Treating early postnatal circuit defect delays Huntington’s disease onset and pathology in mice

Abstract

Recent evidence has shown that even mild mutations in the Huntingtin gene that are associated with late-onset Huntington’s disease (HD) disrupt various aspects of human neurodevelopment. To determine whether these seemingly subtle early defects affect adult neural function, we investigated neural circuit physiology in newborn HD mice. During the first postnatal week, HD mice have less cortical layer 2/3 excitatory synaptic activity than wild-type mice, express fewer glutamatergic receptors, and show sensorimotor deficits. The circuit self-normalizes in the second postnatal week but the mice nonetheless develop HD. Pharmacologically enhancing glutamatergic transmission during the neonatal period, however, rescues these deficits and preserves sensorimotor function, cognition, and spine and synapse density as well as brain region volume in HD adult mice.

Gamma oscillations provide insights into cortical circuit development

“…Maybe coordinated activity patterns can even be used for targeted interventions to correct deviations from the normal developmental trajectory. Along these lines, a recent study showed that correcting developmental deficits of glutamatergic transmission in layer 2/3 of the cortex rescues electrophysiological deficits and prevents the development of symptoms in a mouse model of Huntington’s disease later in life [ 13 ].…”

Disentangling the Connection Between Neurodevelopment and Neurodegeneration in Huntington's Disease

“…Electrical activity in neurons regulates cortical development. Therefore, Braz and colleagues 4 investigated the neurophysiological characteristics of layer 2/3 somatosensory cortical neurons using whole‐cell recordings in three mouse models: Hdh Q7/Q111 mice, where the first exon of HTT is replaced by human exon 1 carrying 111 CAG repeats; HTT flox/flox mice electroporated in utero with a plasmid targeting CRE‐recombinase expression by a NeuroD promoter, therefore depleting the HTT protein in cortical neurons; and wild‐type littermates. Hdh Q7/Q111 mice had abnormal excitatory postsynaptic activity from postnatal day 1 (P1) to P3, alongside simpler dendritic arbors.…”

“…The transient changes present in HD mice during the early postnatal period can be prevented increasing excitatory synaptic responses with an ampakine, resulting in with posterior improvement in phenotypes and pathology in HD mice. Reproduced with permission from Braz et al 4 [Color figure can be viewed at wileyonlinelibrary.com]…”

Evidences for Mutant Huntingtin Inducing Musculoskeletal and Brain Growth Impairments via Disturbing Testosterone Biosynthesis in Male Huntington Disease Animals

“…In support of this, huntingtin has been suggested to play essential roles during development, such as control of mitosis and neurogenesis [ 25 , 26 ], as well as regulation of synaptogenesis and spine structure [ 27 ]. Moreover, HD has been shown to be associated with neurodevelopmental alterations [ 28 , 29 , 30 ].…”