Restoration of BDNF-TrkB signaling rescues deficits in a mouse model of SCA6

Abstract

Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease resulting in motor coordination deficits and cerebellar pathology. Expression of brain-derived neurotrophic factor (BDNF) is reduced in several neurodegenerative diseases, including in post-mortem tissue from SCA6 patients. Here, we show that cerebellar BDNF levels are reduced at an early disease stage in a mouse model of SCA6 (SCA684Q/84Q). One month of voluntary exercise was sufficient to elevate BDNF expression, as well as rescue both motor coordination and cerebellar Purkinje cell firing rate deficits. A BDNF mimetic, 7,8- dihydroxyflavone (7,8-DHF) likewise improved motor coordination and reversed Purkinje cell firing rate deficits, suggesting that exercise acts via BDNF-TrkB signaling. Prolonged chronic 7,8-DHF administration rescued ataxia when treatment commenced near disease onset, but was ineffective when treatment was started late. These data suggest that 7,8-DHF, which is orally bioavailable and crosses the blood-brain barrier, is a promising therapeutic for SCA6 and argue for the importance of early intervention for SCA6.

BDNF is altered in a brain-region specific manner and rescues deficits in Spinocerebellar Ataxia Type 1

“…BDNF plays a key role in a healthy brain function, and loss of BDNF can contribute to pathology in neurodegenerative diseases and depression ( Miranda et al, 2019 ). BDNF expression is decreased in aging, and in patients and in mouse models has been described in other polyQ neurodegenerative diseases such as Huntington’s disease (HD) ( Zuccato and Cattaneo, 2007 ; Zuccato et al, 2001 ) and SCA6 ( Cook et al, 2021 ; Takahashi et al, 2012 ). Decreased BDNF has also been shown to correlate with behavioral impairments in aging, Alzheimer’s disease (AD), and Parkinson’s disease (PD) ( Moriarty et al, 2016 ; Jacobi et al, 2013 ) ( Koscik et al, 2020 ; Seidel et al, 2012b ; Rüb et al, 2013 ).…”

“…To address these questions, we quantified Bdnf expression in four different clinically relevant brain regions -cerebellum, hippocampus, brain stem and motor cortex - using SCA1 knock-in Atxn1 154Q/2Q mice, where Atxn1 gene is expressed throughout the brain ( Watase et al, 2002 ; Asher et al, 2020 ). Recent studies indicate BDNF as an effective treatment for motor or cognitive deficits in brain disorders affecting different brain regions, including Huntington’s disease, Alzheimer’s disease, Parkinson’s disease, and SCA6 ( Zuccato and Cattaneo, 2007 ; Nagahara et al, 2009 ; Cook et al, 2021 ; Howells et al, 2000 ). Therefore, we investigated whether BDNF can rescue both motor and cognitive deficits in SCA1 knock-in mice.…”

Building better brains: the pleiotropic function of neurotrophic factors in postnatal cerebellar development

“…Both mice models display PC pathology, abnormal firing rates and changes in motor behavior. Extrinsic BDNF delivery and subsequent activation of the TrkB-Akt signaling pathway improves the PC firing rate and delays the onset of the observed motor deficits (Mellesmoen et al, 2019;Cook et al, 2022).…”

Regulation of cerebellar network development by granule cells and their molecules

“…Although the source of neurotrophins regulating MLI synaptic differentiation is not completely clarified, BDNF released from GCs is likely involved in the regulation. BDNF is one of the two major neurotrophins activating TrkB (Huang and Reichardt, 2001), and its mRNA is specifically expressed in GCs within the rat cerebellar cortex during postnatal developmental periods (Rocamora et al, 1993), although immunohistochemical BDNF signals were detected in PCs of adult mice (Cook et al, 2022). Similar to PF-PC synapses, PF-MLI synapses are believed to be formed via a tripartite transsynaptic bridge (Andrews and Dravid, 2021), because MLIs express GluD1, which can also form a tripartite trans-synaptic bridge with Cbln1 and NRX (Yasumura et al, 2012), and GluD1 knockout mice showed a reduction of PF-MLI synapses (Figure 3C, Konno et al, 2014).…”