated); C, D, treated with BDNF; E, F, treated with TrkB-IgG. For each condition, examples of cells with well developed (A, C, E) and less well developed (B, D, F ) dendrites are shown. Even at this relatively low magnification, an increase in spine density is apparent after BDNF treatment (C, D). Scale bar: F, 10 m.
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Neurotrophins cooperate with neural activity to modulate CNS neuronal survival and dendritic differentiation. In a previous study, we demonstrated that a critical balance of neurotrophin and neural activity is required for Purkinje cell survival in cocultures of purified granule and Purkinje cells (Morrison and Mason, 1998). Here we investigate whe...
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Context 1
... BDNF, TrkB-IgG, or both were added to granule and Purkinje cell cocultures in serum-free medium 1.5 hr after Baptista et al., 1994). These cells had dendritic processes arranged in a multipolar manner or extended a single or double stem trunk emerging from one pole of the soma. The processes were covered with spines as in vivo ( Fig. 1 A, B). Only the normally developing cells in category 1 were analyzed fur- ther. In both the control cultures and those treated with BDNF, there was little difference in overall dendritic differentiation. Both groups, however, displayed a considerable range in the extent of dendritic development, from short processes with one or two branch points ( Fig. 1 B, D, F ), to dendritic arbors with up to 14 branch points ( Fig. 1 A, C, E). Therefore, despite the deleterious effect of exogenous BDNF on Purkinje cell survival in granule- Purkinje cocultures, general Purkinje dendritic development ap- peared normal. ...
Context 2
... BDNF, TrkB-IgG, or both were added to granule and Purkinje cell cocultures in serum-free medium 1.5 hr after Baptista et al., 1994). These cells had dendritic processes arranged in a multipolar manner or extended a single or double stem trunk emerging from one pole of the soma. The processes were covered with spines as in vivo ( Fig. 1 A, B). Only the normally developing cells in category 1 were analyzed fur- ther. In both the control cultures and those treated with BDNF, there was little difference in overall dendritic differentiation. Both groups, however, displayed a considerable range in the extent of dendritic development, from short processes with one or two branch points ( Fig. 1 B, D, F ), to dendritic arbors with up to 14 branch points ( Fig. 1 A, C, E). Therefore, despite the deleterious effect of exogenous BDNF on Purkinje cell survival in granule- Purkinje cocultures, general Purkinje dendritic development ap- peared normal. ...
Context 3
... BDNF, TrkB-IgG, or both were added to granule and Purkinje cell cocultures in serum-free medium 1.5 hr after Baptista et al., 1994). These cells had dendritic processes arranged in a multipolar manner or extended a single or double stem trunk emerging from one pole of the soma. The processes were covered with spines as in vivo ( Fig. 1 A, B). Only the normally developing cells in category 1 were analyzed fur- ther. In both the control cultures and those treated with BDNF, there was little difference in overall dendritic differentiation. Both groups, however, displayed a considerable range in the extent of dendritic development, from short processes with one or two branch points ( Fig. 1 B, D, F ), to dendritic arbors with up to 14 branch points ( Fig. 1 A, C, E). Therefore, despite the deleterious effect of exogenous BDNF on Purkinje cell survival in granule- Purkinje cocultures, general Purkinje dendritic development ap- peared normal. ...
