Hyperactivity and cortical disinhibition in mice with restricted expression of mutant huntingtin to parvalbumin-positive cells

Abstract

Recent evidence suggests that interneurons are involved in the pathophysiology of Huntington Disease (HD). Abnormalities in the function of interneurons expressing the calcium buffer parvalbumin (PV) have been observed in multiple mouse models of HD, although it is not clear how PV-positive interneuron dysfunction contributes to behavioral and synaptic deficits. Here, we use the cre-lox system to drive expression of mutant huntingtin (mthtt) in parvalbumin (PV)-positive neurons and find that mutant mice exhibit diffuse mthtt immunoreactivity in PV-rich areas at 10 months of age and mthtt aggregates in PV-positive processes at 24 months of age. At midlife, mutant mice are hyperactive and display impaired GABA release in the motor cortex, characterized by reduced miniature inhibitory events and severely blunted responses to gamma frequency stimulation, without a loss of PV-positive interneurons. In contrast, 24 month-old mutant mice show normalized behavior and responses to gamma frequency stimulation, possibly due to compensatory changes in pyramidal neurons or the formation of inclusions with age. These data indicate that mthtt expression in PV-positive neurons is sufficient to drive a hyperactive phenotype and suggest that mthtt-mediated dysfunction in PV-positive neuronal populations could be a key factor in the hyperkinetic behavior observed in HD. Further clarification of the roles for specific PV-positive populations in this phenotype is warranted to definitively identify cellular targets for intervention.

Cortical circuit alterations precede disease onset in Huntington’s disease mice

“…PV INs develop mHTT inclusion bodies and show electrophysiological changes in HD mouse models (Meade et al, 2002;Spampanato et al, 2008). Selective expression of mHTT in this IN population results in specific HD-related phenotypes, including impaired cortical inhibition (Dougherty et al, 2014). It should, however, be noted that our results do not exclude a possible involvement of other IN subtypes in the cortical HD pathology.…”

“…Reductions in certain populations of INs were detected in human postmortem HD brains (Kim et al, 2014;Mehrabi et al, 2016). Furthermore, studies in conditional mouse models demonstrated the importance of mHTT expression in INs for the development of cortical pathology and behavioral defects (Gu et al, 2005), and attributed certain electrophysiological and behavioral alterations specifically to IN dysfunction (Dougherty et al, 2014).…”

Striatal GABAergic interneuron dysfunction in the Q175 mouse model of Huntington's disease

“…PV‐expressing interneurons play a role in movement control as their inhibition (Gittis et al, ) or selective expression of mHtt (Dougherty et al, ) is sufficient to generate a hyperkinetic phenotype in mice. Interestingly, previous studies in R6/2 mice have observed higher levels of mHtt neuronal intranuclear inclusions in PV‐expressing interneurons compared to NOS/SOM‐expressing interneurons (Kosinski et al, ; Meade et al, ).…”

The mitochondrial permeability transition pore regulates Parkinson's disease development in mutant α-synuclein transgenic mice

“…Patch-clamp recording shows deficits in GABAergic inhibitory transmission in frontal cortex of these mice (Ito et al, 2012). Early presymptomatic degeneration or dysfunction of interneurons has also been found in mouse models of amyotrophic lateral sclerosis (Martin and Chang, 2012) and Huntington’s disease (Dougherty et al, 2014). The disease within the cerebello-rubro-thalamo-cortical circuit in our tg mice possibly starts with the degeneration of hαSyn + Golgi cell interneurons in cerebellar cortex because we found these neurons degenerating in 1-month old mice.…”