The group 2 metabotropic glutamate receptor agonist LY379268 rescues neuronal, neurochemical and motor abnormalities in R6/2 Huntington's disease mice

Reiner, Anton; Lafferty, D. C.; Wang, H. B.; Mar, Nobel Del; Deng, Yunping

doi:10.1016/j.nbd.2012.03.025

Cited by 36 publications

(50 citation statements)

References 169 publications

(227 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A one in six series of brain sections from each mouse was mounted as sectioned, and subsequently stained for cresyl violet. Immunohistochemical single-labeling using peroxidase-antiperoxidase (PAP) procedures described previously (Meade et al, 2002; Reiner et al, 2012a) was employed to visualize a variety of neurochemical features in mutant and control brains. To study the laminar organization of cerebral cortex, we used immunolabeling with a mouse monoclonal antibody (Sigma-Aldrich, C89848) to detect the lightly labeled calbindinergic neurons defining layers 2–3 (Van Brederode et al, 1991; Kondo et al, 1997; Fauser et al, 2013), a rabbit polyclonal antibody (Sigma/Aldrich, V2514) to detect VGLUT2+ fibers in layer 4 (Deng et al, 2013), the SMI-32 mouse monoclonal antibody (Covance, SMI-32R) and a rat monoclonal antibody against Ctip2 (Abcam, AB18465) to define neurons in layer 5 (Özdinler et al, 2011; Fauser et al, 2013), and a rabbit polyclonal antibody against FoxP2 (Abcam, AB16046) to define neurons in layer 6 (Özdinler et al, 2011).…”

Section: Methodsmentioning

confidence: 99%

“…Fresh-frozen coronal sections were processed for preproenkephalin (PPE, the enkephalin precursor), preprotachykinin (PPT, the substance P precursor), the D1 dopamine receptor, the D2 dopamine receptor, and brain-derived neurotrophic factor (BDNF) mRNA detection by ISSH, using previously described methods (Sun et al, 2002; Wang et al, 2006; Dragatsis et al, 2009; Reiner et al, 2012a, 2012b). ISHH was performed on 20 μm thick fresh frozen cryostat sections through the cortex and striatum anterior to the anterior commissure.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

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

Dragatsis

Dietrich

Ren

et al. 2018

Neurobiology of Disease

Self Cite

View full text Add to dashboard Cite

We evaluated the impact of early embryonic deletion of huntingtin (htt) from pyramidal neurons on cortical development, cortical neuron survival and motor behavior, using a cre-loxP strategy to inactivate the mouse htt gene (Hdh) in emx1-expressing cell lineages. Western blot confirmed substantial htt reduction in cerebral cortex of these Emx-httKO mice, with residual cortical htt in all likelihood restricted to cortical interneurons of the subpallial lineage and/or vascular endothelial cells. Despite the loss of htt early in development, cortical lamination was normal, as revealed by layer-specific markers. Cortical volume and neuron abundance were, however, significantly less than normal, and cortical neurons showed reduced brain-derived neurotrophic factor (BDNF) expression and reduced activation of BDNF signaling pathways. Nonetheless, cortical volume and neuron abundance did not show progressive age-related decline in Emx-httKO mice out to 24 months. Although striatal neurochemistry was normal, reductions in striatal volume and neuron abundance were seen in Emx-httKO mice, which were again not progressive. Weight maintenance was normal in Emx-httKO mice, but a slight rotarod deficit and persistent hyperactivity were observed throughout the lifespan. Our results show that embryonic deletion of htt from developing pallium does not substantially alter migration of cortical neurons to their correct laminar destinations, but does yield reduced cortical and striatal size and neuron numbers. The Emx-httKO mice were persistently hyperactive, possibly due to defects in corticostriatal development. Importantly, deletion of htt from cortical pyramidal neurons did not yield age-related progressive cortical or striatal pathology.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Dragatsis

Dietrich

Ren

et al. 2018

Neurobiology of Disease

Self Cite

View full text Add to dashboard Cite

show abstract

“…The SEE software uses algorithms to dichotomize mouse movements into lingering episodes and progression segments, and can calculate further parameters for these, such as speed and acceleration, that are robust in characterizing differences among strains, disease states, or treatment groups. [45][46][47][48][49][50] Each animal was brought from its housing room, introduced into the open field arena, and returned after the 30-min session. The arena was 200 cm in diameter with a nonporous gray floor and a 50-cm high gray wall.…”