Context 4
... observations suggested that Purkinje spine density and morphology might be affected by BDN F ( Fig. 1; Morrison and Mason, 1998). To test this hypothesis, we determined the density of total spines and the percentage of filopodia-like spines for each experimental group. Data were collected separately for spines on proximal and distal dendrite segments (see Materials and Methods). In cultures treated with BDN F, the density of total dendritic spines was significantly increased in all three experi- ments (F (3,1506) 49.8, p 0.001) (Figs. 1 A-D, 2, 3). The increase in spine density compared with the control group ranged from 24 to 55% and was 42% on average. The increase in spine density caused by BDN F was blocked with the addition of TrkB- IgG (Fig. 3). TrkB-IgG alone, however, had no significant effect on spine density (Fig. 3). No difference was detected between spine densities on proximal and distal dendrites, so the proximal and distal data were combined (Fig. 3). Thus, exogenous BDNF increased the absolute number of total spines per Purkinje cell. We next examined the proportion of filopodia-like and headed spines. The former are thought to represent immature spines, whereas the latter appear to be more mature, although it is not clear whether all spines on all neurons must progress from filopo- dial to headed forms ( Papa et al., 1995;Dailey and Smith, 1996;Ziv and Smith, 1996). Filopodia-like spines comprised 43.9% of all dendritic protrusions in control cultures (Fig. 3). This percent- age was not consistently changed by treatment with BDNF, TrkB- IgG, or both (Fig. 3). The percentage of filopodia-like spines was not significantly higher on the distal dendritic segments (44.7%) than on proximal segments (40.8%) (data not shown). Thus, although BDN F treatment increased spine density, it did not change the steady-state relative proportion of filopodia-like to headed spines, a possible index of spine ...
Context 5
... observations suggested that Purkinje spine density and morphology might be affected by BDN F ( Fig. 1; Morrison and Mason, 1998). To test this hypothesis, we determined the density of total spines and the percentage of filopodia-like spines for each experimental group. Data were collected separately for spines on proximal and distal dendrite segments (see Materials and Methods). In cultures treated with BDN F, the density of total dendritic spines was significantly increased in all three experi- ments (F (3,1506) 49.8, p 0.001) (Figs. 1 A-D, 2, 3). The increase in spine density compared with the control group ranged from 24 to 55% and was 42% on average. The increase in spine density caused by BDN F was blocked with the addition of TrkB- IgG (Fig. 3). TrkB-IgG alone, however, had no significant effect on spine density (Fig. 3). No difference was detected between spine densities on proximal and distal dendrites, so the proximal and distal data were combined (Fig. 3). Thus, exogenous BDNF increased the absolute number of total spines per Purkinje cell. We next examined the proportion of filopodia-like and headed spines. The former are thought to represent immature spines, whereas the latter appear to be more mature, although it is not clear whether all spines on all neurons must progress from filopo- dial to headed forms ( Papa et al., 1995;Dailey and Smith, 1996;Ziv and Smith, 1996). Filopodia-like spines comprised 43.9% of all dendritic protrusions in control cultures (Fig. 3). This percent- age was not consistently changed by treatment with BDNF, TrkB- IgG, or both (Fig. 3). The percentage of filopodia-like spines was not significantly higher on the distal dendritic segments (44.7%) than on proximal segments (40.8%) (data not shown). Thus, although BDN F treatment increased spine density, it did not change the steady-state relative proportion of filopodia-like to headed spines, a possible index of spine ...
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Citations
... After 4 h, the culture medium was replaced with neurobasal medium (Thermo-Fisher, cat# 21103049) supplemented with 2% B27 (Life Technologies, cat# 17504044), 1x GlutaMAX (Thermo-Fisher, cat# 35-050-061) and 1x penicillin/ streptomycin (Thermo-Fisher, cat# 15140-122). The proliferation of nonneuronal cells was limited using cytosine arabinoside (0.25 μg/ml AraC, Sigma-Aldrich, cat# C1768) when MEM/HS was replaced with neurobasal medium (Shimada et al., 1998;Taylor et al., 2003;Moya-Alvarado et al., 2023). Figures 1-4 and Supplementary Figures S2, S4 were performed in rat cortical neurons and Figures 5, 6 and Supplementary Figures S1, S3 were performed in mouse cortical neurons. ...
