Biology subjects

McCool, S.

Publications and source records attributed to McCool, S..

5 recordsLinked to original sources

bioRxiv2026

Plaque-associated Microglial Polarization in Visual Brain Regions of the 5xFAD Mouse Model

Alzheimers disease (AD), a neurodegenerative disorder associated with amyloid beta (A{beta}) plaque deposition, leads to cognitive decline in affected individuals. Vision changes are some of the first reported symptoms in AD with studies showing both decline in functions performed by the visual system as well as associations between vision loss and cognitive impairment in AD patients. Due to the increasing number of individuals diagnosed with AD and its early impact on vision, we sought to provide an in-depth analysis using immunohistochemistry and 2-photon imaging techniques in the 5xFAD mouse model of amyloidosis to examine specifically how A{beta}, a primary pathology typically preceding many other AD-associated pathologies, affects visual regions of the brain and how microglia, key immune regulators of the brains environment, respond to this AD-like pathology. We found that in the pathway for image-forming vision, including the dorsolateral geniculate nucleus (dLGN) and the primary visual cortex (V1), there was significant A{beta} pathology and shifts in microglial morphology to an amoeboid state and increased phagocytic activity. However, in non-image-forming visual brain regions such as the superior colliculus (SC) and suprachiasmatic nucleus (SCN), there was minimal A{beta} pathology, ramified microglial morphology, and minimal phagocytic activity. Overall, visual brain regions associated with A{beta} plaque deposition experience significant microglial polarization when examining both morphology and function.

neuroscience↗

bioRxiv2025

Compensatory responses to glaucoma pathology in the dorsolateral geniculate nucleus

Glaucoma disrupts the conveyance of retinal signals to visual regions of the brain such as the dorsolateral geniculate nucleus (dLGN) due to degeneration of retinal ganglion cells (RGCs) and their axons. Although plasticity during development allows altered visual experience to modulate dLGN synapses and excitability, evidence for experience-dependent dLGN plasticity in adults is limited. However, glaucoma might trigger compensatory plasticity in adult dLGN, thereby compensating for diminished RGC synaptic drive. Here, we tested this using aged (11-15 month-old) DBA/2J mice, which develop high intraocular pressure and glaucoma. In brain slice recordings, we found that diminished RGC inputs could drive robust action potential firing in dLGN relay neurons that was comparable to controls. This was accompanied by increased intrinsic excitability and decreased magnitude of sustained inhibitory currents from GABA spillover to extrasynaptic receptors. These results implicate multiple cellular and synaptic mechanisms that support signaling despite the diminished RGC inputs in glaucoma. HIGHLIGHTSO_LIRetinogeniculate synapse strength in the dLGN is diminished in the DBA/2J mouse model of glaucoma C_LIO_LIDespite a loss of synaptic strength, retinogeniculate synapses drive robust action potential firing in dLGN relay neurons, suggestive of homeostatic compensation C_LIO_LIdLGN relay neurons from DBA/2J mice have an increase in intrinsic excitability, supporting action potential generation C_LIO_LIReduced extrasynaptic sustained inhibition in DBA/2J dLGN relay neurons can also support synaptically driven action potential firing C_LI

neuroscience↗

bioRxiv2024

Microglia respond to elevated intraocular pressure and synapse loss in the visual thalamus in a mouse model of glaucoma.

Microglia are resident immune cells of the central nervous system and mediate a broad array of adaptations and responses during disease, injury, and development. Typically, microglia morphology is understood to provide a window into their functional state. However, it is apparent that they have the capacity to adopt a broad spectrum of functional phenotypes characterized by numerous morphological profiles and associated gene expression profiles. Glaucoma, which leads to blindness from retinal ganglion cell (RGC) degeneration, is commonly associated with elevated intraocular pressure and has been shown to trigger microglia responses within the retinal layers, at the optic nerve head, and in retinal projection targets in the brain. The goal of this study was to determine the relationship of microglia morphology to intraocular pressure and the loss of retinal ganglion cell output synapses in the dorsolateral geniculate nucleus (dLGN), a RGC projection target in the thalamus that conveys information to the primary visual cortex. We accomplished this by analyzing dLGN microglia morphologies in histological sections from DBA/2J mice, which develop a form of inherited glaucoma. Microglia morphology was analyzed using skeletonized Iba1-fluorescence images and fractal analyses of individually reconstructed microglia cells. We found that microglia adopted more simplified morphologies, characterized by fewer endpoints and less total process length per microglia cell. There was an age-dependent shift in microglia morphology in tissue from control mice (DBA/2JGpnmb+) that was accelerated in DBA/2J mice. Microglia morphological measurements correlated with cumulative intraocular pressure, immunofluorescence labeling for the complement protein C1q, and density of vGlut2-labeled RGC axon terminals. Additionally, fractal analysis revealed a clear distinction between control and glaucoma dLGN, with microglia from ocular hypertensive DBA/2J dLGN tissue showing an elongated rod-like morphology. RNA-sequencing of dLGN tissue samples showed an upregulation of immune system-related gene expression and several specific genes associated with microglia activation and potential neuroprotective functions. These results suggest that microglia in the dLGN alter their physiology to respond to RGC degeneration in glaucoma, potentially contributing to CNS adaptations to neurodegenerative vision loss.

