A mouse model of the schizophrenia-associated 1q21.1 microdeletion syndrome exhibits altered mesolimbic dopamine transmission.

1q21.1 hemizygous microdeletion is a copy number variant leading to eightfold increased risk of schizophrenia. In order to investigate biological alterations induced by this microdeletion, we generated a novel mouse model (Df(h1q21)/+) and characterized it in a broad test battery focusing on schizophrenia-related assays.

Effects of exogenous alpha-synuclein on stimulated dopamine overflow in dorsal striatum.

Alpha-synuclein (α-syn) is mainly a presynaptic protein that has been implicated in Parkinson's disease and various other neurodegenerative disorders. Evidence obtained in knockout mice suggests that α-syn controls plasticity of dopamine (DA) overflow in presynaptic terminals. It is also believed that α-syn spreads and may seed its aggregates from cell to cell.

Characterization of a 32 μm diameter carbon fiber electrode for in vivo fast-scan cyclic voltammetry.

Carbon fiber electrodes (CFE) are commonly used for in vivo detection of catecholamines due to their excellent electrochemical properties and biocompatibility. Fast-scan cyclic voltammetry (FSCV) combined with CFEs permits the detection of catecholamines such as dopamine (DA) with high specificity and reliability. However, advances in neuroscience constantly demand sensors with greater sensitivities and selectivities.

Methylphenidate modifies overflow and presynaptic compartmentalization of dopamine via an α-synuclein-dependent mechanism.

Methylphenidate (MPD) modulates dopamine (DA) overflow in part by redistributing vesicle pools, a function shared by the presynaptic protein α-synuclein (α-syn). We suggest that α-syn modifies the effect of MPD on DA neurotransmission. The effect was studied in the dorsal striatum in wild-type mice and two mouse lines lacking α-syn by using in vivo voltammetry and microdialysis.

Sub-regional differences and mechanisms of the short-term plasticity of dopamine overflow in striatum in mice lacking alpha-synuclein.

Mice lacking the pre-synaptic protein alpha-synuclein (α-syn) demonstrate enhanced facilitation of dopamine (DA) overflow in dorsal striatum following repeated, high-frequency burst stimulation of the dopaminergic pathways. Dorsal striatum is most vulnerable to neurodegeneration in Parkinson's disease. The role of α-syn in facilitation of DA overflow in the ventral striatum, which is less vulnerable to neurodegeneration, is unknown.

Dynamic regulation of dopamine and serotonin responses to salient stimuli during chronic haloperidol treatment.

Antipsychotic drugs are the clinical standard for the treatment of schizophrenia. Although these drugs work initially, many compliant patients relapse due to treatment failure. The known biomarkers can not sufficiently explain antipsychotic treatment failure.

Decreased reuptake of dopamine in the dorsal striatum in the absence of α-synuclein.

The presynaptic protein alpha-synuclein (α-syn) plays a role in dopaminergic neurotransmission in the nigrostriatal dopaminergic system. Mutations in this protein have been linked to pathogenesis of Parkinson's disease. However, the details of regulation of dopamine homeostasis by α-syn and its molecular targets are generally unknown.

Neuromuscular pathology in mice lacking alpha-synuclein.

This work was undertaken in order to study the possible role of alpha-synuclein in the function of the neuro-muscular junction in skeletal muscles. Repeated stimulation of skeletal muscle motor neurons revealed signs of neuromuscular pathology in alpha-synuclein null mutated (C57Bl/6JOlaHsd) and knockout (B6;129X1-Snca(tm1Rosl)/J) mice. This stimulation produced repetitive compound muscle action potentials in both lines of alpha-synuclein deficient mice.

Stimulated dopamine overflow and alpha-synuclein expression in the nucleus accumbens core distinguish rats bred for differential ethanol preference.

The key neurochemical systems and structures involved in the predisposition to substance abuse and preference to ethanol (EtOH) are not known in detail but clearly dopamine (DA) is an important modulator of addiction. Recent data indicate that alpha-synuclein (alpha-syn), a pre-synaptic protein, plays a role in regulation of DA release from the pre-synaptic terminals in striatum and the expression of this protein is different after drug abuse or following abstinence. In the present work, we analysed stimulated DA overflow in the dorsal and ventral striatum in EtOH naïve alko alchohol (AA) and alko non-alchohol (ANA) rats selected for more than 100 generations for their differential EtOH preference.

Behavioural and neurochemical response of alpha-synuclein A30P transgenic mice to the effects of L-DOPA.

Transgenic mice carrying human A30P mutated alpha-synuclein demonstrate hypolocomotion and dysfunction of the presynaptic machinery of dopamine overflow, induced by reducing capacity of the dopamine storage pool. We suggested that overexpression of alpha-synuclein may change sensitivity of these mice to L-DOPA. Current study assessed behavioural and neurochemical responses in A30P mice to L-DOPA using automated activity monitoring and voltammetry.