Brain-derived neurotrophic factor (BDNF) and its tropomyosin receptor kinase B (TrkB) are important signaling proteins that regulate dendritic growth and maintenance in the central nervous system (CNS). After binding of BDNF, TrkB is endocytosed into endosomes and continues signaling within the cell soma, dendrites, and axon. In previous studies, we showed that BDNF signaling initiated in axons triggers long-distance signaling, inducing dendritic arborization in a CREB-dependent manner in cell bodies, processes that depend on axonal dynein and TrkB activities. The binding of BDNF to TrkB triggers the activation of different signaling pathways, including the ERK, PLC-γ and PI3K-mTOR pathways, to induce dendritic growth and synaptic plasticity. How TrkB downstream pathways regulate long-distance signaling is unclear. Here, we studied the role of PLC-γ-Ca ²⁺ in BDNF-induced long-distance signaling using compartmentalized microfluidic cultures. We found that dendritic branching and CREB phosphorylation induced by axonal BDNF stimulation require the activation of PLC-γ in the axons of cortical neurons. Locally, in axons, BDNF increases PLC-γ phosphorylation and induces intracellular Ca ²⁺ waves in a PLC-γ-dependent manner. In parallel, we observed that BDNF-containing signaling endosomes transport to the cell body was dependent on PLC-γ activity and intracellular Ca ²⁺ stores. Furthermore, the activity of PLC-γ is required for BDNF-dependent TrkB endocytosis, suggesting a role for the TrkB/PLC-γ signaling pathway in axonal signaling endosome formation.
... While BDNF exerts cell survival effects through TrkB activation, proBDNF is known to be a proapoptotic mediator through activation of p75 NTR , resulting in axon pruning and cell death (Glass et al., 1991;Ghosh et al., 1994;Singh et al., 2008). As BDNF and TrkB are expressed in cerebellar PCs, they play a role in PC dendritogenesis and spine formation both in vitro and in vivo (Schwartz et al., 1997;Shimada et al., 1998;Yamashita et al., 2011). Lärkfors et al. (1996) found that survival of PCs increases after in vitro treatment with BDNF. ...
... References BDNF CGN survival Bulleit and Hsieh (2000), Kubo et al. (1995), Leeds et al. (2005), Lindholm et al. (1993), Nonomura et al. (1996), Ortega et al. (2010, Sanchez-Perez et al. (2005), Shimoke et al. (1997), Skaper et al. (1998), Tong and Perez-Polo (1998), Zirrgiebel et al. (1995), and Koshimizu et al. (2010) CGN migration Borghesani et al. (2002), Kokubo et al. (2009), andZhou et al. (2007) CGN neurite outgrowth Gao et al. (1995), Nonomura et al. (1996), and Tanaka et al. (2000) PC survival Lärkfors et al. (1996), Rakotomamonjy and Goumari (2019), and Morrison and Mason (1998) PC neurite outgrowth Schwartz et al. (1997), Shimada et al. (1998), and Yamashita et al. (2011) Circuit wiring Bosman et al. (2006), Carter et al. (2002), Minichiello (1996), Rico et al. (2002), Schwartz et al. (1997), Shinoda et al. Circuit wiring Lackey and Sillitoe (2020) Cerebellar foliation Karam et al. (2000) and Rogers et al. (1999) EGF CGN survival Abe et al. (1991, Morrison et al. (1988), Yamada et al. (1997), Gunn-Moore and Tavaré (1998) and Leutz and Schachner (1981) CGN migration Carrasco et al. (2003), and Martinez et al. (2011) CGN neurite development Abe et al. (1991, Morrison et al. (1988), and Yamada et al. (1997) NSC proliferation Okano-Uchida et al. (2013) and Leutz and Schachner (1981) GDNF CGN survival Subramaniam et al. (2008) PC survival Mount et al. (1995) PC neurite outgrowth Mount et al. (1995) MLI survival Sergaki and Ibáñez (2017) NGF CGN survival Legrand and Clos (1991), Muller et al. (1994), Khursigara et al. (2001), Kisiswa et al. (2018), and Vicario et al. (2015) PC CGN migration Neveu and Arenas (1996) PC survival Lärkfors et al. (1996) and Mount et al. (1998) PC neurite outgrowth Joo et al. (2014), Neveu and Arenas (1996), and Tepper et al. (2020) Circuit wiring Sadakata et al. (2014), Shinoda et al. (2019), and Sherrard and Bower (2002) (Continued) ...
