Alterations in KIDINS220/ARMS Expression Impact Sensory Processing and Social Behavior in Adult Mice.

Kinase D-interacting substrate of 220 kDa (Kidins220) is a transmembrane protein that participates in neural cell survival, maturation, and plasticity. Mutations in the human KIDINS220 gene are associated with a neurodevelopmental disorder ('SINO' syndrome) characterized by spastic paraplegia, intellectual disability, and in some cases, autism spectrum disorder. To better understand the pathophysiology of KIDINS220-linked pathologies, in this study, we assessed the sensory processing and social behavior of transgenic mouse lines with reduced Kidins220 expression: the CaMKII-driven conditional knockout (cKO) line, lacking Kidins220 in adult forebrain excitatory neurons, and the Kidins220floxed line, expressing constitutively lower protein levels. We show that alterations in Kidins220 expression levels and its splicing pattern cause impaired response to both auditory and olfactory stimuli. Both transgenic lines show impaired startle response to high intensity sounds, with preserved pre-pulsed inhibition, and strongly reduced social odor recognition. In the Kidins220floxed line, olfactory alterations are associated with deficits in social memory and increased aggressive behavior. Our results broaden our knowledge of the SINO syndrome; understanding sensory information processing and its deviations under neuropathological conditions is crucial for devising future therapeutic strategies to enhance the quality of life of affected individuals.

Conditional knockout of REST/NRSF in excitatory neurons reduces seizure susceptibility to chemical kindling.

The repressor element-1 silencing transcription factor/neuron-restrictive silencer factor (REST/NRSF) is an epigenetic master regulator that plays a crucial role during nervous system development and maturation. REST function was originally described during development, where it determines neuronal phenotype. However, recent studies showed that REST participates in several processes in the adult brain, including neuronal plasticity and epileptogenesis. In this regard, the relationships between REST and epilepsy are still controversial and need further investigation. As forebrain excitatory neurons are the common final pathway of seizure susceptibility, we investigated the role of REST in epilepsy by inducing REST conditional knockout (REST-cKO) specifically in excitatory neurons of the hippocampus. To target the excitatory neuronal population, we cloned the calcium/calmodulin-dependent protein kinase IIα minimal promoter upstream of Cre recombinase. After assessing the specificity of the promoter's expression, the transgenes were packaged in an engineered adeno-associated virus able to cross the blood-brain and blood-cerebrospinal fluid barriers and delivered in the lateral ventricles of 2-month-old RESTflox/flox mice to characterize, after 1 month, the cognitive phenotype and the seizure propensity. We show that REST-cKO mice display lower levels of anxiety in the light-dark test with respect to control mice but have unaltered motor, social, and cognitive profiles. The evaluation of the susceptibility to epileptic seizures showed that REST-cKO mice are more resistant to pentylenetetrazole-induced kindling but not to seizures induced by a single administration of the convulsant and show higher survival rates. Overall, these data suggest that the absence of REST in forebrain excitatory neurons decreases seizure susceptibility, pointing to a pro-epileptogenic role of the transcriptional repressor under conditions of pathological excitation/inhibition imbalance.

Astrocytes and brain-derived neurotrophic factor (BDNF).

Astrocytes are emerging in the neuroscience field as crucial modulators of brain functions, from the molecular control of synaptic plasticity to orchestrating brain-wide circuit activity for cognitive processes. The cellular pathways through which astrocytes modulate neuronal activity and plasticity are quite diverse. In this review, we focus on neurotrophic pathways, mostly those mediated by brain-derived neurotrophic factor (BDNF). Neurotrophins are a well-known family of trophic factors with pleiotropic functions in neuronal survival, maturation and activity. Within the brain, BDNF is the most abundantly expressed and most studied of all neurotrophins. While we have detailed knowledge of the effect of BDNF on neurons, much less is known about its physiology on astroglia. However, over the last years new findings emerged demonstrating that astrocytes take an active part into BDNF physiology. In this work, we discuss the state-of-the-art knowledge about astrocytes and BDNF. Indeed, astrocytes sense extracellular BDNF through its specific TrkB receptors and activate intracellular responses that greatly vary depending on the brain area, stage of development and receptors expressed. Astrocytes also uptake and recycle BDNF / proBDNF at synapses contributing to synaptic plasticity. Finally, experimental evidence is now available describing deficits in astrocytic BDNF in several neuropathologies, suggesting that astrocytic BDNF may represent a promising target for clinical translation.

