Food restriction enhances visual cortex plasticity in adulthood

Neural circuits display a heightened sensitivity to external stimuli during well-established windows in early postnatal life. After the end of these critical periods, brain plasticity dramatically wanes. The visual system is one of the paradigmatic models for studying experience-dependent plasticity. Here we show that food restriction can be used as a strategy to restore plasticity in the adult visual cortex of rats. A short period of food restriction in adulthood is able both to reinstate ocular dominance plasticity and promote recovery from amblyopia. These effects are accompanied by a reduction of intracortical inhibition without modulation of brain-derived neurotrophic factor expression or extracellular matrix structure. Our results suggest that food restriction could be investigated as a potential way of modulating plasticity

A mouse model for creatine transporter deficiency reveals early onset cognitive impairment and neuropathology associated with brain aging.

Mutations in the creatine (Cr) transporter (CrT) gene lead to cerebral creatine deficiency syndrome-1 (CCDS1), an X-linked metabolic disorder characterized by cerebral Cr deficiency causing intellectual disability, seizures, movement and autistic-like behavioural disturbances, language and speech impairment. Since no data are available about the neural and molecular underpinnings of this disease, we performed a longitudinal analysis of behavioural and pathological alterations associated with CrT deficiency in a CCDS1 mouse model. We found precocious cognitive and autistic-like defects, mimicking the early key features of human CCDS1. Moreover, mutant mice displayed a progressive impairment of short and long-term declarative memory denoting an early brain aging. Pathological examination showed a prominent loss of GABAergic synapses, marked activation of microglia, reduction of hippocampal neurogenesis and the accumulation of autofluorescent lipofuscin. Our data suggest that brain Cr depletion causes both early intellectual disability and late progressive cognitive decline, and identify novel targets to design intervention strategies aimed at overcoming brain CCDS1 alterations

Selective Disruption of Perineuronal Nets in Mice Lacking Crtl1 is Sufficient to Make Fear Memories Susceptible to Erasure

The ability to store, retrieve, and extinguish memories of adverse experiences is an essential skill for animals' survival. The cellular and molecular factors that underlie such processes are only partially known. Using chondroitinase ABC treatment targeting chondroitin sulfate proteoglycans (CSPGs), previous studies showed that the maturation of the extracellular matrix makes fear memory resistant to deletion. Mice lacking the cartilage link protein Crtl1 (Crtl1-KO mice) display normal CSPG levels but impaired CSPG condensation in perineuronal nets (PNNs). Thus, we asked whether the presence of PNNs in the adult brain is responsible for the appearance of persistent fear memories by investigating fear extinction in Crtl1-KO mice. We found that mutant mice displayed fear memory erasure after an extinction protocol as revealed by analysis of freezing and pupil dynamics. Fear memory erasure did not depend on passive loss of retention; moreover, we demonstrated that, after extinction training, conditioned Crtl1-KO mice display no neural activation in the amygdala (Zif268 staining) in comparison to control animals. Taken together, our findings suggest that the aggregation of CSPGs into PNNs regulates the boundaries of the critical period for fear extinction

Novel translational phenotypes and biomarkers for creatine transporter deficiency

Abstract Creatine transporter deficiency is a metabolic disorder characterized by intellectual disability, autistic-like behaviour and epilepsy. There is currently no cure for creatine transporter deficiency, and reliable biomarkers of translational value for monitoring disease progression and response to therapeutics are sorely lacking. Here, we found that mice lacking functional creatine transporter display a significant alteration of neural oscillations in the EEG and a severe epileptic phenotype that are recapitulated in patients with creatine transporter deficiency. In-depth examination of knockout mice for creatine transporter also revealed that a decrease in EEG theta power is predictive of the manifestation of spontaneous seizures, a frequency that is similarly affected in patients compared to healthy controls. In addition, knockout mice have a highly specific increase in haemodynamic responses in the cerebral cortex following sensory stimuli. Principal component and Random Forest analyses highlighted that these functional variables exhibit a high performance in discriminating between pathological and healthy phenotype. Overall, our findings identify novel, translational and non-invasive biomarkers for the analysis of brain function in creatine transporter deficiency, providing a very reliable protocol to longitudinally monitor the efficacy of potential therapeutic strategies in preclinical, and possibly clinical, studies

