SorCS2 Dynamically Interacts with TrkB and GluN2B to Control Neurotransmission and Huntington’s Disease Progression

Background: Huntington’s disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor dysfunction and loss of medium spiny neurons (MSNs) in dorsal striatum. Brain-derived neurotrophic factor (BDNF) sustains functionality and integrity of MSNs, and thus reduced BDNF signaling is integral to the disease. Mutations in BDNF receptor SorCS2 were recently identified in HD patients. Our study investigates the role of SorCS2 in MSNs biology and in HD progression. Methods: We derived a double transgenic line by crossbreeding SorCS2 deficient (KO) mice with the HD mouse model R6/1. Subsequently, we characterized the SorCS2 KO; R6/1 line by a set of behavioral and biochemical studies to evaluate phenotypes related to HD. Moreover, in combination with electrophysiology and super resolution microscopy techniques, we addressed the molecular mechanism by which SorCS2 controls synaptic activity in MSNs neurons. Results: We show that SorCS2 is expressed in MSNs with reduced levels in R6/1 HD model, and that SorCS2 deficiency exacerbates the disease progression in R6/1 mice. Furthermore, we find that SorCS2 binds TrkB and the NMDA receptor subunit GluN2B, which is required to control neurotransmission in corticostriatal synapses. While BDNF stimulates SorCS2-TrkB complex formation to enable TrkB signaling, it disengages SorCS2 from GluN2B, leading to enrichment of the subunit at postsynaptic densities. Consequently, long-term potentiation (LTP) is abolished in SorCS2 deficient mice, despite increased striatal TrkB and unaltered BDNF expression. However, the addition of exogenous BDNF rescues the phenotype. Finally, GluN2B, but not GluN2A, currents are also severely impaired in the SorCS2 KO mice. Conclusions: We formulate a novel molecular mechanism by which SorCS2 acts as a molecular switch. SorCS2 targets TrkB and GluN2B into postsynaptic densities to enable BDNF signaling and NMDAR dependent neurotransmission in the dorsal striatum. Remarkably, the binding between SorCS2 and TrkB or GluN2B, respectively, is mutually exclusive and controlled by BDNF. This mechanism provides an explanation why deficient SorCS2 signaling severely aggravates HD progression in mice. Moreover, we provide evidence that this finding might represent a general mechanism of SorCS2 signaling found in other brain areas, thus increasing its relevance for other neurological and psychiatric impairments.

BDNF SNP C270T Modifies the Association Between History of Head Injury and Cognitive Status in Older Adults

Brain derived neurotrophic factor (BDNF), is a neurotrophin involved in neurogenesis and neuroplasticity. Several BDNF genes have been associated with cognitive function. Studies suggest head injury (HI) alters BDNF levels, and activities enhancing BDNF signaling promote better cognitive outcomes. We investigated the relationship between HI and BDNF single-nucleotide polymorphisms (SNPs) in predicting cognitive performance in a population-based sample of older adults. 4165 participants (56.7% female), dementia-free at baseline, were assessed triennially [follow-up years: mean (SD) = 5.85 (4.20), median = 7.33, maximum = 11.39]. Mean (SD) age was 75.36 (6.84). Cognition was assessed using the Modified Mini-Mental State Exam (3MS) and HI history from self-report. We examined interactions between BDNF SNPs [rs56164415 (BDNF C270T), rs6265 (Val66Met), rs2289656 (BDNF receptor trkB), and rs2072446 (NGF/BDNF receptor p75)] and history of HI (none, one, or multiple) in predicting cognitive decline. Covariates included age, education, sex, and apolipoprotein (APOE) E4 allele presence. Linear mixed-effect models indicated BDNF C270T significantly modified the association between HI and cognitive status (p < .006). Specifically, minor T allele carriers with single or multiple HI scored on average 2.08 and 3.21 points lower on the 3MS, respectively, than non-T carriers with no HI. Unexpectedly, there was a trend for APOE4*HI (p = .078) in that APOE E4 carriers with multiple HI scored higher than those lacking APOE E4 and HI. In this population-based sample, rs56164415 predicted cognitive outcomes that varied by history of HI. Factors influencing BDNF signaling may provide a potential avenue for intervention in recovery from HI.

