Intersectin deficiency impairs cortico-striatal neurotransmission and causes obsessive-compulsive behaviors in mice.

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. Mutations in the large synaptic scaffold protein intersectin1 (ITSN1) have been identified in patients presenting with ASD symptoms including stereotypic behaviors, although a causal relationship between stereotypic behavior and intersectin function has not been established. 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. Moreover, we delineate a molecular pathomechanism for the neuropsychiatric symptoms of patients carrying intersectin mutations that correlates with the observation that NMDA receptor dysfunction is a recurrent feature in the development of ASD/OCD-like symptoms.

Seed-induced Aß deposition alters neuronal function and impairs olfaction in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß (Aß) which ultimately forms plaques. These Aß deposits can be induced in APP transgenic mouse models by prion-like seeding. It has been widely accepted that anosmia and hyposmia occur during the early stages of AD, even before cognitive deficits are present. In order to determine the impact of seed-induced Aß deposits on olfaction, we performed intracerebral injections of seed-competent brain homogenate into the olfactory bulb of young pre-depositing APP transgenic mice. Remarkably, we observed a dramatic olfactory impairment in those mice. Furthermore, the number of newborn neurons as well as the activity of cells in the mitral cell layer was decreased. Notably, exposure to an enriched environment reduced Aß seeding, vivified neurogenesis and most importantly reversed olfactory deficits. Based on our findings, we conclude that altered neuronal function as a result of induced Aß pathology might contribute to olfactory dysfunction in AD.