Lytic Cell Death in Specific Microglial Subsets Is Required for Preventing Atypical Behavior in Mice

Microglial Dyshomeostasis: A Common Substrate in Neurodevelopmental and Neurodegenerative Diseases

“…Furthermore, they determined that the disruption of inflammasome formation through the Caspase-1 knockout reduced the microglial expression of mannose receptor C type 2 (Mrc2), a gene involved in phagocytosis. This observation coupled with the increase in neuron number in the thalamic reticular nucleus (TRN) implicates altered microglial phagocytosis as contributing to ADHD pathology [17]. These findings provide evidence that heightened microglial inflammatory responses (increased activation and release of proinflammatory cytokines) coupled with reduced microglial homeostatic functions (phagocytosis) contribute to the onset and symptomatology of ADHD.…”

“…We closely examined seven recent studies [11][12][13][14][15][16][17], which tested a causal link between microglial dysfunction and pathogenesis in neurodevelopmental disorders; five of these studies employed the targeted genetic manipulation of microglial proteins in mice to test its consequence on synaptic integrity (structure and function), brain connectivity, neuroinflammation and social behavior with relevance to ASD or ADHD; one study used a murine model of ADHD to examine the therapeutic action of a clinically approved methylphenidate (MPH) via microglial pathways; one study conducted a functional analysis of microglial activation in an ADHD patient cohort (see summary in Figure 1 and Table 1). NLR family pyrin domain-containing 3 (Nlrp3).…”

“…Inflammasomes are multimeric cytosolic protein complexes of the innate immune system that assemble to sense and mediate the activation of inflammatory responses [30]. Chuang et al (2021) focused on microglia inflammasome components in the context of ADHD during neural development [17]. They employed genetically modified mice with a brain-wide deletion of inflammasome-related genes, including caspase-1, interleukin-1 receptor (IL1R), gasdermin D (GSDMD) and NOD-like receptor family pyrin domain containing 3 (NLRP3) and evaluated ADHD-like behaviors.…”