The cerebellum is a multifunctional brain region that controls diverse motor and non-motor behaviors. As a result, impairments in the cerebellar architecture and circuitry lead to a vast array of neuropsychiatric and neurodevelopmental disorders. Neurotrophins and neurotrophic growth factors play essential roles in the development as well as maintenance of the central and peripheral nervous system which is crucial for normal brain function. Their timely expression throughout embryonic and postnatal stages is important for promoting growth and survival of both neurons and glial cells. During postnatal development, the cerebellum undergoes changes in its cellular organization, which is regulated by a variety of molecular factors, including neurotrophic factors. Studies have shown that these factors and their receptors promote proper formation of the cerebellar cytoarchitecture as well as maintenance of the cerebellar circuits. In this review, we will summarize what is known on the neurotrophic factors' role in cerebellar postnatal development and how their dysregulation assists in developing various neurological disorders. Understanding the expression patterns and signaling mechanisms of these factors and their receptors is crucial for elucidating their function within the cerebellum and for developing therapeutic strategies for cerebellar-related disorders.
... Similar results are obtained when adult pyramidal neurons (cortical layers II-III) in the sensory-motor cortex express CREB-DN-EGFP in vivo (Figure 3-figure supplement 3). This circuit requires BDNF and TrkB to sustain normal neuronal morphology (Andreska et al., 2020;Shimada et al., 1998). When transduced with AAV1 expressing mCherry, the cortico-callosal pathway is labeled (Figure 3-figure supplement 3A). ...
... After 4 hr, the culture medium was replaced with neurobasal medium supplemented with 2% B27, 1 x GlutaMAX and 1 x penicillin/streptomycin. The proliferation of nonneuronal cells was limited by applying cytosine arabinoside (AraC; 0.25 µg/mL) when the MEM/ HS was replaced with neurobasal medium and removed two days later (Shimada et al., 1998;Taylor et al., 2003). ...
Brain-derived neurotrophic factor (BDNF) and its receptors tropomyosin kinase receptor B (TrkB) and the p75 neurotrophin receptor (p75) are the primary regulators of dendritic growth in the CNS. After being bound by BDNF, TrkB and p75 are endocytosed into endosomes and continue signaling within the cell soma, dendrites, and axons. We studied the functional role of BDNF axonal signaling in cortical neurons derived from different transgenic mice using compartmentalized cultures in microfluidic devices. We found that axonal BDNF increased dendritic growth from the neuronal cell body in a cAMP response element-binding protein (CREB)-dependent manner. These effects were dependent on axonal TrkB but not p75 activity. Dynein-dependent BDNF-TrkB-containing endosome transport was required for long-distance induction of dendritic growth. Axonal signaling endosomes increased CREB and mTOR kinase activity in the cell body, and this increase in the activity of both proteins was required for general protein translation and the expression of Arc, a plasticity-associated gene, indicating a role for BDNF-TrkB axonal signaling endosomes in coordinating the transcription and translation of genes whose products contribute to learning and memory regulation.
... On the other hand, in vitro studies have shown that BDNF and TrkB modulate the dendritic development and spine density of PCs. However, BDNF treatment of primary culture of purified PCs did not elicit the generation of mature dendrites and spines, whereas chronic treatment with BDNF of GCs/PCs co-cultures increased the number of PC dendritic spines and synapses, suggesting a critical role of neuronal activity in mediating this BDNF response (Shimada et al., 1998;Tanaka et al., 2008). ...
Brain-derived neurotrophic factor (BDNF) is one of the most studied neurotrophins in the mammalian brain, essential not only to the development of the central nervous system but also to synaptic plasticity. BDNF is present in various brain areas, but highest levels of expression are seen in the cerebellum and hippocampus.
