One of the long-standing goals of gene therapy is to deliver vectors directly from the circulatory system to diseased organs. Efforts to achieve this goal using recombinant adeno-associated virus (AAV) vectors have been hampered by the fact that most vectors end up in the liver after systemic delivery. In addition, tissue-specific barriers, such as the blood-brain barrier (BBB), can restrict vector access from the blood to certain organs.
AAV9, originally isolated by James Wilson and colleagues, is one of a lineage of AAVs that includes more than 100 new serotypes that remain poorly characterized. Of these, AAV9 stands out. Vectors carrying capsids from these serotypes are approximately 100 times more efficient than AAV2 at delivering transduction to rodent muscle, liver, and lung. A major reason for the growing popularity of AAV9 in the treatment of neurological diseases is its superior ability to cross the BBB. The prospect of delivering therapeutic genes directly to the brain via the vasculature promises a more direct approach to treating a variety of neurological diseases, especially infantile genetic diseases that affect the structure and function of large areas of the brain. Because AAV9 also effectively transduces spinal motor neurons and dorsal root ganglia after systemic delivery, this vector may merit accelerated clinical development for the treatment of diseases that also affect spinal cord structure and function, such as amyotrophic lateral sclerosis, neuropathic pain, spinal cord injury, and certain ataxias.
Social behavior is essential for human connection and belonging, and often influences disorders such as autism spectrum disorder (ASD). The mesoaccumbens pathway (VTA and NAc) plays a key role in social behavior and has been implicated in ASD. Here, researchers used the Shank3-deficient rat model to examine the effects of Shank3 mutations on the midbrain nucleus accumbens pathway during behavior. The results showed that Shank3-deficient rats displayed atypical social interactions and had difficulty adjusting behavior based on reward value, which was associated with altered neuronal activity in VTA dopaminergic and GABAergic neurons and reduced dopamine release in the NAc. Furthermore, the study demonstrated that manipulation of VTA neuronal activity normalized this behavior, providing insight into the effects of Shank3 mutations on social reward and behavior and identifying potential neural pathways for intervention.
To investigate the effects of Shank3 mutations on the neural activity of VTA-GABA neurons during social interactions, the researchers injected the VTA with AAV9-CAG-FLEX-GCaMP6m virus, which is responsible for expressing GCaMP6 in a Cre-dependent manner, and rAAV-hVGAT1-Cre-WPRE-hGH polyA virus, which expresses Cre recombinase under the control of the vesicular GABA transporter (vGAT) promoter, which is commonly used to target GABAergic neurons60 (Figures 1A and 1B). Recordings showed that while WT rats showed a slight increase in VTA-GABA activity when approaching social stimuli, both Shank3-Het and Shank3-KO rats showed significantly higher increases in VTA-GABA activity (Figures 1C-E). In the social vs. food task (Figure 1F), the researchers observed a similar trend of increased VTA-GABA activity only when rats approached social stimuli but not food stimuli (Figure 1G-I and Figure 1J-L, respectively). Taken together, these findings suggest that Shank3-deficient rats exhibit abnormal increases in VTA-GABA neural activity that are specific to social interactions and not universal to all stimuli.
Figure 1. Shank3-deficient rats show abnormal increase in VTA-GABA neural activity during social interaction. (Barbier M, et al., 2023)
Customer Reviews
Neuronal Specificity
I’m impressed by the neuronal specificity of the Syn-FLEX-NES-jRCaMP1a AAV (Serotype 8). It precisely targets our cell types of interest, reducing off-target effects and improving the quality of our experiments.
United Kingdom
05/08/2023
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