| 1 | Front Cell Neurosci 2014 -1 8: 87 |
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| PMID | 24744698 |
| Title | Sarm1 deficiency impairs synaptic function and leads to behavioral deficits, which can be ameliorated by an mGluR allosteric modulator. |
| Abstract | Innate immune responses have been shown to influence brain development and function. Dysregulation of innate immunity is significantly associated with psychiatric disorders such as autism spectrum disorders and schizophrenia, which are well-known neurodevelopmental disorders. Recent studies have revealed that critical players of the innate immune response are expressed in neuronal tissues and regulate neuronal function and activity. For example, SARM1, a negative regulator that acts downstream of Toll-like receptor (TLR) 3 and 4, is predominantly expressed in neurons. We have previously shown that SARM1 regulates neuronal morphogenesis and the expression of inflammatory cytokines in the brain, which then affects learning ability, cognitive flexibility, and social interaction. Because impaired neuronal morphogenesis and dysregulation of cytokine expression may disrupt neuronal activity, we investigated whether SARM1 knockdown affects the synaptic responses of neurons. We here show that reduced SARM1 expression impairs metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) formation but enhances N-methyl-D-aspartate receptor (NMDAR)-dependent long-term potentiation production in hippocampal CA1 neurons. The expression levels of post-synaptic proteins, including NR2a, NR1, Shank1 and Shank3, are also altered in SARM1 knockdown mice, suggesting a role for SARM1 in the maintenance of synaptic homeostasis. The addition of a positive allosteric modulator of mGluR5, CDPPB, ameliorates the LTD defects in slice recording and the behavioral deficits in social interaction and associative memory. These results suggest an important role for mGluR5 signaling in the function of SARM1. In conclusion, our study demonstrates a role for SARM1 in the regulation of synaptic plasticity. Through these mechanisms, SARM1 knockdown results in the impairment of associative memory and social interactions in mice. |
| SCZ Keywords | schizophrenia |
| 2 | Brain Behav. Immun. 2014 Mar 37: 142-51 |
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| PMID | 24321214 |
| Title | Sarm1, a neuronal inflammatory regulator, controls social interaction, associative memory and cognitive flexibility in mice. |
| Abstract | Impaired neurodevelopment leads to several psychiatric disorders, including autism, schizophrenia and attention deficiency hyperactivity disorder. Our prior study showed that sterile alpha and TIR motif-containing 1 protein (SARM1) regulates neuronal morphogenesis through at least two pathways. SARM1 controls neuronal morphogenesis, including dendritic arborization, axonal outgrowth and establishment of neuronal polarity, through the MKK-JNK pathway. Neuronally expressed SARM1 also regulates the expression of inflammatory cytokines in the brain, which have also been shown to impact brain development and function. Because the reduction of SARM1 expression negatively influences neuronal development, here we investigated whether SARM1 controls mouse behaviors. We analyzed two independent SARM1 transgenic mouse lines using a series of behavioral assays, and found that the reduction of SARM1 protein levels had a limited effect on locomotion and anxiety. However, SARM1 knockdown mice exhibited impairments in cued and contextual fear conditioning as well as cognitive flexibility. Moreover, the three-chambered social test, reciprocal social interaction and social transmission of food preference further illustrated deficiencies in SARM1 knockdown mice in social interaction. These findings suggest that SARM1, a molecule that regulates innate immunity and neuronal morphogenesis, regulates social behaviors and cognition. We conclude that SARM1 is involved in immune response, neural development and psychiatric disorders. |
| SCZ Keywords | schizophrenia |