Matrix metalloproteinases (MMPs) are a group of over twenty proteases, operating chiefly extracellularly to cleave components of the extracellular matrix, cell adhesion molecules as well as cytokines and growth factors. By virtue of their expression and activity patterns in animal models and clinical investigations, as well as functional studies with gene knockouts and enzyme inhibitors, MMPs have been demonstrated to play a paramount role in many physiological and pathological processes in the brain. In particular, they have been shown to influence learning and memory processes, as well as major neuropsychiatric disorders such as schizophrenia, various kinds of addiction, epilepsy, fragile X syndrome, and depression. A possible link connecting all those conditions is either physiological or aberrant synaptic plasticity where some MMPs, e.g., MMP-9, have been demonstrated to contribute to the structural and functional reorganization of excitatory synapses that are located on dendritic spines. Another common theme linking the aforementioned pathological conditions is neuroinflammation and MMPs have also been shown to be important mediators of immune responses.

In aggregate, our results indicate a novel mechanism of alcohol craving that involves MMP-9-dependent synaptic plasticity in CeA.

Whole-brain imaging with light-sheet fluorescence microscopy and optically cleared tissue is a new, rapidly developing research field. Whereas successful attempts to clear and image mouse brain have been reported, a similar result for rats has proven difficult to achieve. Herein, we report on creating novel transgenic rat harboring fluorescent reporter GFP under control of neuronal gene promoter. We then present data on clearing the rat brain, showing that FluoClearBABB was found superior over passive CLARITY and CUBIC methods. Finally, we demonstrate efficient imaging of the rat brain using light-sheet fluorescence microscopy.

Abbreviations used: DAPI, 4,6¢-diamidino-2-phenylindole; EGFP, enhanced green fluorescent protein; ER, endoplasmic reticulum; GFP, green fluorescent protein; MAP2, microtubule-associated protein 2; SE, status epilepticus; Ttyh, tweety homologue. AbstractWe have previously shown that Ttyh1 mRNA is expressed in neurons and its expression is up-regulated in the brain during epileptogenesis and epilepsy. In this study, we aimed to elucidate the role of Ttyh1 in neurons. We found widespread expression of Ttyh1 protein in neurons in vivo and in vitro. Ttyh1 immunoreactivity in vitro was frequently found in invaginations of dendritic spines; however, Ttyh1, seldom co-localized with synaptic markers in vivo. Silencing Ttyh1 expression with siRNA in hippocampal cultures resulted in alterations of MAP2 distribution along neurites causing it to appear in the form of chains of beads. Over-expression of Ttyh1 caused intense neuritogenesis and the formation of numerous filopodia-like protrusions. Similar protrusions were also produced in SH-SY5Y neuroblastoma cells overexpressing Ttyh1. Using a biotin-streptavidin pull-down assay and mass spectrometry, we identified proteins that can form complexes with Ttyh1 in the brain. Ttyh1 binding proteins are often expressed in the endoplasmic reticulum or the Golgi apparatus or are localized at synapses. Finally, we found increased expression of Ttyh1 in the inner molecular layer of the dentate gyrus in an animal model of epilepsy. On the basis of our findings, we propose Ttyh1 involvement in brain pathology.

Dendritic spines are the locus for excitatory synaptic transmission in the brain and thus play a major role in neuronal plasticity. The ability to alter synaptic connections includes volumetric changes in dendritic spines that are driven by scaffolds created by the extracellular matrix (ECM). Here, we review the effects of the proteolytic activity of ECM proteases in physiological and pathological structural plasticity. We use matrix metalloproteinase-9 (MMP-9) as an example of an ECM modifier that has recently emerged as a key molecule in regulating the morphology and dysmorphology of dendritic spines that underlie synaptic plasticity and neurological disorders, respectively. We summarize the influence of MMP-9 on the dynamic remodeling of the ECM via the cleavage of extracellular substrates. We discuss its role in the formation, modification, and maintenance of dendritic spines in learning and memory. Finally, we review research that implicates MMP-9 in aberrant synaptic plasticity and spine dysmorphology in neurological disorders, with a focus on morphological abnormalities of dendritic protrusions that are associated with epilepsy.