neuroscience↗

bioRxiv2024

Amyloid Beta Pathology Accelerates Alterations in the Visual Pathway of the 5xFAD Mouse

Alzheimers disease (AD) is a neurodegenerative disorder characterized by the formation of amyloid beta plaques and neurofibrillary tangles that leads to decreased quality of life due to behavioral, motor, and cognitive impairments. Due to the widespread pathological nature of AD, many brain regions are affected by amyloid beta plaques including regions important for vision such as the lateral geniculate nucleus (LGN) of the thalamus which is critical for relaying signals from the retina to the primary visual cortex. Using a wide range of techniques including electrophysiological approaches, in vivo and ex vivo imaging methods, and immunohistochemistry in a mouse model with progressing amyloidosis (5xFAD), the goal of this study was to determine whether AD-like pathology disrupts neuronal and synaptic structure and function in the visual system. In vivo electroretinogram recordings revealed photoreceptor dysfunction in the 6- and 9-month-old 5xFAD mice, while optical coherence tomography indicated no changes in retinal thickness. In the dorsolateral geniculate nucleus (dLGN), the rodent homolog of the primate LGN, we identified decreased densities of retinal ganglion cell axon terminals and fewer thalamocortical (TC) neuron cell bodies. No detectable deficits in excitatory synaptic function or TC neuron dendritic structure were seen in the dLGN, and reflexive visual behavior was also found to be normal in the 5xFAD mice. These results indicate relatively modest amyloid-triggered dysfunction in these stages of the visual system suggesting that amyloid beta plaque formation may play only a small role in the visual system dysfunction seen in AD patients. These results may also point to potential compensatory mechanisms that preserve function of visual pathways in the 5xFAD visual system.

neuroscience↗

bioRxiv2024

Nonuniform scaling of synaptic inhibition in the dorsolateral geniculate nucleus in a mouse model of glaucoma.

Elevated intraocular pressure (IOP) triggers glaucoma by damaging the output neurons of the retina called retinal ganglion cells (RGCs). This leads to the loss of RGC signaling to visual centers of the brain such as the dorsolateral geniculate nucleus (dLGN), which is critical for processing and relaying information to the cortex for conscious vision. In response to altered levels of activity or synaptic input, neurons can homeostatically modulate postsynaptic neurotransmitter receptor numbers, allowing them to scale their synaptic responses to stabilize spike output. While prior work has indicated unaltered glutamate receptor properties in the glaucomatous dLGN, it is unknown whether glaucoma impacts dLGN inhibition. Here, using DBA/2J mice, which develop elevated IOP beginning at 6-7 months of age, we tested whether the strength of inhibitory synapses on dLGN thalamocortical relay neurons is altered in response to the disease state. We found an enhancement of feed-forward disynaptic inhibition arising from local interneurons along with increased amplitude of quantal inhibitory synaptic currents. A combination of immunofluorescence staining for the GABAA-1 receptor subunit, peak-scaled nonstationary fluctuation analysis, and measures of homeostatic synaptic scaling indicated this was the result of an approximately 1.4-fold increase in GABA receptor number at post-synaptic inhibitory synapses, although several pieces of evidence strongly indicate a non-uniform scaling across inhibitory synapses within individual relay neurons. Together, these results indicate an increase in inhibitory synaptic strength in the glaucomatous dLGN, potentially pointing toward homeostatic compensation for disruptions in network and neuronal function triggered by increased IOP. Significance StatementElevated eye pressure in glaucoma leads to loss of retinal outputs to the dorsolateral geniculate nucleus (dLGN), which is critical for relaying information to the cortex for conscious vision. Alterations in neuronal activity, as could arise from excitatory synapse loss, can trigger homeostatic adaptations to synaptic function that attempt to maintain activity within a meaningful dynamic range, although whether this occurs uniformly at all synapses within a given neuron or is a non-uniform process is debated. Here, using a mouse model of glaucoma, we show that dLGN inhibitory synapses undergo non-uniform upregulation due to addition of post-synaptic GABA receptors. This is likely to be a neuronal adaptation to glaucomatous pathology in an important sub-cortical visual center.

neuroscience↗