Differential loss of thalamostriatal and corticostriatal input to striatal projection neuron types prior to overt motor symptoms in the Q140 knock-in mouse model of Huntington's disease

Abstract

Motor slowing and forebrain white matter loss have been reported in premanifest Huntington's disease (HD) prior to substantial striatal neuron loss. These findings raise the possibility that early motor defects in HD may be related to loss of excitatory input to striatum. In a prior study, we showed that in the heterozygous Q140 knock-in mouse model of HD that loss of thalamostriatal axospinous terminals is evident by 4 months, and loss of corticostriatal axospinous terminals is evident at 12 months, before striatal projection neuron pathology. In the present study, we specifically characterized the loss of thalamostriatal and corticostriatal terminals on direct (dSPN) and indirect (iSPN) pathway striatal projection neurons, using immunolabeling to identify thalamostriatal (VGLUT2+) and corticostriatal (VGLUT1+) axospinous terminals, and D1 receptor immunolabeling to distinguish dSPN (D1+) and iSPN (D1−) synaptic targets. We found that the loss of corticostriatal terminals at 12 months of age was preferential for D1+ spines, and especially involved smaller terminals, presumptively of the intratelencephalically projecting (IT) type. By contrast, indirect pathway D1− spines showed little loss of axospinous terminals at the same age. Thalamostriatal terminal loss was comparable for D1+ and D1− spines at both 4 and 12 months. Regression analysis showed that the loss of VGLUT1+ terminals on D1+ spines was correlated with a slight decline in open field motor parameters at 12 months. Our overall results raise the possibility that differential thalamic and cortical input loss to SPNs is an early event in human HD, with cortical loss to dSPNs in particular contributing to premanifest motor slowing.

Effect of early embryonic deletion of huntingtin from pyramidal neurons on the development and long-term survival of neurons in cerebral cortex and striatum

“…It may be that this exuberant corticostriatal connectivity, if persistent, could account for the hyperactivity we saw in our mice. Given the current understanding of basal ganglia functional organization, preferentially increased input to the striatal go-neurons of the direct pathway would be one way in which exuberant corticostriatal connectivity in cortical Htt-KO mice could yield hyper-activity (Deng et al, 2014). It is also possible that the massive loss of huntingtin from corticostriatal terminals in the Emx-htt KO mice accounts for the phenotype.…”

Age-dependent alterations in the cortical entrainment of subthalamic nucleus neurons in the YAC128 mouse model of Huntington's disease

“…Specifically, the hyperdirect pathway has been implicated in action suppression (Aron and Poldrack, 2006;Frank, 2006;Jahfari et al, 2011) and blockade of STN neuronal activity through discrete lesions or pharmacological inactivation (Whittier and Mettler, 1949;Carpenter et al, 1950;Hamada and DeLong, 1992) produces hyperkinetic movement disorders which mimic chorea, the most common symptom of HD. Progressive synaptic disconnection of cortical input at the level of the striatum has been reported in HD (Cepeda et al, 2007;Miller et al, 2011;Unschuld et al, 2012;Deng et al, 2013Deng et al, , 2014, however, neural transmission within the corticosubthalamic pathway remains uninvestigated thus far. Based on the importance of control exerted by the STN on motor commands, elucidating alterations in processing between the cortex and STN could have valuable implications for understanding the pathophysiology of HD.…”

Transplantation of mononuclear cells from bone marrow in a rat model of Huntington’s disease

“…1 The striatum is the major site of HD degeneration 2 and is characterized by a marked loss of the striatal medium-sized spiny projection neurons. 3 As no cure is currently available, management of symptoms is the primary goal in treating HD.…”