Differential expression of synapsin II in cancers of the breast.

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding synapsin II, SYN2, when comparing primary tumors of the breast to the tissue of origin, the normal breast. SYN2 mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of SYN2 in primary tumors of the breast was correlated with recurrence-free survival in patients with luminal A and luminal B cancers, demonstrating a complex relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by molecular subtype. SYN2 may be of relevance to initiation, maintenance or progression of cancers of the female breast.

Physical Activity Reduces Epilepsy Incidence: a Retrospective Cohort Study in Swedish Cross-Country Skiers and an Experimental Study in Seizure-Prone Synapsin II Knockout Mice

Background Epilepsy patients commonly exercise less than the general population. Animal studies indicate beneficial effects of physical activity in established epilepsy, while its effect on the development is currently less known. Methods Here, we investigated the incidence of epilepsy during 20 years in a cohort of participants from the long-distance Swedish cross-country ski race Vasaloppet (n = 197,685) and compared it to the incidence of non-participating-matched controls included in the Swedish population register (n = 197,684). Individuals diagnosed with diseases such as stroke and epilepsy before entering the race were excluded from both groups. Experimentally, we also determined how physical activity could affect the development of epilepsy in epilepsy-prone synapsin II knockout mice (SynIIKO), with and without free access to a running wheel. Results We identified up to 40–50% lower incidence of epilepsy in the Vasaloppet participants of all ages before retirement. A lower incidence of epilepsy in Vasaloppet participants was seen regardless of gender, education and occupation level compared to controls. The participants included both elite and recreational skiers, and in a previous survey, they have reported a higher exercise rate than the general Swedish population. Sub-analyses revealed a significantly lower incidence of epilepsy in participants with a faster compared to slower finishing time. Dividing participants according to specified epilepsy diagnoses revealed 40–50% decrease in focal and unspecified epilepsy, respectively, but no differences in generalized epilepsy. Voluntary exercise in seizure-prone SynIIKO mice for 1 month before predicted epilepsy development decreased seizure manifestation from > 70 to 40%. Brain tissue analyses following 1 month of exercise showed increased hippocampal neurogenesis (DCX-positive cells), while microglial (Iba1) and astrocytic activation (GFAP), neuronal Map2, brain-derived neurotrophic factor and its receptor tyrosine receptor kinase B intensity were unaltered. Continued exercise for additionally 2 months after predicted seizure onset in SynIIKO mice resulted in a 5-fold reduction in seizure manifestation (from 90 to 20%), while 2 months of exercise initiated at the time of predicted seizure development gave no seizure relief, suggesting exercise-induced anti-epileptogenic rather than anti-convulsive effect. Conclusion The clinical study and the experimental findings in mice indicate that physical activity may prevent or delay the development of epilepsy.

Short-term plasticity at cerebellar granule cell to molecular layer interneuron synapses expands information processing

Information processing by cerebellar molecular layer interneurons (MLIs) plays a crucial role in motor behavior. MLI recruitment is tightly controlled by the profile of short-term plasticity (STP) at granule cell (GC)-MLI synapses. While GCs are the most numerous neurons in the brain, STP diversity at GC-MLI synapses is poorly documented. Here, we studied how single MLIs are recruited by their distinct GC inputs during burst firing. Using slice recordings at individual GC-MLI synapses of mice, we revealed four classes of connections segregated by their STP profile. Each class differentially drives MLI recruitment. We show that GC synaptic diversity is underlain by heterogeneous expression of synapsin II, a key actor of STP and that GC terminals devoid of synapsin II are associated with slow MLI recruitment. Our study reveals that molecular, structural and functional diversity across GC terminals provides a mechanism to expand the coding range of MLIs.

Molecular and functional heterogeneity of cerebellar granule cell terminals expands temporal coding in molecular layer interneurons

In the cerebellum, molecular layer interneurons (MLIs) play an essential role in motor behavior by exerting precise temporal control of Purkinje cells, the sole output of the cerebellar cortex. The recruitment of MLIs is tightly controlled by the release of glutamate from granule cells (GCs) during high-frequency activities. Here we study how single MLIs are recruited by their distinct unitary GC inputs during burst of GC stimulations. Stimulation of individual GC-MLI synapses revealed four classes of connections segregated by their profile of short-term plasticity. Each class of connection differentially drives MLI recruitment. Molecular and ultrastructural analyses revealed that GC-MLI synaptic diversity is underlain by heterogeneous expression of synapsin II at individual GC terminals. In synapsin II knock-out mice, the number of classes is reduced to profiles associated with slow MLI recruitment. Our study reveals that molecular diversity across GC terminals enables diversity in temporal coding by MLIs and thereby influences the processing of sensory information by cerebellar networks.

Pharmacoinformatics and Molecular Docking Studies Reveal Potential Novel Compounds Against Schizophrenia by Target SYN II

Background: Synapsin II regulates neurotransmitter release from mature nerve terminals and plays important role in the formation of new nerve terminals. The associations of SYN II are identified in various studies that are linked to the onset of Schizophrenia. Schizophrenia is characterized by abnormal behavior like obsession, dampening of emotions and auditory hallucination. Methods: The bioinformatics approaches were utilized for structural modeling and docking analyses of SYN II followed by pharmacophore generation to identify potent inhibitors. Results: The comparative modeling approach was employed to generate the 3D model having 82.404% quality factor calculated by Errat. Pharmacophore was constructed by utilizing merge molecular and chemical features of selected five FDA approved Schizophrenia drugs by LigandScout 4.1.5. Comparative docking analyses were performed by utilizing the selected drugs and top screened hits by GOLD and AutoDock Vina. Conclusion: It was proposed that Aripiprazole drug and scrutinized compounds have strong binding affinities among the other selected drugs. The reported compounds may be used for further analyses in the drug discovery processes, as they have shown good human intestinal absorption and are noncarcinogenic. The present study provides the structural insights which may be used for further understating of the Schizophrenia therapeutic purposes by targeting SYN II and other inhibitors haunting.