What is it about?
The generation of appropriate behavioral responses involves dedicated neuronal circuits. The cortico-striatal-thalamo-cortical loop is especially important for the expression of motor routines and habits. Defects in this circuitry are closely linked to obsessive stereotypic behaviors, hallmarks of neuropsychiatric diseases including autism spectrum disorders (ASDs) and obsessive–compulsive disorders (OCDs). However, our knowledge of the essential synaptic machinery required to maintain balanced neurotransmission and plasticity within the cortico-striatal circuitry remains fragmentary. We report here that deletion of the two closely related proteins ITSN1 and ITSN2 leads to severe ASD/OCD-like behavioral alterations and defective cortico-striatal neurotransmission in knockout (KO) mice. Cortico-striatal function was compromised at multiple levels in ITSN1/2-depleted animals. Morphological analyses showed that the striatum of intersectin KO mice is decreased in size. Striatal neurons exhibit reduced complexity and an underdeveloped dendritic spine architecture. These morphological abnormalities correlate with defects in cortico-striatal neurotransmission and plasticity as well as reduced N-methyl-D-aspartate (NMDA) receptor currents as a consequence of postsynaptic NMDA receptor depletion. Our findings unravel a physiological role of intersectin in cortico-striatal neurotransmission to counteract ASD/OCD.
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Why is it important?
The compulsion to carry out stereotypic motor routines is a hallmark of neuropsychiatric diseases like autism spectrum and obsessive–compulsive disorders and interferes with the ability to cope with everyday life. Recently, mutations in intersectin1 (ITSN1) have been identified in patients with neurological symptoms including stereotypic behaviors. However, a causal relationship between intersectin and these symptoms has not been established. We show that deletion of ITSN1/2 in mice leads to stereotypic behavior, morphological abnormalities, and defective cortico-striatal neurotransmission linked to reduced N-methyl-D-aspartate (NMDA) receptor currents. With that we delineate a molecular pathomechanism for the neuropsychiatric symptoms of patients carrying intersectin mutations and support the notion that NMDA receptor dysfunction is a common feature in the development of behavioral alterations typical of autism spectrum and obsessive compulsive disorders.
Perspectives
Our neurons use neurotransmitters to communicate with each other. For this to work smoothly, the right amount of neurotransmitter receptors needs to be in place to respond to these signals. However, it is becoming increasingly clear that not only neurotransmitter receptors are essential, but also diverse accessory proteins are needed to stabilize and anchor the receptors. The intersectins have now joined the ranks of these scaffolding proteins that safeguard neurotransmission and prevent us from being caught in repetitive behaviour loops.
Tanja Maritzen
RPTU Kaiserslautern-Landau
Read the Original
This page is a summary of: Intersectin deficiency impairs cortico-striatal neurotransmission and causes obsessive–compulsive behaviors in mice, Proceedings of the National Academy of Sciences, August 2023, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2304323120.
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