Alterations of
dendritic spines in hiv associated neurocognitive disorders
Infection by the Human Immunodeficiency Virus (HIV) alters not only the immune system, but also the Central Nervous System (CNS). Invasion of the CNS by HIV-1 can cause HIV-associated neurocognitive disorders (HAND) and damage is usually observed through non-apoptotic pathways. One prominent pathway is synaptodendritic injury, which compromises the ability of neurons to communicate with each other; however, the mechanisms involved in neuronal injury are still unclear. Previous studies from our lab show that the HIV-1 envelope protein, gp120, increases neuronal expression of the protein ferritin heavy chain (FHC), a novel negative regulator of chemokine receptors function. Specifically, FHC disrupts the CXCL12/CXCR4 chemokine/receptor axis, a signaling pathway involved in CNS development as well as in the regulation of important functions of the adult brain, such as neurotransmission and cell differentiation. Our previous studies also demonstrated that the CXCL12/CXCR4 pair contributes to spine homeostasis and changes in FHC are involved in HIV neuropathology. In this study, we focus on alterations caused by HIV-1 proteins in the dendritic arbor of pyramidal neurons in different areas of the rat cerebral cortex. We investigated the effect of isolated envelope proteins, namely gp120, or multiple proteins. The two animal models used for this purpose are adult Sprague Dawley (SD) rats treated with gp120IIIB and Fisher 344 (F344) HIV-Tg rats, which express 7 of the 9 HIV genes. Controls groups were vehicle-treated SD and F344 wild type rats, respectively. Either Golgi stain or diolistic labeling was used to visualize neurons in brain cortex sections of the experimental and control group animals. The Neurolucida software was used for tracing and 3D reconstruction of imaged neurons. Both dendritic spine density and morphology were examined in the prefrontal, motor, and somatosensory cortex of each animal group. Furthermore, behavioral studies were conducted to determine cognitive deficits caused by the viral proteins in the two animal models. In previous studies we had found that HIV can cause reduction in spine density of pyramidal neurons in layer II/III of the prefrontal cortex. The objective of the present study was twofold: a) to correlate the observed dendritic changes with the ability to learn new tasks, and b) to investigate whether injury is limited to layer II/III of the prefrontal cortex. Our results show a reduction in spine density in the motor cortex, and no significant difference in spine density in the somatosensory cortex in both models. Morphological alterations were observed in all 3 regions, including the prefrontal cortex, with a shift towards an immature spine type found in both HIV animal models. Slight differences were detected between brain areas and rodent models. These results demonstrate that alterations are not limited to the prefrontal cortex and highlight the variable regional susceptibility of neurons to the damage induced by HIV proteins and inflammation, which may underlie the cognitive and behavioral symptoms observed in patients. Furthermore, the shift towards immature spine morphology in our two animal models of HAND suggests that these neurons may not be able to sequester incoming excitatory neurotransmission in a regulated fashion, leading to neuronal injury and dysfunction.
Infection by the Human Immunodeficiency Virus (HIV) alters not only the immune system, but also the Central Nervous System (CNS). Invasion of the CNS by HIV-1 can cause HIV-associated neurocognitive disorders (HAND) and damage is usually observed through non-apoptotic pathways. One prominent pathway is synaptodendritic injury, which compromises the ability of neurons to communicate with each other; however, the mechanisms involved in neuronal injury are still unclear. Previous studies from our lab show that the HIV-1 envelope protein, gp120, increases neuronal expression of the protein ferritin heavy chain (FHC), a novel negative regulator of chemokine receptors function. Specifically, FHC disrupts the CXCL12/CXCR4 chemokine/receptor axis, a signaling pathway involved in CNS development as well as in the regulation of important functions of the adult brain, such as neurotransmission and cell differentiation. Our previous studies also demonstrated that the CXCL12/CXCR4 pair contributes to spine homeostasis and changes in FHC are involved in HIV neuropathology. In this study, we focus on alterations caused by HIV-1 proteins in the dendritic arbor of pyramidal neurons in different areas of the rat cerebral cortex. We investigated the effect of isolated envelope proteins, namely gp120, or multiple proteins. The two animal models used for this purpose are adult Sprague Dawley (SD) rats treated with gp120IIIB and Fisher 344 (F344) HIV-Tg rats, which express 7 of the 9 HIV genes. Controls groups were vehicle-treated SD and F344 wild type rats, respectively. Either Golgi stain or diolistic labeling was used to visualize neurons in brain cortex sections of the experimental and control group animals. The Neurolucida software was used for tracing and 3D reconstruction of imaged neurons. Both dendritic spine density and morphology were examined in the prefrontal, motor, and somatosensory cortex of each animal group. Furthermore, behavioral studies were conducted to determine cognitive deficits caused by the viral proteins in the two animal models. In previous studies we had found that HIV can cause reduction in spine density of pyramidal neurons in layer II/III of the prefrontal cortex. The objective of the present study was twofold: a) to correlate the observed dendritic changes with the ability to learn new tasks, and b) to investigate whether injury is limited to layer II/III of the prefrontal cortex. Our results show a reduction in spine density in the motor cortex, and no significant difference in spine density in the somatosensory cortex in both models. Morphological alterations were observed in all 3 regions, including the prefrontal cortex, with a shift towards an immature spine type found in both HIV animal models. Slight differences were detected between brain areas and rodent models. These results demonstrate that alterations are not limited to the prefrontal cortex and highlight the variable regional susceptibility of neurons to the damage induced by HIV proteins and inflammation, which may underlie the cognitive and behavioral symptoms observed in patients. Furthermore, the shift towards immature spine morphology in our two animal models of HAND suggests that these neurons may not be able to sequester incoming excitatory neurotransmission in a regulated fashion, leading to neuronal injury and dysfunction.