Section: Figmentioning

confidence: 99%

“…50 Unbiased stereological counts were obtained using Stereo Investigator (Micro-Brightfield, Colchester, VT) with the optical fractionator method.…”

mentioning

confidence: 99%

“…50,73 In brief, an image of each section through the forebrain in a 1-in-12 cresyl violet series (3-6 weeks after blast), or a 1-in-12 SMI-32 immunostained series (2 weeks after blast), from the rostral telencephalic pole to the diencephalon, was captured using an Aperio ScanScope XT scanner. NIH ImageJ software was used to measure the area occupied by the forebrain from the end of the olfactory bulb to the level at which the internal capsule detaches from the diencephalon.…”

mentioning

confidence: 99%

See 1 more Smart Citation

A Novel Closed-Head Model of Mild Traumatic Brain Injury Using Focal Primary Overpressure Blast to the Cranium in Mice

Guley

Rogers

Mar

et al. 2016

Journal of Neurotrauma

104

View full text Add to dashboard Cite

Mild traumatic brain injury (TBI) from focal head impact is the most common form of TBI in humans. Animal models, however, typically use direct impact to the exposed dura or skull, or blast to the entire head. We present a detailed characterization of a novel overpressure blast system to create focal closed-head mild TBI in mice. A high-pressure air pulse limited to a 7.5 mm diameter area on the left side of the head overlying the forebrain is delivered to anesthetized mice. The mouse eyes and ears are shielded, and its head and body are cushioned to minimize movement. This approach creates mild TBI by a pressure wave that acts on the brain, with minimal accompanying head acceleration-deceleration. A single 20-psi blast yields no functional deficits or brain injury, while a single 25-40 psi blast yields only slight motor deficits and brain damage. By contrast, a single 50-60 psi blast produces significant visual, motor, and neuropsychiatric impairments and axonal damage and microglial activation in major fiber tracts, but no contusive brain injury. This model thus reproduces the widespread axonal injury and functional impairments characteristic of closed-head mild TBI, without the complications of systemic or ocular blast effects or head acceleration that typically occur in other blast or impact models of closed-skull mild TBI. Accordingly, our model provides a simple way to examine the biomechanics, pathophysiology, and functional deficits that result from TBI and can serve as a reliable platform for testing therapies that reduce brain pathology and deficits.

show abstract

Progression of basal ganglia pathology in heterozygous Q175 knock‐in Huntington's disease mice

Deng

Wang

Joni

et al. 2020

J of Comparative Neurology

View full text Add to dashboard Cite

We used behavioral testing and morphological methods to detail the progression of basal ganglia neuron type-specific pathology and the deficits stemming from them in male heterozygous Q175 mice, compared to age-matched WT males. A rotarod deficit was not present in Q175 mice until 18 months, but increased open field turn rate (reflecting hyperkinesia) and open field anxiety were evident at 6 months. No loss of striatal neurons was seen out to 18 months, but ENK+ and DARPP32+ striatal perikarya were fewer by 6 months, due to diminished expression, with further decline by 18 months. No reduction in SP+ striatal perikarya or striatal interneurons was seen in Q175 mice at 18 months, but cholinergic interneurons showed dendrite attenuation by 6 months. Despite reduced ENK expression in indirect pathway striatal perikarya, ENK-immunostained terminals in globus pallidus externus (GPe) were more abundant at 6 months and remained so out to 18 months. Similarly, SP-immunostained terminals from striatal direct pathway neurons were more abundant in globus pallidus internus and substantia nigra at 6 months and remained so at 18 months. FoxP2+ arkypallidal GPe neurons and subthalamic nucleus neurons were lost by 18 months but not prototypical PARV+ GPe neurons or dopaminergic nigral neurons. Our results show that striatal projection neuron abnormalities and behavioral abnormalities reflecting them develop between 2 and 6 months of age in Q175 male heterozygotes, indicating early effects of the HD mutation. The striatal pathologies resemble those in human HD, but are less severe at 18 months than even in premanifest HD.

show abstract

The group 2 metabotropic glutamate receptor agonist LY379268 rescues neuronal, neurochemical and motor abnormalities in R6/2 Huntington's disease mice

Cited by 36 publications

References 169 publications

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

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

A Novel Closed-Head Model of Mild Traumatic Brain Injury Using Focal Primary Overpressure Blast to the Cranium in Mice

Progression of basal ganglia pathology in heterozygous Q175 knock‐in Huntington's disease mice

Contact Info

Product

Resources

About