Characterization of the striatal dopaminergic neurotransmission in MEN2B mice with elevated cerebral tissue dopamine.

The Ret receptor tyrosine kinase is the common signaling receptor for the glial cell line-derived neurotrophic factor (GDNF) family ligands. The Met918Thr mutation leads to constitutive activation of Ret and is responsible for dominantly inherited cancer syndrome MEN2B. Previously, we found that the mice carrying the mutation (MEN2B mice) have profoundly increased tissue dopamine (DA) concentrations in the striatum as well as increased striatal levels of tyrosine hydroxylase (TH) and dopamine transporter.

Site-specific role of catechol-O-methyltransferase in dopamine overflow within prefrontal cortex and dorsal striatum.

Accumulating evidence from clinical and preclinical studies shows that catechol-O-methyltransferase (COMT) plays a significant role in dopamine metabolism in the prefrontal cortex, but not in the striatum. However, to what extent dopamine overflow in the prefrontal cortex and striatum is controlled by enzymatic degradation versus reuptake is unknown. We used COMT deficient mice to investigate the role of COMT in these two brain regions with in vivo voltammetry.

Mechanics of self-stimulation and dopamine release in the nucleus accumbens.

Robust self-stimulation can be obtained from electrodes implanted in the medial forebrain bundle. We used in-vivo voltammetry to monitor stimulated dopamine release in the mouse nucleus accumbens during implantation of the stimulating electrodes. The higher the level of stimulated dopamine release during electrode implantation, the lower was the threshold for self-stimulation and the shorter the duration of the stimulation train when it was controlled by animal.

Brain reward in the absence of alpha-synuclein.

Alpha-synuclein has been implicated in the pathophysiology of Parkinson's disease. Recent studies revealed its role as a negative regulator of dopamine release in the nigrostriatal dopaminergic system. Alpha-synuclein may, however, play a more universal role in dopaminergic neurotransmission.

Abnormal compartmentalization of norepinephrine in mouse dentate gyrus in alpha-synuclein knockout and A30P transgenic mice.

In the dentate gyrus of the mouse hippocampus, presynaptic recruitment of norepinephrine in response to repeated-burst stimulation can be described in terms of an interaction between storage and readily releasable pools. The dynamics of this interaction depends on neuronal activity (bursting), so that the higher the demand for norepinephrine, the faster it is delivered from the storage pool. We also found that alpha-synuclein, a presynaptic protein that plays a crucial role in dopamine compartmentalization in the striatum, is also involved in the compartmentalization of norepinephrine in the dentate gyrus.

Noradrenaline overflow in mouse dentate gyrus following locus coeruleus and natural stimulation: real-time monitoring by in vivo voltammetry.

The pattern of catecholaminergic innervation of the dentate gyrus (DG) of the hippocampus, particularly the relatively dense and selective noradrenergic input, creates favourable conditions for real-time monitoring of noradrenaline (NA) release following stimulation of the locus coeruleus (LC) by in vivo voltammetry. Two electrochemically active species with different temporal characteristics were registered in the DG following electrical stimulation of the LC. Several approaches, including testing of anatomical and pharmacological specificity, coating of microelectrodes with Nafion and use of fast cyclic voltammetry, were used to verify the characteristics of electrochemical responses.

Locomotor activity and evoked dopamine release are reduced in mice overexpressing A30P-mutated human alpha-synuclein.

We have generated a transgenic mouse line overexpressing mutated human A30P alpha-synuclein under the control of the prion-related protein promoter. Immunohistology revealed mutated human A30P alpha-synuclein protein in numerous brain areas, but no gross morphological changes, Lewy bodies, or loss of dopaminergic cell bodies. The transgenic mice displayed decreased locomotion, impaired motor coordination, and balance.

Role of alpha-synuclein in presynaptic dopamine recruitment.

Real-time monitoring of stimulated dopamine release in mice with different alpha-synuclein expression was used to study the role of alpha-synuclein in presynaptic dopamine recruitment. Repeated electrical stimulations of ascending dopaminergic pathways decreased the capacity of the readily releasable pool (RRP) and temporarily increased its refilling rate, significantly slowing the rate of dopamine decline in mice with normally expressed alpha-synuclein. Mice with alpha-synuclein null mutation demonstrated a permanent increase of the refilling rate.

Atipamezole, an alpha2-adrenoceptor antagonist, augments the effects of L-DOPA on evoked dopamine release in rat striatum.

The effects of atipamezole, an alpha(2)-adrenoceptor antagonist, L-3,4-dihydroxyphenylalanine (L-DOPA) and the combination of these drugs on dopamine overflow were studied in dopaminergic presynaptic terminals of rat caudate and nucleus accumbens. Dopamine overflow evoked by 100 pulses of electrical stimulation of the medial forebrain bundle at a low (20 Hz) and high (50 Hz) frequency was measured by in vivo voltammetry. L-DOPA (15 mg/kg) increased dopamine overflow in the caudate nucleus, but this dose had no effects in the nucleus accumbens.