RAB39B-mediated trafficking of the GluA2-AMPAR subunit controls dendritic spine maturation and intellectual disability-related behaviour.

Mutations in the RAB39B gene cause X-linked intellectual disability (XLID), comorbid with autism spectrum disorders or early Parkinson's disease. One of the functions of the neuronal small GTPase RAB39B is to drive GluA2/GluA3 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) maturation and trafficking, determining AMPAR subunit composition at glutamatergic postsynaptic neuronal terminals. Taking advantage of the Rab39b knockout murine model, we show that a lack of RAB39B affects neuronal dendritic spine refinement, prompting a more Ca2+-permeable and excitable synaptic network, which correlates with an immature spine arrangement and behavioural and cognitive alterations in adult mice. The persistence of immature circuits is triggered by increased hypermobility of the spine, which is restored by the Ca2+-permeable AMPAR antagonist NASPM. Together, these data confirm that RAB39B controls AMPAR trafficking, which in turn plays a pivotal role in neuronal dendritic spine remodelling and that targeting Ca2+-permeable AMPARs may highlight future pharmaceutical interventions for RAB39B-associated disease conditions.

Cognitive maps in imagery neglect.

Patients with imagery neglect (RI+) show peculiar difficulties in orienting themselves in the environment. Navigational impairments could be due to a deficit in creating or using a mental representation of the environment (Guariglia, Piccardi, Iaria, Nico, & Pizzamiglio, 2005) or, according to the BBB model (Burgess, Becker, King, & O'Keefe, 2001), to a specific deficit in a mechanism that transforms an allocentric representation into an egocentric one and vice versa. Previous studies, however, do not allow discerning between a deficit in forming or in using a cognitive map, taking no notice of the fact that these are two different abilities underlain by different neuroanatomical areas, which could be independently impaired. Furthermore, the BBB model has never been verified in a population of brain-damaged patients. Therefore, we administered two tasks that separately assess the ability to create and use a cognitive map of the environment to 28 right brain-damaged patients (4 patients with imagery neglect and 4 patients with perceptual neglect) and 11 healthy participants. RI+ patients showed no specific deficit in creating or using a cognitive map, but failed to transform an egocentric representation of the environment into an allocentric one and vice versa, as predicted by the BBB model.

Map-following skills in left and right brain-damaged patients with and without hemineglect.

Map-following tasks require a "semantic interpretation" of the map, which could be affected by left brain damage, and "superimposition of the map upon the space," which could be compromised by right lesions and particularly by the presence of hemineglect. Participants followed a pathway depicted on a map of a real environment. The pathway included four left and four right turns. A legend explained the meaning of each symbol that appeared on the map. Our results showed no deficits in left brain-damaged patients, but poor performance in right brain-damaged patients affected by hemineglect. This deficit can be ascribed to their impaired egocentric frame of reference, but we cannot exclude a prevalent role of the right hemisphere in their use of the allocentric information on the map despite the presence of hemineglect. Indeed, three right brain-damaged patients without hemineglect showed a specific deficit in performing the task. We discuss the results in light of the possible impairment of the parietomedial temporal pathway, which supports spatial navigation and could be responsible for the patients' deficit.