Abstract
ABSTRACTFriedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder with progressive ataxia that affects both the peripheral and central nervous system (CNS). While later CNS neuropathology involves loss of large principal neurons and glutamatergic and GABAergic synaptic terminals in the cerebellar dentate nucleus, early pathological changes in FRDA cerebellum remain largely uncharacterized. Here, we report early cerebellar VGLUT1 (SLC17A7)-specific parallel fiber (PF) synaptic deficits and dysregulated cerebellar circuit in the frataxin knock-in/knockout (KIKO) FRDA mouse model. At asymptomatic ages, VGLUT1 levels in cerebellar homogenates are significantly decreased, whereas VGLUT2 (SLC17A6) levels are significantly increased, in KIKO mice compared with age-matched controls. Additionally, GAD65 (GAD2) levels are significantly increased, while GAD67 (GAD1) levels remain unaltered. This suggests early VGLUT1-specific synaptic input deficits, and dysregulation of VGLUT2 and GAD65 synaptic inputs, in the cerebellum of asymptomatic KIKO mice. Immunohistochemistry and electron microscopy further show specific reductions of VGLUT1-containing PF presynaptic terminals in the cerebellar molecular layer, demonstrating PF synaptic input deficiency in asymptomatic and symptomatic KIKO mice. Moreover, the parvalbumin levels in cerebellar homogenates and Purkinje neurons are significantly reduced, but preserved in other interneurons of the cerebellar molecular layer, suggesting specific parvalbumin dysregulation in Purkinje neurons of these mice. Furthermore, a moderate loss of large principal neurons is observed in the dentate nucleus of asymptomatic KIKO mice, mimicking that of FRDA patients. Our findings thus identify early VGLUT1-specific PF synaptic input deficits and dysregulated cerebellar circuit as potential mediators of cerebellar dysfunction in KIKO mice, reflecting developmental features of FRDA in this mouse model.
Highlights
Friedreich ataxia (FRDA) is the most common form of hereditary ataxia, affecting ∼5000 people in the USA
Frataxin is highly expressed in cerebellar Purkinje neurons and dentate nucleus (DN) large principal neurons of C57BL/6 wild-type mice We first examined the expression and distribution of frataxin in C57BL/6 wild-type mouse cerebellum using double immunohistochemical staining with anti-PV and anti-frataxin antibodies
PV immunoreactivity is abundant in Purkinje neurons and other interneurons in the molecular layer (ML) (Fig. 1B,B′), while frataxin immunoreactivity (Fig. 1A,A′) is widely distributed in the ML, Purkinje layer (PL) and granular layer (GL), with a high level of expression of frataxin in PV-positive Purkinje neurons (Fig. 1A-C,A′-C′)
Summary
Friedreich ataxia (FRDA) is the most common form of hereditary ataxia, affecting ∼5000 people in the USA. Most affected individuals inherit two alleles containing expanded GAA repeats in intron 1 of the frataxin (FXN) gene, resulting in chromatin condensation and reduced expression of the mitochondrial protein frataxin (Bidichandani et al, 1998; Campuzano et al, 1996; Chutake et al, 2014; Grabczyk and Usdin, 2000). Symptoms begin as early as 5 years old and worsen over time, with an initial presentation of ataxia, absent lower limb reflexes, and loss of position and vibration sense. This pattern of neurodegeneration results in progressive ataxia, dysmetria and dysarthria (Lynch et al, 2012; Lynch and Seyer, 2014; Pandolfo, 2009). Postmortem studies show degeneration of the large sensory neurons and their axons in the spinal cord, while the cerebellum overtly degenerates to a lesser extent, largely within the dentate nucleus (DN) (Koeppen et al, 2011a,b, 2009)
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