Sex-dependent impaired locomotion and motor coordination in the HdhQ200/200 mouse model of Huntington's Disease.

Huntington's Disease (HD) is a fatal neurodegenerative disease characterized by severe loss of medium spiny neuron (MSN) function and striatal-dependent behaviors. We report that female HdhQ200/200 mice display an earlier onset and more robust deterioration in spontaneous locomotion and motor coordination measured at 8 months of age compared to male HdhQ200/200 mice. Remarkably, HdhQ200/200 mice of both sexes exhibit comparable impaired spontaneous locomotion and motor coordination at 10 months of age and reach moribund stage by 12 months of age, demonstrating reduced life span in this model system. Histopathological analysis revealed enhanced mutant huntingtin protein aggregation in male HdhQ200/200 striatal tissue at 8 months of age compared to female HdhQ200/200. Functional analysis of calcium dynamics in MSNs of female HdhQ200/200 mice using GCaMP6m imaging revealed elevated responses to excitatory cortical-striatal stimulation suggesting increased MSN excitability. Although there was no down-regulation of the expression of common HD biomarkers (DARPP-32, enkephalin and CB1R), we measured a sex-dependent reduction of the astrocytic glutamate transporter, GLT-1, in female HdhQ200/200 mice that was not detected in male HdhQ200/200 mice when compared to respective wild-type littermates. Our study outlines a sex-dependent rapid deterioration of striatal-dependent behaviors occurring in the HdhQ200/200 mouse line that does not involve alterations in the expression of common HD biomarkers and yet includes impaired MSN function.

Voluntary oral consumption of Δ9-tetrahydrocannabinol by adolescent rats impairs reward-predictive cue behaviors in adulthood.

Few preclinical approaches are available to study the health impact of voluntary consumption of edibles containing the psychoactive drug Δ9-tetrahydrocannabinol (THC). We developed and validated such approach by measuring voluntary oral consumption of THC-containing gelatin by rats and used it to study if and how THC consumption during adolescence impacts adult behavior. We found that adolescent rats of both sexes consumed enough THC to trigger acute hypothermia, analgesic, and locomotor responses, and that 15 days of access to THC-gelatin in adolescence resulted in the down-regulation of cannabinoid 1 receptors (CB1Rs) in adulthood in a sex and brain area specific manner. Remarkably, THC consumption by adolescent male rats and not female rats led to impaired Pavlovian reward-predictive cue behaviors in adulthood consistent with a male-specific loss of CB1R-expressing vGlut-1 synaptic terminals in the ventral tegmental area (VTA). Thus, voluntary oral consumption of THC during adolescence is associated with sex-dependent behavioral impairment in adulthood.

ABHD6: Its Place in Endocannabinoid Signaling and Beyond.

The endocannabinoid (eCB) signaling system modulates neurotransmission and inflammation, among other physiological functions. Its newest member, α/ß-hydrolase domain-containing 6 (ABHD6), has emerged as a promising therapeutic target to treat several devastating diseases, including epilepsy. Here, we review the molecular mechanisms that mediate and control eCB signaling and, within it, the specific role of ABHD6. We also discuss how ABHD6 controls the abundance of additional lipids and the trafficking of ionotropic receptors to plasma membranes. We finish with several unexplored questions regarding this novel enzyme. Our current understanding of the molecular mechanism and biological function of ABHD6 provides a strong foundation for the development of small-molecule therapeutics to treat devastating diseases.

Sex-dependent behavioral impairments in the HdhQ350/+ mouse line.

Huntington's Disease (HD) is an autosomal dominant neurodegenerative disease characterized by gradual deterioration of motor and cognitive functions and development of psychiatric deficits. Animal models provide powerful means to study the pathological processes, molecular dysfunctions and symptoms associated with HD. We performed a longitudinal behavioral study of the newly developed HdhQ350/+ mouse line, a knock-in model that expresses a repeat of 350 glutamines. We found remarkable sex-dependent differences on symptom onset and severity. While both sexes lose weight and grip strength, only HdhQ350/+ males have impaired motor coordination as measured by the rotarod and alterations in gait as measured by the catwalk assay. While HdhQ350/+ females do not exhibit impairment in motor coordination, we found a reduction in dark phase locomotor activity. Male and female HdhQ350/+ mice do not show anxiety as measured by the elevated plus maze or changes in exploration as measured by the open field test. To investigate these sex-dependent differences, we performed western blot analyses of striatal tissue. We measured equal mutant huntingtin protein expression in both sexes and found evidence of aggregation. We found the expected decrease of DARPP-32 expression only in female HdhQ350/+ mice. Remarkably, we found no evidence of reduction in synaptophysin or CB1 receptors in HdhQ350/+ tissue of either sex. Our study indicates that male and female HdhQ350/+ mice differentially recapitulate select behavioral impairments commonly measured in other HD mouse models with limited sex-dependent changes in recognized histopathological markers. We conclude that expanded polyglutamine repeats influence HD pathogenesis in a sex-dependent manner.

ABHD6 blockade exerts antiepileptic activity in PTZ-induced seizures and in spontaneous seizures in R6/2 mice.

The serine hydrolase α/ß-hydrolase domain 6 (ABHD6) hydrolyzes the most abundant endocannabinoid (eCB) in the brain, 2-arachidonoylglycerol (2-AG), and controls its availability at cannabinoid receptors. We show that ABHD6 inhibition decreases pentylenetetrazole (PTZ)-induced generalized tonic-clonic and myoclonic seizure incidence and severity. This effect is retained in Cnr1(-/-) or Cnr2(-/-) mice, but blocked by addition of a subconvulsive dose of picrotoxin, suggesting the involvement of GABAA receptors. ABHD6 inhibition also blocked spontaneous seizures in R6/2 mice, a genetic model of juvenile Huntington's disease known to exhibit dysregulated eCB signaling. ABHD6 blockade retained its antiepileptic activity over chronic dosing and was not associated with psychomotor or cognitive effects. While the etiology of seizures in R6/2 mice remains unsolved, involvement of the hippocampus is suggested by interictal epileptic discharges, increased expression of vGLUT1 but not vGAT, and reduced Neuropeptide Y (NPY) expression. We conclude that ABHD6 inhibition may represent a novel antiepileptic strategy.