Abstract
Mutations in the human HERC1 E3 ubiquitin ligase protein develop intellectual disability. The tambaleante (tbl) mouse carries a HERC1 mutation characterized by cerebellar ataxia due of adult cerebellar Purkinje cells death by extensive autophagy. Our previous studies demonstrated that both the neuromuscular junction and the peripheral nerve myelin sheaths are also affected in this mutant. Moreover, there are signs of dysregulated autophagy in the central nervous system in the tbl mouse, affecting spinal cord motor neurons, and pyramidal neurons of the neocortex and the hippocampal CA3 region. The tbl mutation affects associative learning, with absence of short- and long-term potentiation in the lateral amygdala, altered spinogenesis in their neurons, and a dramatic decrease in their glutamatergic input. To assess whether other brain areas engaged in learning processes might be affected by the tbl mutation, we have studied the tbl hippocampus using behavioral tests, ex vivo electrophysiological recordings, immunohistochemistry, the Golgi-Cox method and transmission electron microscopy. The tbl mice performed poorly in the novel-object recognition, T-maze and Morris water maze tests. In addition, there was a decrease in glutamatergic input while the GABAergic one remains unaltered in the hippocampal CA1 region of tbl mice, accompanied by changes in the dendritic spines, and signs of cellular damage. Moreover, the proportions of immature and mature neurons in the dentate gyrus of the tbl hippocampus differ relative to the control mice. Together, these observations demonstrate the important role of HERC1 in regulating synaptic activity during learning.
Highlights
At the end of the 1980’s, the tambaleante mutant mouse was described as a model of adult cerebellar ataxia, a phenotype caused by the nearly complete loss of cerebellar Purkinje cells (Wassef et al, 1987; Rossi et al, 1995)
HERC1 is an ubiquitin ligase of the HECT (Homologous to the E6-AP Carboxyl Terminus) family that belongs to the ubiquitin– proteasome system (UPS) (Sánchez-Tena et al, 2016; Schneider et al, 2018; García-Cano et al, 2019)
The behavioral results presented here show that memory and learning processes involving the hippocampus are impaired in tbl mice, which is perhaps not surprising given that several spontaneous mutations affecting cerebellar Purkinje cells induce hippocampal damage
Summary
At the end of the 1980’s, the tambaleante (tbl) mutant mouse was described as a model of adult cerebellar ataxia, a phenotype caused by the nearly complete loss of cerebellar Purkinje cells (Wassef et al, 1987; Rossi et al, 1995) This Purkinje cell death was later proposed to be a model of autophagy (Dusart et al, 2006), and molecular studies identified the spontaneous Gly483Glu. HERC1 Mutation Impairs Learning substitution in the RCC1 (Regulator of Chromosome Condensation 1) domain of the HERC1 ubiquitin ligase as the mutation that induces the overexpression of the protein responsible for this cell death (Mashimo et al, 2009). Proteins with mutations in its RCC1-like domain (RLD) are involved in several other neuropathologies, such as juvenile amyotrophic lateral sclerosis 2 and X-linked retinitis pigmentosa (Mashimo et al, 2009)
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