Massage accelerates brain development and the maturation of visual function

Environmental enrichment (EE) was shown recently to accelerate brain development in rodents. Increased levels of maternal care, and particularly tactile stimulation through licking and grooming, may represent a key component in the early phases of EE. We hypothesized that enriching the environment in terms of body massage may thus accelerate brain development in infants. We explored the effects of body massage in preterm infants and found that massage accelerates the maturation of electroencephalographic activity and of visual function, in particular visual acuity. In massaged infants, we found higher levels of blood IGF-1. Massage accelerated the maturation of visual function also in rat pups and increased the level of IGF-1 in the cortex. Antagonizing IGF-1 action by means of systemic injections of the IGF-1 antagonist JB1 blocked the effects of massage in rat pups. These results demonstrate that massage has an influence on brain development and in particular on visual development and suggest that its effects are mediated by specific endogenous factors such as IGF-1

A Comprehensive Atlas of Perineuronal Net Distribution and Colocalization with Parvalbumin in the Adult Mouse Brain

Perineuronal nets (PNNs) surround specific neurons in the brain and are involved in various forms of plasticity and clinical conditions. However, our understanding of the PNN role in these phenomena is limited by the lack of highly quantitative maps of PNN distribution and association with specific cell types. Here, we present a comprehensive atlas of Wisteria Floribunda Agglutinin (WFA) positive PNNs and colocalization with parvalbumin (PV) cells for over 600 regions of the adult mouse brain. Data analysis shows that PV expression is a good predictor of PNN aggregation. In the cortex, PNNs are dramatically enriched in layer 4 of all primary sensory areas in correlation with thalamocortical input density, and their distribution mirrors intracortical connectivity patterns. Gene expression analysis identifies many PNN correlated genes. Strikingly, PNN anticorrelated transcripts are enriched in synaptic plasticity genes, generalizing PNN role as circuit stability factors

Cyclocreatine treatment ameliorates the cognitive, autistic and epileptic phenotype in a mouse model of Creatine Transporter Deficiency

Creatine Transporter Deficiency (CTD) is an inborn error of metabolism presenting with intellectual disability, behavioral disturbances and epilepsy. There is currently no cure for this disorder. Here, we employed novel biomarkers for monitoring brain function, together with well-established behavioral readouts for CTD mice, to longitudinally study the therapeutic efficacy of cyclocreatine (cCr) at the preclinical level. Our results show that cCr treatment is able to partially correct hemodynamic responses and EEG abnormalities, improve cognitive deficits, revert autistic-like behaviors and protect against seizures. This study provides encouraging data to support the potential therapeutic benefit of cyclocreatine or other chemically modified lipophilic analogs of Cr

mGluR5 PAMs rescue cortical and behavioural defects in a mouse model of CDKL5 deficiency disorder

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a devastating rare neurodevelopmental disease without a cure, caused by mutations of the serine/threonine kinase CDKL5 highly expressed in the forebrain. CDD is characterized by early-onset seizures, severe intellectual disabilities, autistic-like traits, sensorimotor and cortical visual impairments (CVI). The lack of an effective therapeutic strategy for CDD urgently demands the identification of novel druggable targets potentially relevant for CDD pathophysiology. To this aim, we studied Class I metabotropic glutamate receptors 5 (mGluR5) because of their important role in the neuropathological signs produced by the lack of CDKL5 in-vivo, such as defective synaptogenesis, dendritic spines formation/maturation, synaptic transmission and plasticity. Importantly, mGluR5 function strictly depends on the correct expression of the postsynaptic protein Homer1bc that we previously found atypical in the cerebral cortex of Cdkl5-/y mice. In this study, we reveal that CDKL5 loss tampers with (i) the binding strength of Homer1bc-mGluR5 complexes, (ii) the synaptic localization of mGluR5 and (iii) the mGluR5-mediated enhancement of NMDA-induced neuronal responses. Importantly, we showed that the stimulation of mGluR5 activity by administering in mice specific positive-allosteric-modulators (PAMs), i.e., 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) or RO6807794, corrected the synaptic, functional and behavioral defects shown by Cdkl5-/y mice. Notably, in the visual cortex of 2 CDD patients we found changes in synaptic organization that recapitulate those of mutant CDKL5 mice, including the reduced expression of mGluR5, suggesting that these receptors represent a promising therapeutic target for CDD