Sex-dependent effects of monomeric α-synuclein on calcium and cell death of lateral hypothalamic mouse neurons are altered by orexin.

Parkinson's Disease (PD) patients experience sleeping disorders in addition to the disease-defining symptomology of movement dysfunctions. The prevalence of PD is sex-based and presence of sleeping disorders in PD also shows sex bias with a stronger phenotype in males. In addition to loss of dopamine-containing neurons in the striatum, arousal-related, orexin-containing neurons in the lateral hypothalamus (LH) are lost in PD, which could contribute to state-related disorders. As orexin has been shown to be involved in sleeping disorders and to have neuroprotective effects, we asked whether orexin could protect sleep-related LH neurons from damage putatively from the protein α-synuclein (α-syn), which is found at high levels in the PD brain and that we have shown is associated with putatively excitotoxic rises in intracellular calcium in brainstem sleep-controlling nuclei, especially in males. Accordingly, we monitored intracellular calcium transients induced by α-syn and whether concurrent exposure to orexin affected those transients in LH cells of the mouse brain slice using calcium imaging. Further, we used an assay of cell death to determine whether LH cell viability was influenced when α-syn and orexin were co-applied when compared to exposure to α-syn alone. We found that excitatory calcium events induced by α-syn were reduced in amplitude and frequency when orexin was co-applied, and when data were evaluated by sex, this effect was found to be greater in females. In addition, α-syn exposure was associated with cell death that was higher in males, and interestingly, reduced cell death was noted when orexin was present, which did not show a sex bias. We interpret our findings to indicate that orexin is protective to α-syn-mediated damage to hypothalamic neurons, and the actions of orexin on α-syn-induced cellular effects differ between sexes, which could underlie sex-based differences in sleeping disorders in PD.

Protocol for quantifying pyramidal neuron hyperexcitability in a mouse model of neurodevelopmental encephalopathy.

Here, we present a protocol for quantifying pyramidal neuron hyperexcitability in a mouse model of STXBP1 neurodevelopmental encephalopathy (Stxbp1hap). We describe steps for preparing brain slices, positioning electrodes, and performing an excitability test to investigate microcircuit failures. This protocol is based on recording layer 2/3 cortical pyramidal neurons in response to stimulation of two independent sets of excitatory axons that recruit feedforward inhibition microcircuits. For complete details on the use and execution of this protocol, please refer to Dos Santos et al.1.

Microcircuit failure in STXBP1 encephalopathy leads to hyperexcitability.

De novo mutations in STXBP1 are among the most prevalent causes of neurodevelopmental disorders and lead to haploinsufficiency, cortical hyperexcitability, epilepsy, and other symptoms in people with mutations. Given that Munc18-1, the protein encoded by STXBP1, is essential for excitatory and inhibitory synaptic transmission, it is currently not understood why mutations cause hyperexcitability. We find that overall inhibition in canonical feedforward microcircuits is defective in a P15-22 mouse model for Stxbp1 haploinsufficiency. Unexpectedly, we find that inhibitory synapses formed by parvalbumin-positive interneurons were largely unaffected. Instead, excitatory synapses fail to recruit inhibitory interneurons. Modeling confirms that defects in the recruitment of inhibitory neurons cause hyperexcitation. CX516, an ampakine that enhances excitatory synapses, restores interneuron recruitment and prevents hyperexcitability. These findings establish deficits in excitatory synapses in microcircuits as a key underlying mechanism for cortical hyperexcitability in a mouse model of Stxbp1 disorder and identify compounds enhancing excitation as a direction for therapy.

Lower calcium levels in hair of Parkinson's disease patients are associated with presence of sleeping disturbances.

Objectives: To investigate the correlation between sleep disorders and the concentrations of three metals analyzed from hair samples of PD patients.The hypothesis of an involvement of an imbalance of metals in the development of Parkinson's Disease (PD) has been strengthened by several clinical chemistry studies. Interestingly, while sparse, some studies have correlated the imbalance of metals in PD patients with comorbidities present in this disease. Although not all PD sufferers present sleep disturbances, significant disorders of sleep are common in this population. Methods: Sleep evaluation was divided into three parameters: sleep quality, excessive daytime sleepiness and clinically probable REM Sleep Behavior Disorder. Flame atomic absorption spectrometry (F AAS) was used to assess the concentrations of calcium, iron and zinc in hair samples collected from a population of PD patients registered in a Brazilian city and from controls (a total of 53 subjects). All subjects lived within a restricted geographical region and were exposed to similar environmental conditions. Results: PD patients with poor sleep quality and excessive daytime sleepiness exhibited significant differences in concentrations of calcium, but not iron or zinc when compared to levels found in controls and PD patients who do not report these sleeping problems. Discussion: Our data suggest that different subgroups of PD patients exist, and clinical chemistry could be useful as a biomarker for these subgroups, which needs to be confirmed in a larger patient population. Further, our data raise the question regarding whether normalization of calcium levels could improve the sleep quality and somnolence in PD patients.