A Single Domain Shark Antibody Targeting the Transferrin Receptor 1 Delivers a TrkB Agonist Antibody to the Brain and Provides Full Neuroprotection in a Mouse Model of Parkinson's Disease.

Single domain shark antibodies that bind to the transferrin receptor 1 (TfR1) on brain endothelial cells have been used to shuttle antibodies and other cargos across the blood brain barrier (BBB) to the brain. For these studies the TXB4 brain shuttle was fused to a TrkB neurotrophin receptor agonist antibody. The TXB4-TrkB fusion retained potent agonist activity at its cognate receptor and after systemic administration showed a 12-fold increase in brain levels over the unmodified antibody. Only the TXB4-TrkB antibody fusion was detected within the brain and localized to TrkB positive cells in the cortex and tyrosine hydroxylase (TH) positive dopaminergic neurons in the substantia nigra pars compacta (SNc), where it was associated with activated ERK1/2 signaling. When tested in the 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease (PD), TXB4-TrkB, but not the unmodified antibody, completely prevented the 6-OHDA induced death of TH positive neurons in the SNc. In conclusion, the fusion of the TXB4 brain shuttle allows a TrkB agonist antibody to reach neuroprotective concentrations in the brain parenchyma following systemic administration.

Kidins220/ARMS modulates brain morphology and anxiety-like traits in adult mice.

Kinase D interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), is a transmembrane scaffold protein that participates in fundamental aspects of neuronal physiology including cell survival, differentiation, and synaptic plasticity. The Kidins220 constitutive knockout line displays developmental defects in the nervous and cardiovascular systems that lead to embryonic lethality, which has so far precluded the study of this protein in the adult. Moreover, Kidins220 mRNA is tightly regulated by alternative splicing, whose impact on nervous system physiology has not yet been addressed in vivo. Here, we have asked to what extent the absence of Kidins220 splicing and the selective knockout of Kidins220 impact on adult brain homeostasis. To answer this question, we used a floxed line that expresses only the full-length, non-spliced Kidins220 mRNA, and a forebrain-specific, CaMKII-Cre driven Kidins220 conditional knockout (cKO) line. Kidins220 cKO brains are characterized by enlarged ventricles in the absence of cell death, and by deficient dendritic arborization in several cortical regions. The deletion of Kidins220 leads to behavioral changes, such as reduced anxiety-like traits linked to alterations in TrkB-BDNF signaling and sex-dependent alterations of hippocampal-dependent spatial memory. Kidins220 floxed mice present similarly enlarged brain ventricles and increased associative memory. Thus, both the absolute levels of Kidins220 expression and its splicing pattern are required for the correct brain development and related expression of behavioral phenotypes. These findings are relevant in light of the increasing evidence linking mutations in the human KIDINS220 gene to the onset of severe neurodevelopmental disorders.

Intranasal oxytocin increases heart-rate variability in men at clinical high risk for psychosis: a proof-of-concept study.

Autonomic nervous system (ANS) dysfunction (i.e., increased sympathetic and/or decreased parasympathetic activity) has been proposed to contribute to psychosis vulnerability. Yet, we still lack directed therapeutic strategies that improve ANS regulation in psychosis or at-risk states. The oxytocin system constitutes a potential therapeutic target, given its role in ANS regulation. However, whether intranasal oxytocin ameliorates autonomic regulation during emerging psychosis is currently unknown. We pooled together two datasets, one of 30 men at clinical high risk for psychosis (CHR-P), and another of 17 healthy men, who had participated in two double-blinded, placebo-controlled, randomised, crossover MRI studies with similar protocols. All participants self-administered 40 IU of intranasal oxytocin or placebo using a nasal spray. We recorded pulse plethysmography during a period of 8 min at about 1 h post dosing and estimated heart rate (HR) and high-frequency HR variability (HF-HRV), an index of cardio-parasympathetic activity. CHR-P and healthy men did not differ at resting HR or HF-HRV under placebo. We found a significant condition × treatment effect for HF-HRV, showing that intranasal oxytocin, compared with placebo, increased HF-HRV in CHR-P but not in healthy men. The main effects of treatment and condition were not significant. In this proof-of-concept study, we show that intranasal oxytocin increases cardio-parasympathetic activity in CHR-P men, highlighting its therapeutic potential to improve autonomic regulation in this clinical group. Our findings support the need for further research on the preventive and therapeutic potential of intranasal oxytocin during emerging psychosis, where we lack effective treatments.