Neurodegenerative diseases are progressive conditions that affect the neurons of the central nervous system (CNS) and result in their damage and death. Neurodevelopmental disorders include intellectual disability, autism spectrum disorder, and attention-deficit/hyperactivity disorder and stem from the disruption of essential neurodevelopmental processes. The treatment of neurodegenerative and neurodevelopmental conditions, together affecting ∼120 million people worldwide, is challenged by the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier that prevent the crossing of drugs from the systemic circulation into the CNS. The nose-to-brain pathway that bypasses the BBB and increases the brain bioavailability of intranasally administered drugs is promising to improve the treatment of CNS conditions. This pathway is more efficient for nanoparticles than for solutions, hence, the research on intranasal nano-drug delivery systems has grown exponentially over the last decade. Polymeric nanoparticles have become key players in the field owing to the high design and synthetic flexibility. This review describes the challenges faced for the treatment of neurodegenerative and neurodevelopmental conditions, the molecular and cellular features of the nasal mucosa and the contribution of intranasal nano-drug delivery to overcome them. Then, a comprehensive overview of polymeric nanocarriers investigated to increase drug bioavailability in the brain is introduced.

D -serine is a physiologic coagonist of NMDA receptors, but little is known about the regulation of its synthesis and synaptic turnover. The amino acid exchangers ASCT1 (Slc1a4) and ASCT2 (Slc1a5) are candidates for regulating d -serine levels. Using ASCT1 and ASCT2 KO mice, we report that ASCT1, rather than ASCT2, is a physiologic regulator of d -serine metabolism. ASCT1 is a major d -serine uptake system in astrocytes and can also export l -serine via heteroexchange, supplying neurons with the substrate for d -serine synthesis. ASCT1-KO mice display lower levels of brain d -serine along with higher levels of l -alanine, l -threonine, and glycine. Deletion of ASCT1 was associated with neurodevelopmental alterations including lower hippocampal and striatal volumes and changes in the expression of neurodevelopmental-relevant genes. Furthermore, ASCT1-KO mice exhibited deficits in motor function, spatial learning, and affective behavior, along with changes in the relative contributions of d -serine vs. glycine in mediating NMDA receptor activity. In vivo microdialysis demonstrated lower levels of extracellular d -serine in ASCT1-KO mice, confirming altered d -serine metabolism. These alterations are reminiscent of some of the neurodevelopmental phenotypes exhibited by patients with ASCT1 mutations. ASCT1-KO mice provide a useful model for potential therapeutic interventions aimed at correcting the metabolic impairments in patients with ASCT1 mutations.

Antidepressant medication constitutes the first line pharmacological treatment for posttraumatic stress disorder (PTSD), however, because many patients display no beneficial drug effects it has been suggested that combinations of antidepressants with additional drugs may be necessary. The defining symptoms of PTSD include re-experiencing, avoidance and hyperarousal. In addition, PTSD patients were shown to become easily distracted and often suffer from poor concentration together with indications of comorbidity with attention-deficit hyperactivity disorder (ADHD). Methylphenidate (MPH) is the most common and effective drug treatment for ADHD, thus we aimed to investigate the effects of MPH treatment, by itself or in combination with the antidepressants fluoxetine (FLU) or desipramine (DES). We modified an animal model of PTSD by exposing rats to chronic stress and evaluating the subsequent development of behavioral PTSD-like symptoms, as well as the effects on proinflammatory cytokines, which were implicated in PTSD. We report that while FLU or DES had a beneficial effect on avoidance and hyperarousal symptoms, MPH improved all three symptoms. Moreover, the combination of MPH with DES produced the most dramatic beneficial effects. Serum levels of interleukin-1β (IL-1β) and IL-6 were elevated in the PTSD-like group compared with the control group, and were decreased by MPH, FLU, DES or the combination drug treatments, with the combination of DES+MPH producing the most complete rescue of the inflammatory response. Considering the versatile symptoms of PTSD, our results suggest a new combined treatment for PTSD comprising the antidepressant DES and the psychostimulant MPH.

Social cooperation is defined as a joint action for mutual benefit that depends on the individual and the counterparts’ behaviors. To gain valid evidence for social cooperation behavior we conducted a series of experiments in our suggested fully automated non-conditioned maze and depicted three major findings: (i) During 18 days of training the rats showed a progressive social learning curve as well as latent social learning; (ii) Examining the perceptual communication between the cooperating partners, we found a correlation between the available perceptual modalities and the social cooperation performance; and (iii) Investigating contextual learning as a competing process to the social cooperation, we found that additional contextual cues impaired the social cooperation performance. In conclusion, our suggested automated cooperation maze is designed to further our understanding of social cooperation under normal conditions, such as decision-making and to examine the neural basis of social cooperation. A variety of neuropsychiatric disorders are characterized by disruptions in social behavior and social cognition, including depression, autism spectrum disorders, obsessive-compulsive disorder and schizophrenia. Thus, on the pathological end, our maze for social cooperation evaluation can contribute significantly to the investigation of a wide range of social cooperation impairments in a rodent model.