After birth, BDNF acts in the cerebellum as a mitogenic and chemotactic factor, stimulating the cerebellar granule cell precursors to proliferate, migrate and maturate, while in the hippocampus BDNF plays a fundamental role in synaptic transmission and plasticity, representing a key regulator for the long-term potentiation, learning and memory. Furthermore, the expression of BDNF is highly regulated and changes of its expression are associated with both physiological and pathological conditions.
The purpose of this review is to provide an overview of the current state of knowledge on the BDNF biology and its neurotrophic role in the proper development and functioning of neurons and synapses in two important brain areas of postnatal neurogenesis, the cerebellum and hippocampus.
Dysregulation of BDNF expression and signaling, resulting in alterations in neuronal maturation and plasticity in both systems, is a common hallmark of several neurodevelopmental diseases, such as autism spectrum disorder, suggesting that neuronal malfunction present in these disorders is the result of excessive or reduced of BDNF support.
We believe that the more the relevance of the pathophysiological actions of BDNF, and its downstream signals, in early postnatal development will be highlighted, the more likely it is that new neuroprotective therapeutic strategies will be identified in the treatment of various neurodevelopmental disorders.
... [118][119][120][121][122][123] For instance, several studies have shown that the long-term administration of BDNF in primary rodent pyramidal hippocampal neurons or cerebellar purkinje neurons leads to increased dendritic spine density. [124][125][126][127] Studies have found this to be directly mediated through TrkB signaling, as Trk receptor antagonists can directly prevent the BDNF-induced increase in spine density. 128,129 At the same time, in vivo and in vitro studies have demonstrated the ability for BDNF to alter the morphology of spines, altering post-synaptic densities and neurotransmitter receptor distributions. ...
Chronic exposure to uncontrollable stress causes loss of spines and dendrites in the prefrontal cortex (PFC), a recently evolved brain region that provides top-down regulation of thought, action, and emotion. PFC neurons generate top-down goals through recurrent excitatory connections on spines. This persistent firing is the foundation for higher cognition, including working memory, and abstract thought. However, exposure to acute uncontrollable stress drives high levels of catecholamine release in the PFC, which activates feedforward calcium-cAMP signaling pathways to open nearby potassium channels, rapidly weakening synaptic connectivity to reduce persistent firing. Chronic stress exposures can further exacerbate these signaling events leading to loss of spines and resulting in marked cognitive impairment. In this review, we discuss how stress signaling mechanisms can lead to spine loss, including changes to BDNF-mTORC1 signaling, calcium homeostasis, actin dynamics, and mitochondrial actions that engage glial removal of spines through inflammatory signaling. Stress signaling events may be amplified in PFC spines due to cAMP magnification of internal calcium release. As PFC dendritic spine loss is a feature of many cognitive disorders, understanding how stress affects the structure and function of the PFC will help to inform strategies for treatment and prevention.
... It has been demonstrated that the growing PC dendrites are covered with numerous dendritic protrusions, including dendritic filopodia and immature spines (Kawabata Shimada et al., 1998). Given that dendritic protrusions are known to serve as branch precursors in some neurons, we next analyzed the protrusions in PCs with or without βIII spectrin expression. ...
The mechanism underlying the geometrical patterning of axon and dendrite wiring remains elusive, despite its critical importance in the formation of functional neural circuits. Cerebellar Purkinje cell (PC) arborizes a typical planar dendrite, which forms an orthogonal network with granule cell (GC) axons. By using electrospun nanofiber substrates, we reproduce the perpendicular contacts between PC dendrites and GC axons in culture. In the model system, PC dendrites show a preference to grow perpendicular to aligned GC axons, which presumably contribute to the planar dendrite arborization in vivo . We show that βIII spectrin, a causal gene for spinocerebellar ataxia type 5 (SCA5), is required for the biased growth of dendrites. βIII spectrin deficiency causes actin mislocalization and excessive microtubule invasion in dendritic protrusions, resulting in abnormally oriented branch formation. Furthermore, disease-associated mutations affect the ability of βIII spectrin to control dendrite orientation. These data indicate that βIII spectrin organizes the dendritic cytoskeleton and thereby regulates the oriented growth of dendrites with respect to the afferent axons.
