Progressive synaptic pathology of motor cortical neurons in a BAC transgenic mouse model of Huntington's disease

Abstract

Huntington’s disease (HD) is a neurodegenerative disorder caused by a polyglutamine repeat expansion in huntingtin. A newly developed BAC transgenic mouse model (BACHD) reproduces phenotypic features of HD including predominantly neuropil associated protein aggregation and progressive motor dysfunction with selective neurodegeneration. Motor dysfunction has been shown to precede neuropathology in BACHD mice. We therefore investigated the progression of synaptic pathology in pyramidal cells and interneurons of the superficial motor cortex of BACHD mice. Whole-cell patch clamp recordings were performed on layer 2/3 primary motor cortical pyramidal cells and PV interneurons from BACHD mice at 3 months, when the mice begin to demonstrate mild motor dysfunction, and at 6 months, when the motor dysfunction is more severe. Changes in synaptic variances were detectable at 3 months and at 6 months BACHD mice display progressive synaptic pathology in the form of reduced cortical excitation and loss of inhibition onto pyramidal cells. These results suggest that progressive alterations of the superficial cortical circuitry may contribute to the decline of motor function in BACHD mice. The synaptic pathology occurs prior to neuronal degeneration and may therefore prove useful as a target for future therapeutic design.

Neuronal circuitry regulates the response of Caenorhabditis elegans to misfolded proteins

“…Cell-nonautonomous effects of afferent sensory and cortical projections on the toxicity and degeneration of the motor neuron has been described recently in mouse models of human ALS, spinal muscular atrophy, and Huntington disease (47)(48)(49). If protein folding homeostasis in diverse tissues of other metazoans is under the regulation of sensory neuronal modalities as we have described for C. elegans, this would suggest that another method for treatment of human conformational diseases could involve modulation of neurosensory systems.…”

Impaired Long-Term Potentiation in the Prefrontal Cortex of Huntington’s Disease Mouse Models: Rescue by D₁ Dopamine Receptor Activation

“…In our hands, the failure of LTP in R6/1 and R6/1-89Q slices might also reflect a higher threshold for LTP induction caused by a greater level of magnesium voltage-dependent blockade of NMDA channels, a phenomenon that might be sensitive to postsynaptic D 1 receptor modulation. Similarly, it has been reported that motor cortical neurones in BAC transgenic mouse model of HD exhibit a progressive reduction in excitability [48] .…”

Reduced Activity of AMP-Activated Protein Kinase Protects against Genetic Models of Motor Neuron Disease

“…These results suggest that the beneficial effects of decreasing aak-2 activity may be through improving the functioning of neurons under conditions of stress and proteotoxicity. Several reports highlight the presence of neuronal dysfunction before neuronal death in several models of neurodegenerative disease, such as ALS (Gould et al, 2006;Ilieva et al, 2008), spinal muscular atrophy (Mentis et al, 2011), spinocerebellar ataxia (Barnes et al, 2011;Shakkottai et al, 2011), and Huntington's disease (Spampanato et al, 2008). Therefore, manipulations that may benefit neuronal function may at least be partially independent of processes that lead eventually to neuronal death in these disease models.…”