Sleep maintains excitatory synapse diversity in the cortex and hippocampus.

Insufficient sleep is a global problem with serious consequences for cognition and mental health.1 Synapses play a central role in many aspects of cognition, including the crucial function of memory consolidation during sleep.2 Interference with the normal expression or function of synapse proteins is a cause of cognitive, mood, and other behavioral problems in over 130 brain disorders.3 Sleep deprivation (SD) has also been reported to alter synapse protein composition and synapse number, although with conflicting results.4,5,6,7 In our study, we conducted synaptome mapping of excitatory synapses in 125 regions of the mouse brain and found that sleep deprivation selectively reduces synapse diversity in the cortex and in the CA1 region of the hippocampus. Sleep deprivation targeted specific types and subtypes of excitatory synapses while maintaining total synapse density (synapse number/area). Synapse subtypes with longer protein lifetimes exhibited resilience to sleep deprivation, similar to observations in aging and genetic perturbations. Moreover, the altered synaptome architecture affected the responses to neural oscillations, suggesting that sleep plays a vital role in preserving cognitive function by maintaining the brain's synaptome architecture.

Developmental disruption and restoration of brain synaptome architecture in the murine Pax6 neurodevelopmental disease model.

Neurodevelopmental disorders of genetic origin delay the acquisition of normal abilities and cause disabling phenotypes. Nevertheless, spontaneous attenuation and even complete amelioration of symptoms in early childhood and adolescence can occur in many disorders, suggesting that brain circuits possess an intrinsic capacity to overcome the deficits arising from some germline mutations. We examined the molecular composition of almost a trillion excitatory synapses on a brain-wide scale between birth and adulthood in mice carrying a mutation in the homeobox transcription factor Pax6, a neurodevelopmental disorder model. Pax6 haploinsufficiency had no impact on total synapse number at any age. By contrast, the molecular composition of excitatory synapses, the postnatal expansion of synapse diversity and the acquisition of normal synaptome architecture were delayed in all brain regions, interfering with networks and electrophysiological simulations of cognitive functions. Specific excitatory synapse types and subtypes were affected in two key developmental age-windows. These phenotypes were reversed within 2-3 weeks of onset, restoring synapse diversity and synaptome architecture to the normal developmental trajectory. Synapse subtypes with rapid protein turnover mediated the synaptome remodeling. This brain-wide capacity for remodeling of synapse molecular composition to recover and maintain the developmental trajectory of synaptome architecture may help confer resilience to neurodevelopmental genetic disorders.

A brain atlas of synapse protein lifetime across the mouse lifespan.

The lifetime of proteins in synapses is important for their signaling, maintenance, and remodeling, and for memory duration. We quantified the lifetime of endogenous PSD95, an abundant postsynaptic protein in excitatory synapses, at single-synapse resolution across the mouse brain and lifespan, generating the Protein Lifetime Synaptome Atlas. Excitatory synapses have a wide range of PSD95 lifetimes extending from hours to several months, with distinct spatial distributions in dendrites, neurons, and brain regions. Synapses with short protein lifetimes are enriched in young animals and in brain regions controlling innate behaviors, whereas synapses with long protein lifetimes accumulate during development, are enriched in the cortex and CA1 where memories are stored, and are preferentially preserved in old age. Synapse protein lifetime increases throughout the brain in a mouse model of autism and schizophrenia. Protein lifetime adds a further layer to synapse diversity and enriches prevailing concepts in brain development, aging, and disease.

A Comparative Study of High-Contrast Fluorescence Lifetime Probes for Imaging Amyloid in Tissue.

Optical imaging of protein aggregates in living and post-mortem tissue can often be impeded by unwanted fluorescence, prompting the need for novel methods to extract meaningful signal in complex biological environments. Historically, benzothiazolium derivatives, prominently Thioflavin T, have been the state-of-the-art fluorescent probes for amyloid aggregates, but their optical, structural, and binding properties typically limit them to in vitro applications. This study compares the use of novel uncharged derivative, PAP_1, with parent Thioflavin T as a fluorescence lifetime imaging probe. This is applied specifically to imaging recombinant α-synuclein aggregates doped into brain tissue. Despite the 100-fold lower brightness of PAP_1 compared to that of Thioflavin T, PAP_1 binds to α-synuclein aggregates with an affinity several orders of magnitude greater than Thioflavin T; thus, we observe a specific decrease in the fluorescence lifetime of PAP_1 bound to α-synuclein aggregates, resulting in a separation of >1.4 standard deviations between PAP_1-stained brain tissue background and α-synuclein aggregates that is not observed with Thioflavin T. This enables contrast between highly fluorescent background tissue and amyloid fibrils that is attributed to the greater affinity of PAP_1 for α-synuclein aggregates, avoiding the substantial off-target staining observed with Thioflavin T.

Compressive Pressure Versus Time in Cauda Equina Syndrome: A Systematic Review and Meta-Analysis of Experimental Studies.

STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: To examine the relationship between compressive pressure and its duration in cauda equina compression, and the effects of subsequent decompression, on neurophysiological function, and pathophysiology in animal studies. We further aim to investigate these relationships with systemic blood pressure to assess whether a vascular component in the underlying mechanism may contribute to the clinical heterogeneity of this disease. SUMMARY OF BACKGROUND DATA: The complex relationship between preoperative factors and outcomes in cauda equina syndrome (CES) suggests heterogeneity within CES which may inform better understanding of pathophysiological process, their effect on neurological function, and prognosis. METHODS: Systematic review identified 17 relevant studies including 422 animals and reporting electrophysiological measures (EP), histopathology, and blood flow. Modeling using meta-regression analyzed the relationship between compressive pressure, duration of compression, and electrophysiological function in both compression and decompression studies. RESULTS: Modeling suggested that electrophysiological dysfunction in acute cauda equina compression has a sigmoidal response, with particularly deterioration when mean arterial blood pressure is exceeded and, additionally, sustained for approximately 1 hour. Accounting for pressure and duration may help risk-stratify patients pre-decompression. Outcomes after decompression appeared to be related more to the degree of compression, where exceeding systolic blood pressure tended to result in an irreversible lesion, rather than duration of compression. Prognosis was most strongly associated with residual pre-decompression function. CONCLUSION: Compressive pressure influences effects and outcomes of cauda equina compression. We suggest the presence of two broad phenotypic groups within CES defined by the degree of ischaemia as a potential explanatory pathophysiological mechanism. LEVEL OF EVIDENCE: 1.