... This allows BDNF-mediated short-term changes in synaptic transmission which then are further strengthened by dendritic growth and structural refinement of synapses in an activitydependent manner (Lohof et al. 1993;Lu 2004;McAllister et al. 1999;Wang et al. 1995). In fact, BDNF stimulation increases synapse numbers in hippocampal and cerebellar neurons (Shimada et al. 1998;Tyler and Pozzo-Miller 2001) and also modulates dendritic complexity especially in the striatum (Rauskolb et al. 2010) and hippocampus . Association of TrkB with postsynaptic spines was further confirmed by co-localization and coimmunoprecipitation with PSD-95 which modulates guidance and anchoring of transmembrane receptors and ion channels into dendritic spines (Ji et al. 2005;Scannevin and Huganir 2000;Sheng 2001;Zhao et al. 2009). ...
Neurotrophin signaling via receptor tyrosine kinases is essential for the development and function of the nervous system in vertebrates. TrkB activation and signaling show substantial differences to other receptor tyrosine kinases of the Trk family that mediate the responses to nerve growth factor and neurotrophin-3. Growing evidence suggests that TrkB cell surface expression is highly regulated and determines the sensitivity of neurons to brain-derived neurotrophic factor (BDNF). This translocation of TrkB depends on co-factors and modulators of cAMP levels, N-glycosylation, and receptor transactivation. This process can occur in very short time periods and the resulting rapid modulation of target cell sensitivity to BDNF could represent a mechanism for fine-tuning of synaptic plasticity and communication in complex neuronal networks. This review focuses on those modulatory mechanisms in neurons that regulate responsiveness to BDNF via control of TrkB surface expression.
... The maturation process of dendritic spines involves the progressive increase in their density, associated to a reduction in the number of filopodia (Dunaevsky et al. 1999;Nimchinsky et al. 2002). Several studies have shown that long-term in vitro treatment with exogenous BDNF increases dendritic spine density in pyramidal hippocampal neurons (Gottmann et al. 2009;Ji et al. 2005;Tyler and Pozzo-Miller 2001; for reviews see Zagrebelsky and Korte 2014) and in cerebellar Purkinje cells (Shimada et al. 1998). These growth-promoting effects of BDNF occur in a TrkBdependent manner. ...
... These growth-promoting effects of BDNF occur in a TrkBdependent manner. Indeed, activation of TrkB is induced by BDNF application protocols known to increase dendritic spine density (Ji et al. 2010), and the increase in spine density upon BDNF treatment is prevented by simultaneously inhibiting the Trk receptors using K252a (Tyler and Pozzo-Miller 2001) or more specifically by TrkB receptor bodies (Shimada et al. 1998). Accordingly, activation of signaling pathways downstream of TrkB has been shown to be involved in the effects of BDNF on spine formation (Fig. 1a). ...
Dendritic spines are tiny membrane specialization forming the postsynaptic part of most excitatory synapses. They have been suggested to play a crucial role in regulating synaptic transmission during development and in adult learning processes. Changes in their number, size, and shape are correlated with processes of structural synaptic plasticity and learning and memory and also with neurodegenerative diseases, when spines are lost. Thus, their alterations can correlate with neuronal homeostasis, but also with dysfunction in several neurological disorders characterized by cognitive impairment. Therefore, it is important to understand how different stages in the life of a dendritic spine, including formation, maturation, and plasticity, are strictly regulated. In this context, brain-derived neurotrophic factor (BDNF), belonging to the NGF-neurotrophin family, is among the most intensively investigated molecule. This review would like to report the current knowledge regarding the role of BDNF in regulating dendritic spine number, structure, and plasticity concentrating especially on its signaling via its two often functionally antagonistic receptors, TrkB and p75NTR. In addition, we point out a series of open points in which, while the role of BDNF signaling is extremely likely conclusive, evidence is still missing.
