TGF-β/Smad3 Signalling Modulates GABA Neurotransmission: Implications in Parkinson's Disease.

γ-Aminobutiryc acid (GABA) is found extensively in different brain nuclei, including parts involved in Parkinson's disease (PD), such as the basal ganglia and hippocampus. In PD and in different models of the disorder, an increase in GABA neurotransmission is observed and may promote bradykinesia or L-Dopa-induced side-effects. In addition, proteins involved in GABA receptor (GABAR) trafficking, such as GABARAP, Trak1 or PAELR, may participate in the aetiology of the disease.

Smad3 deficiency inhibits dentate gyrus LTP by enhancing GABAA neurotransmission.

Transforming growth factor-β signaling through intracellular Smad3 has been implicated in Parkinson's disease (PD) and it fulfills an important role in the neurogenesis and synaptic plasticity that occurs in the adult dentate gyrus (DG). The long-term potentiation (LTP) induced in the DG by high-frequency stimulation of the medial perforant pathway is abolished in the DG of Smad3-deficient mice, but not in the CA1 hippocampal region. Here, we show that NMDA- and AMPA-type glutamate receptors do not participate in the inhibition of LTP associated with Smad3 deficiency.

Models of α-synuclein aggregation in Parkinson's disease.

Parkinson's disease (PD) is not only characterized by motor disturbances but also, by cognitive, sensory, psychiatric and autonomic dysfunction. It has been proposed that some of these symptoms might be related to the widespread pathology of α-synuclein (α-syn) aggregation in different nuclei of the central and peripheral nervous system. However, the pathogenic formation of α-syn aggregates in different brain areas of PD patients is poorly understood.

Smad3 is required for the survival of proliferative intermediate progenitor cells in the dentate gyrus of adult mice.

Background: New neurons are continuously being generated in the adult hippocampus, a phenomenon that is regulated by external stimuli, such as learning, memory, exercise, environment or stress. However, the molecular mechanisms underlying neuron production and how they are integrated into existing circuits under such physiological conditions remain unclear. Indeed, the intracellular modulators that transduce the extracellular signals are not yet fully understood.

Dopamine and α-synuclein dysfunction in Smad3 null mice.

Background: Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration in the substantia nigra (SN). Transforming growth factor-β1 (TGF-β1) levels increase in patients with PD, although the effects of this increment remain unclear. We have examined the mesostriatal system in adult mice deficient in Smad3, a molecule involved in the intracellular TGF-β1 signalling cascade.

TIMP-1 abolishes MMP-9-dependent long-lasting long-term potentiation in the prefrontal cortex.

Background: Understanding of the molecular mechanisms of prefrontal cortex (PFC) plasticity is important for developing new treatment strategies for mental disorders such as depression and schizophrenia. Long-term potentiation (LTP) is a valid model for synaptic plasticity. The extracellular proteolytic system composed of matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) has recently been shown to play major role in the hippocampal plasticity.

Ca2+/calmodulin kinase kinase alpha is dispensable for brain development but is required for distinct memories in male, though not in female, mice.

In neurons, the Ca(2+)/calmodulin (CaM) kinase cascade transduces Ca(2+) signaling into gene transcription. The CaM kinase cascade is known to be important for brain development as well as memory formation in adult brain, although the functions of some cascade members remain unknown. Here we have generated null and hypomorphic mutants to study the physiological role of CaM kinase kinase alpha (CaMKKalpha), which phosphorylates and activates both CaM kinase I (CaMKI) and CaMKIV, the output kinases of the cascade.

Dual role for TGF-beta1 in apoptosis.

The exposure of cells to TGF-beta1 can trigger a variety of cellular responses including the inhibition of cell growth, migration, differentiation and apoptosis. TGF-beta1-regulated apoptosis is cell type and context-dependent, indeed TGF-beta1 provides signals for both cell survival or apoptosis. The molecular mechanisms underlying the role of TGF-beta1 in apoptosis remains unclear.

Transforming growth factor beta1 overexpression in the nigrostriatal system increases the dopaminergic deficit of MPTP mice.

Idiopathic Parkinson's disease (PD) is characterized by mesencephalic dopaminergic neuron cell death and striatal dopamine (DA) depletion. The factors involved in the pathogenesis of the disease are still unknown. Transforming growth factor beta1 (TGFbeta1) is increased in the striatum of patients with PD.

Inducible cAMP early repressor, an endogenous antagonist of cAMP responsive element-binding protein, evokes neuronal apoptosis in vitro.

Active CREB (cAMP responsive element-binding protein) transcription factor is crucial for neuronal survival. Several members of the CREM/ICER (cAMP responsive element modulator/inducible cAMP early repressor) protein family may act as endogenous CREB antagonists. However, their involvement in a process of programmed cell death remains unexplored.