Higher zinc concentrations in hair of Parkinson's disease are associated with psychotic complications and depression.

Parkinson's disease (PD) is classically considered a motor disease; however, several non-motor symptoms are also present, including psychiatric complaints. In recent decades, the metals Ca, Fe, and Zn have gained prominence as potential etiologic factors in motoric signs of PD. However, metal alterations could be associated with the non-motor symptoms of PD. We wished to correlate the levels of these metals with the co-occurrence of depression, anxiety, and psychotic symptoms in PD patients. To this end, the Beck Depression Inventory, the Beck Anxiety Inventory, and the Scales for Outcomes in Parkinson's disease-Psychiatric Complications (SCOPA-PC) were implemented to evaluate mood disorders and psychiatric complications. Flame atomic absorption spectrometry (FAAS) was used to assess concentrations of Ca, Fe, and Zn in hair samples collected from 22 clinically diagnosed PD patients, which represented the entire cohort of accessible patients in a Brazilian health registry, and 33 healthy individuals. While Ca and Fe alterations were not found to be associated with psychiatric complaints in the PD group, significantly higher levels of Zn were correlated in PD patients with depression and some psychotic symptoms. Within individual domains of the SCOPA-PC, significantly higher levels of Zn were correlated with the presence of hallucination, illusion, and paranoid ideation when compared to controls and PD patients who did not present these symptoms. Although our sample size is small and findings need to be replicated in larger and heterogeneous populations, our results provide a new perspective on the use of monitoring of Zn levels as a potential biomarker of psychiatric complaints, and may be useful in the development of more effective therapeutic approaches for the management of PD patients with co-occurrence of psychiatric disorders.

Relação entre qualidade do sono e funções cognitivas em pacientes com doença de Parkinson / Relación entre la calidad del sueño y función cognitiva en pacientes con la enfermedad de Parkinson / Relationship between quality of sleep and cognitive function in patients with Parkinsons disease

Descrever as características clínicas e demográficas de pacientes com Doença de Parkinson, bem como verificar a relação entre a qualidade do sono e as funções cognitivas. Trata-se de um estudo descritivo-analítico de corte transversal em que foram avaliados episódios de depressão, ansiedade, estado geral e progressão da doença, sonolência, qualidade do sono e funções cognitivas de 24 pacientes com Doença de Parkinson sem demência. Analisando os resultados do teste de memória tardia e a as alterações do sono, encontrou-se correlação do tipo inversa e moderada. O componente latência do sono teve uma correlação inversa e moderada com a memória, e também com a função visuoespacial. Outras relações também foram observadas como entre a qualidade subjetiva do sono e a função visuoespacial, a latência do sono e o resultado global do SCOPA-COG, e entre a duração do sono e a atenção. Todas essas correlações foram inversas e de caráter fraco. Esse estudo sugere que os déficits cognitivos leves, na ausência de demência, foram relacionados com qualidade ruim do sono.

Describir las características clínicas de pacientes con la enfermedad de Parkinson, así como la relación entre la calidad del sueño y las funciones cognitivas. Se realizó un estudio descriptivo-analítico de corte transversal que evaluó: los episodios de depresión, ansiedad, estado de salud general, progresión de la enfermedad, sueño, calidad del sueño y funciones cognitivas de 24 pacientes con enfermedad de Parkinson sin demencia. Se observó una relación inversa de tipo moderada entre la memoria tardía y trastornos del sueño. El componente de la latencia del sueño tuvo una correlación inversa moderada con la memoria, y con la función visuoespacial. También se observaron otras relaciones entre la calidad subjetiva del sueño y la función visuoespacial, la latencia del sueño y el resultado global de la SCOPA-COG, y entre la duración del sueño y la atención. Se observó que estas correlaciones fueron inversas y de carácter débil. Este estudio sugiere que los déficits cognitivos leves en ausencia de demencia se relacionaron con la mala calidad del sueño.

Here, we describe the clinical characteristics of patients with Parkinson's disease, as well as study the relationship between sleep quality and cognitive functions. This is a descriptive-analytical cross-sectional study in which we evaluate episodes of depression and anxiety, as well as the state of general health, disease progression, sleepiness, sleep quality and cognitive functions of 24 patients with Parkinson's disease without dementia. We found a moderate inverse correlation between memory and sleep disturbances, and a moderate inverse correlation of memory and visuospatial function. We also observed other associations between subjective sleep quality and visuospatial function, sleep latency and the overall result of the SCOPA-COG, and between sleep duration and attention; all of these correlations were inverse and weak. This study suggests that mild cognitive deficits in the absence of dementia are associated with poor sleep quality.