... Similar results are obtained when adult pyramidal neurons (cortical layers II-III) in the sensory-motor cortex express CREB-DN-EGFP in vivo (Figure 3-figure supplement 3). This circuit requires BDNF and TrkB to sustain normal neuronal morphology (Andreska et al., 2020;Shimada et al., 1998). When transduced with AAV1 expressing mCherry, the cortico-callosal pathway is labeled (Figure 3-figure supplement 3A). ...
... After 4 hr, the culture medium was replaced with neurobasal medium supplemented with 2% B27, 1 x GlutaMAX and 1 x penicillin/streptomycin. The proliferation of nonneuronal cells was limited by applying cytosine arabinoside (AraC; 0.25 µg/mL) when the MEM/ HS was replaced with neurobasal medium and removed two days later (Shimada et al., 1998;Taylor et al., 2003). ...
Brain-derived neurotrophic factor (BDNF) and its receptors tyrosine kinase receptor B (TrkB) and the p75 neurotrophin receptor (p75) are the primary regulators of dendritic growth in the central nervous system (CNS). After being bound by BDNF, TrkB and p75 are endocytosed into endosomes and continue signaling within the cell soma, dendrites, and axons. We studied the functional role of BDNF axonal signaling in cortical neurons derived from different transgenic mice using compartmentalized cultures in microfluidic devices. We found that axonal BDNF increased dendritic growth from the neuronal cell body in a cAMP response element-binding protein (CREB)-dependent manner. These effects were dependent on axonal TrkB but not p75 activity. Dynein-dependent BDNF-TrkB-containing endosome transport was required for long-distance induction of dendritic growth. Axonal signaling endosomes increased CREB and mTOR kinase activity in the cell body, and this increase in the activity of both proteins was required for general protein translation and the expression of Arc, a plasticity-associated gene, indicating a role for BDNF-TrkB axonal signaling endosomes in coordinating the transcription and translation of genes whose products contribute to learning and memory regulation.
... Cerebella of BTBR mouse displayed hypotrophic Purkinje neurons at an early developmental period. The abnormal development of granule cells could ultimately regulate the growth of PCs (Salinas et al., 1994;Shimada et al., 1998;Sadakata et al., 2004), and we inferred that the disrupted patterning of Purkinje cells may be secondary to abnormal GC development. We cannot ignore the fact that PCs are the sole efferent neurons in cerebellum which connect to the outer brain and participate in more complicated neural activity. ...
Motor control and learning impairments are common complications in individuals with autism spectrum disorder (ASD). Abnormal cerebellar development during critical phases may disrupt these motor functions and lead to autistic motor dysfunction. However, the underlying mechanisms behind these impairments are not clear. Here, we utilized BTBR T⁺ Itprtf/J (BTBR) mice, an animal model of autism, to investigate the involvement of abnormal cerebellar development in motor performance. We found BTBR mice exhibited severe dystonia-like behavior and motor coordination or motor learning impairments. The onset of these abnormal movements coincided with the increased proliferation of granule neurons and enhanced foliation, and Purkinje cells displayed morphological hypotrophy with increased dendritic spine formation but suppressed maturation. The migration of granule neurons seemed unaffected. Transcriptional analyses confirmed the differential expression of genes involved in abnormal neurogenesis and revealed TRPC as a critical regulator in proliferation and synaptic formation. Taken together, these findings indicate that abnormal cerebellar development is closely related to dystonia-like behavior and motor dysfunction of BTBR mice and that TRPC may be a novel risk gene for ASD that may participate in the pathological process of autistic movement disorders.