General Anesthesia During Neurodevelopment Reduces Autistic Behavior in Adult BTBR Mice, a Murine Model of Autism

Preclinical studies suggest that repeated exposure to anesthetics during a critical period of neurodevelopment induces long-term changes in synaptic transmission, plasticity, and behavior. Such changes are of great concern, as similar changes have also been identified in animal models of neurodevelopmental disorders (NDDs) such as autism. Because of overlapping synaptic changes, it is also possible that anesthetic exposures have a more significant effect in individuals diagnosed with NDDs. Thus, we evaluated the effects of early, multiple anesthetic exposures in BTBR mice, an inbred strain that displays autistic behavior. We discovered that three cycles of sevoflurane anesthesia (2.5%, 1 h) with 2-h intervals between each exposure in late postnatal BTBR mice did not aggravate, but instead improved pathophysiological mechanisms involved with autistic behavior. Sevoflurane exposures restored E/I balance (by increasing inhibitory synaptic transmission), and increased mitochondrial respiration and BDNF signaling in BTBR mice. Most importantly, such changes were associated with reduced autistic behavior in BTBR mice, as sociability was increased in the three-chamber test and repetitive behavior was reduced in the self-grooming test. Our results suggest that anesthetic exposures during neurodevelopment may affect individuals diagnosed with NDDs differently.

SorCS2 dynamically interacts with TrkB and GluN2B to control neurotransmission and Huntington’s disease progression

Background Huntington’s disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor dysfunction and loss of medium spiny neurons (MSNs) in dorsal striatum. Brain-derived neurotrophic factor (BDNF) sustains functionality and integrity of MSNs, and thus reduced BDNF signaling is integral to the disease. Mutations in BDNF receptor SorCS2 were recently identified in HD patients. Our study investigates the role of SorCS2 in MSNs biology and in HD progression. Methods We derived a double transgenic line by crossbreeding SorCS2 deficient (KO) mice with the HD mouse model R6/1. Subsequently, we characterized the SorCS2 KO; R6/1 line by a set of behavioral and biochemical studies to evaluate phenotypes related to HD. Moreover, in combination with electrophysiology and super resolution microscopy techniques, we addressed the molecular mechanism by which SorCS2 controls synaptic activity in MSNs neurons. Results We show that SorCS2 is expressed in MSNs with reduced levels in R6/1 HD model, and that SorCS2 deficiency exacerbates the disease progression in R6/1 mice. Furthermore, we find that SorCS2 binds TrkB and the NMDA receptor subunit GluN2B, which is required to control neurotransmission in corticostriatal synapses. While BDNF stimulates SorCS2-TrkB complex formation to enable TrkB signaling, it disengages SorCS2 from GluN2B, leading to enrichment of the subunit at postsynaptic densities. Consequently, long-term potentiation (LTP) is abolished in SorCS2 deficient mice, despite increased striatal TrkB and unaltered BDNF expression. However, the addition of exogenous BDNF rescues the phenotype. Finally, GluN2B, but not GluN2A, currents are also severely impaired in the SorCS2 KO mice. Conclusions We formulate a novel molecular mechanism by which SorCS2 acts as a molecular switch. SorCS2 targets TrkB and GluN2B into postsynaptic densities to enable BDNF signaling and NMDAR dependent neurotransmission in the dorsal striatum. Remarkably, the binding between SorCS2 and TrkB or GluN2B, respectively, is mutually exclusive and controlled by BDNF. This mechanism provides an explanation why deficient SorCS2 signaling severely aggravates HD progression in mice. Moreover, we provide evidence that this finding might represent a general mechanism of SorCS2 signaling found in other brain areas, thus increasing its relevance for other neurological and psychiatric impairments.

Trichostatin A reduces nerve cell apoptosis in depressive rats by regulating CREB/BDNF signaling pathway

Purpose: To investigate the influence of trichostatin A on nerve cell apoptosis in depressive rats and to explore the probable molecular mechanism of action.Methods: A total of 36 Sprague-Dawley rats weighing 200 - 220 g were divided into sham group (n = 12), model group (n = 12) and trichostatin group (n = 12) by randomization. The protein expressions of phosphorylated cAMP responsive element-binding protein (p-CREB) and BDNF, as well as the mRNA expression levels of B-cell lymphoma-2 (Bcl-2) and caspase-3 in each group of rat hippocampus were determined by Western blotting and quantitative reverse transcription-polymerase chain reaction (qRTPCR), respectively. The apoptosis of nerve cells in the brain tissues of the rats was labeled using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining.Results: Compared with those in the sham group, the degree of sucrose preference decreased markedly, while the immobility time after forced swimming test was extended, and the relative expression levels of p-CREB and BDNF proteins in the hippocampus declined (p < 0.05). The mRNA levels of Bcl-2 and caspase-3 and cell apoptosis rate were increased in the model group (p < 0.05). In comparison with the model group, the trichostatin group exhibited increased sucrose preference degree, shortened immobility time following a forced swimming test, and elevated relative expression levels p-CREB and BDNF proteins in the hippocampus (p < 0.05), but lowered mRNA levels of Bcl-2 and caspase-3 and cell apoptosis rate, displaying statistically significant differences (p < 0.05).Conclusion: Trichostatin A reduces cell apoptosis and ameliorates the depression-like behaviors of rats via the regulation of CREB/BDNF signaling pathway. These findings provide new insights into Trichostatin A for the management of depression.