Impairment of Macroautophagy in Dopamine Neurons Has Opposing Effects on Parkinsonian Pathology and Behavior.

Parkinson's disease (PD) is characterized by the death of dopamine neurons in the substantia nigra pars compacta (SNc) and accumulation of α-synuclein. Impaired autophagy has been implicated and activation of autophagy proposed as a treatment strategy. We generate a human α-synuclein-expressing mouse model of PD with macroautophagic failure in dopamine neurons to understand the interaction between impaired macroautophagy and α-synuclein.

Changes in SK channel expression in the basal ganglia after partial nigrostriatal dopamine lesions in rats: Functional consequences.

Parkinson's disease (PD) is a progressive neurodegenerative disease originating from the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNC). The small-conductance calcium-activated potassium (SK) channels play an essential role in the regulation of midbrain DA neuron activity patterns, as well as excitability of other types of neurons of the basal ganglia. We therefore questioned whether the SK channel expression in the basal ganglia is modified in parkinsonian rats and how this could impact behavioral performance in a reaction time task.

LRRK2 BAC transgenic rats develop progressive, L-DOPA-responsive motor impairment, and deficits in dopamine circuit function.

Mutations in leucine-rich repeat kinase 2 (LRRK2) lead to late-onset, autosomal dominant Parkinson's disease, characterized by the degeneration of dopamine neurons of the substantia nigra pars compacta, a deficit in dopamine neurotransmission and the development of motor and non-motor symptoms. The most prevalent Parkinson's disease LRRK2 mutations are located in the kinase (G2019S) and GTPase (R1441C) encoding domains of LRRK2. To better understand the sequence of events that lead to progressive neurophysiological deficits in vulnerable neurons and circuits in Parkinson's disease, we have generated LRRK2 bacterial artificial chromosome transgenic rats expressing either G2019S or R1441C mutant, or wild-type LRRK2, from the complete human LRRK2 genomic locus, including endogenous promoter and regulatory regions.

Bee Venom Alleviates Motor Deficits and Modulates the Transfer of Cortical Information through the Basal Ganglia in Rat Models of Parkinson's Disease.

Recent evidence points to a neuroprotective action of bee venom on nigral dopamine neurons in animal models of Parkinson's disease (PD). Here we examined whether bee venom also displays a symptomatic action by acting on the pathological functioning of the basal ganglia in rat PD models. Bee venom effects were assessed by combining motor behavior analyses and in vivo electrophysiological recordings in the substantia nigra pars reticulata (SNr, basal ganglia output structure) in pharmacological (neuroleptic treatment) and lesional (unilateral intranigral 6-hydroxydopamine injection) PD models.

SK channel blockade reverses cognitive and motor deficits induced by nigrostriatal dopamine lesions in rats.

Parkinson's disease has traditionally been viewed as a motor disorder caused by the loss of dopamine (DA) neurons. However, emotional and cognitive syndromes can precede the onset of the motor deficits and provide an opportunity for therapeutic intervention. Potassium channels have recently emerged as potential new targets in the treatment of Parkinson's disease.

Region-specific deficits in dopamine, but not norepinephrine, signaling in a novel A30P α-synuclein BAC transgenic mouse.

Parkinson's disease (PD) is a neurodegenerative disorder classically characterized by the death of dopamine (DA) neurons in the substantia nigra pars compacta and by intracellular Lewy bodies composed largely of α-synuclein. Approximately 5-10% of PD patients have a familial form of Parkinsonism, including mutations in α-synuclein. To better understand the cell-type specific role of α-synuclein on DA neurotransmission, and the effects of the disease-associated A30P mutation, we generated and studied a novel transgenic model of PD.

Deficits in dopaminergic transmission precede neuron loss and dysfunction in a new Parkinson model.

The pathological end-state of Parkinson disease is well described from postmortem tissue, but there remains a pressing need to define early functional changes to susceptible neurons and circuits. In particular, mechanisms underlying the vulnerability of the dopamine neurons of the substantia nigra pars compacta (SNc) and the importance of protein aggregation in driving the disease process remain to be determined. To better understand the sequence of events occurring in familial and sporadic Parkinson disease, we generated bacterial artificial chromosome transgenic mice (SNCA-OVX) that express wild-type α-synuclein from the complete human SNCA locus at disease-relevant levels and display a transgene expression profile that recapitulates that of endogenous α-synuclein.

A novel selective metabotropic glutamate receptor 4 agonist reveals new possibilities for developing subtype selective ligands with therapeutic potential.

Metabotropic glutamate (mGlu) receptors are promising targets to treat numerous brain disorders. So far, allosteric modulators are the only subtype selective ligands, but pure agonists still have strong therapeutic potential. Here, we aimed at investigating the possibility of developing subtype-selective agonists by extending the glutamate-like structure to hit a nonconsensus binding area.

Characterization of 5-HT(1A/1B)-/- mice: an animal model sensitive to anxiolytic treatments.

Selective serotonin (5-HT) re-uptake inhibitors (SSRIs) are commonly used in the treatment of generalized anxiety disorder in Humans. However, because only few animal models display overt anxious-like behavior, detailed preclinical studies of the anxiolytic properties of antidepressants are still lacking. Here, we studied the neurochemical and behavioral effects of a double 5-HT(1A/1B) receptor knockout in mice (5-HT(1A/1B)-/-) as compared to their wild-type littermates (5-HT(1A/1B)+/+).

Synergistic neurochemical and behavioural effects of acute intrahippocampal injection of brain-derived neurotrophic factor and antidepressants in adult mice.

Preclinical data support the view that brain-derived neurotrophic factor (BDNF) and serotonergic systems regulate circuits involved in affective disorders. The present study examined neurochemical and behavioural consequences of an acute intrahippocampal injection of BDNF combined with an antidepressant by using in-vivo intracerebral microdialysis in the ventral hippocampus (vHi) in conscious mice and behavioural paradigms predictive of antidepressant and anxiolytic-like effects [the mouse forced swim test (FST), the open-field (OF) paradigm and the elevated plus maze (EPM)]. Neurochemical data revealed that BDNF (100 ng) potentiated the effects of the systemic administration of a serotonin selective reuptake inhibitor (SSRI; paroxetine 4 mg/kg i.

Interplay of beta2* nicotinic receptors and dopamine pathways in the control of spontaneous locomotion.

Acetylcholine (ACh) is a known modulator of the activity of dopaminergic (DAergic) neurons through the stimulation of nicotinic ACh receptors (nAChRs). Yet, the subunit composition and specific location of nAChRs involved in DA-mediated locomotion remain to be established in vivo. Mice lacking the beta2 subunit of nAChRs (beta2KO) display striking hyperactivity in the open field, which suggests an imbalance in DA neurotransmission.

Influence of brain-derived neurotrophic factor (BDNF) on serotonin neurotransmission in the hippocampus of adult rodents.

Whereas SSRIs produce rapid blockade of the serotonin transporter (SERT) in vitro and in vivo, the onset of an observable clinical effect takes longer to occur and a variety of pharmacological effects caused by antidepressants have been speculated to be involved either in initiating antidepressant effects and/or enhancing their effects on serotonergic transmission so as to cause clinical improvement. Among such secondary factors is increased activity of brain-derived neurotrophic factor (BDNF), which requires the Tropomyosine-related kinase B receptor (TrkB) for its effects. To begin an analysis of the influence of BDNF on serotonergic activity, we studied the acute effects of BDNF on SERT activity.

Consequences of changes in BDNF levels on serotonin neurotransmission, 5-HT transporter expression and function: studies in adult mice hippocampus.

In vivo intracerebral microdialysis is an important neurochemical technique that has been applied extensively in genetic and pharmacological studies aimed at investigating the relationship between neurotransmitters. Among the main interests of microdialysis application is the infusion of drugs through the microdialysis probe (reverse dialysis) in awake, freely moving animals. As an example of the relevance of intracerebral microdialysis, this review will focus on our recent neurochemical results showing the impact of Brain-Derived Neurotrophic Factor (BDNF) on serotonergic neurotransmission in basal and stimulated conditions.

Brain-derived neurotrophic factor-deficient mice exhibit a hippocampal hyperserotonergic phenotype.

Growing evidence supports the involvement of brain-derived neurotrophic factor (BDNF) in mood disorders and the mechanism of action of antidepressant drugs. However, the relationship between BDNF and serotonergic signalling is poorly understood. Heterozygous mutants BDNF +/- mice were utilized to investigate the influence of BDNF on the serotonin (5-HT) system and the activity of the serotonin transporter (SERT) in the hippocampus.