BDNF-TrkB signaling in striatopallidal neurons controls inhibition of locomotor behaviour

The physiology of brain-derived neurotrophic factor signaling in enkephalinergic striatopallidal neurons is poorly understood. Changes in cortical Bdnf expression levels, and/or impairment in brain-derived neurotrophic factor anterograde transport induced by mutant huntingtin (mHdh) are believed to cause striatopallidal neuron vulnerability in early-stage Huntington’s disease. Although several studies have confirmed a link between altered cortical brain-derived neurotrophic factor signaling and striatal vulnerability, it is not known whether the effects are mediated via the brain-derived neurotrophic factor receptor TrkB, and whether they are direct or indirect. Using a novel genetic mouse model, here, we show that selective removal of brain-derived neurotrophic factor–TrkB signaling from enkephalinergic striatal targets unexpectedly leads to spontaneous and drug-induced hyperlocomotion. This is associated with dopamine D2 receptor-dependent increased striatal protein kinase C and MAP kinase activation, resulting in altered intrinsic activation of striatal enkephalinergic neurons. Therefore, brain-derived neurotrophic factor/TrkB signaling in striatopallidal neurons controls inhibition of locomotor behavior by modulating neuronal activity in response to excitatory input through the protein kinase C/MAP kinase pathway

Derangement of Ras-Guanine Nucleotide-Releasing Factor 1 (Ras-GRF1) and Extracellular Signal-Regulated Kinase (ERK) Dependent Striatal Plasticity in L-DOPA-Induced Dyskinesia

BACKGROUND: Bidirectional long-term plasticity at the corticostriatal synapse has been proposed as a central cellular mechanism governing dopamine-mediated behavioral adaptations in the basal ganglia system. Balanced activity of medium spiny neurons (MSNs) in the direct and the indirect pathways is essential for normal striatal function. This balance is disrupted in Parkinson's disease and in L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), a common motor complication of current pharmacotherapy of Parkinson's disease. METHODS: Electrophysiological recordings were performed in mouse cortico-striatal slice preparation. Synaptic plasticity, such as long-term potentiation (LTP) and depotentiation, was investigated. Specific pharmacological inhibitors or genetic manipulations were used to modulate the Ras-extracellular signal-regulated kinase (Ras-ERK) pathway, a signal transduction cascade implicated in behavioral plasticity, and synaptic activity in different subpopulations of striatal neurons was measured. RESULTS: We found that the Ras-ERK pathway, is not only essential for long-term potentiation induced with a high frequency stimulation protocol (HFS-LTP) in the dorsal striatum, but also for its reversal, synaptic depotentiation. Ablation of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a neuronal activator of Ras proteins, causes a specific loss of HFS-LTP in the medium spiny neurons in the direct pathway without affecting LTP in the indirect pathway. Analysis of LTP in animals with unilateral 6-hydroxydopamine lesions (6-OHDA) rendered dyskinetic with chronic L-DOPA treatment reveals a complex, Ras-GRF1 and pathway-independent, apparently stochastic involvement of ERK. CONCLUSIONS: These data not only demonstrate a central role for Ras-ERK signaling in striatal LTP, depotentiation, and LTP restored after L-DOPA treatment but also disclose multifaceted synaptic adaptations occurring in response to dopaminergic denervation and pulsatile administration of L-DOPA

Transient developmental imbalance of cortical interneuron subtypes presages long-term changes in behavior

Cortical GABAergic interneurons are generated in large numbers in the ganglionic eminences and migrate into the cerebral cortex during embryogenesis. At early postnatal stages, during neuronal circuit maturation, autonomous and activity-dependent mechanisms operate within the cortex to adjust cell numbers by eliminating naturally occurring neuron excess. Here, we show that when cortical interneurons are generated in aberrantly high numbers—due to a defect in precursor cell proliferation during embryogenesis—extra parvalbumin interneurons persist in the postnatal mouse cortex during critical periods of cortical network maturation. Even though cell numbers are subsequently normalized, behavioral abnormalities remain in adulthood. This suggests that timely clearance of excess cortical interneurons is critical for correct functional maturation of circuits that drive adult behavior

Mechanisms underlying the impairment of hippocampal long-term potentiation and memory in experimental Parkinson's disease

Although patients with Parkinson's disease show impairments in cognitive performance even at the early stage of the disease, the synaptic mechanisms underlying cognitive impairment in this pathology are unknown. Hippocampal long-term potentiation represents the major experimental model for the synaptic changes underlying learning and memory and is controlled by endogenous dopamine. We found that hippocampal long-term potentiation is altered in both a neurotoxic and transgenic model of Parkinson's disease and this plastic alteration is associated with an impaired dopaminergic transmission and a decrease of NR2A/NR2B subunit ratio in synaptic N-methyl-d-aspartic acid receptors. Deficits in hippocampal-dependent learning were also found in hemiparkinsonian and mutant animals. Interestingly, the dopamine precursor l-DOPA was able to restore hippocampal synaptic potentiation via D1/D5 receptors and to ameliorate the cognitive deficit in parkinsonian animals suggesting that dopamine-dependent impairment of hippocampal long-term potentiation may contribute to cognitive deficits in patients with Parkinson's disease

Targeting NR2A-containing NMDA receptors reduces L-DOPA-induced dyskinesias

Levodopa (L-DOPA)-induced dyskinesias represent the main side effect of the therapeutic strategy clinically used in Parkinson's disease (PD) treatment. The first beneficial "honeymoon" phase of L-DOPA therapy is followed by a phase of deterioration in which L-DOPA administration causes motor fluctuations in the drug efficacy ("on-off" state) and dyskinesias. Alterations of the composition and function of N-methyl-D-aspartate (NMDA) receptor represent one of the main causes for the striatal synaptic changes described in experimental model of dyskinesias. In the present study, the modulation of the composition of synaptic NMDA receptor by using a cell-permeable peptide targeting NR2A subunit during the development of dyskinesias led to a reduction of the percentage of parkinsonian rats developing dyskinetic movements

Dopamine-dependent long-term depression is expressed in striatal spiny neurons of both direct and indirect pathways: implications for Parkinson's disease

Striatal medium spiny neurons (MSNs) are divided into two subpopulations exerting distinct effects on motor behavior. Transgenic mice carrying bacterial artificial chromosome (BAC) able to confer cell type-specific expression of enhanced green fluorescent protein (eGFP) for dopamine (DA) receptors have been developed to characterize differences between these subpopulations. Analysis of these mice, in contrast with original pioneering studies, showed that striatal long-term depression (LTD) was expressed in indirect but not in the direct pathway MSNs. To address this mismatch, we applied a new approach using combined BAC technology and receptor immunohistochemistry. We demonstrate that, in physiological conditions, DA-dependent LTD is expressed in both pathways showing that the lack of synaptic plasticity found in D(1) eGFP mice is associated to behavioral deficits. Our findings suggest caution in the use of this tool and indicate that the "striatal segregation" hypothesis might not explain all synaptic dysfunctions in Parkinson's disease

D1 and NMDA receptor interplay in physiological and pathological conditions : focus on Parkinson's disease

Functional and structural interactions between D1 receptor (D1R) and NMDA receptor (NMDAR) have been shown to play a critical role in many functions of the brain. Interestingly, when these subtle interactions become abnormal, they might contribute to several diseases.Here we show that prolonged activation of D1R by SKF 38393 is able, in vitro as well as in vivo, to significantly reduce the quantity of NR2A subunit at the postsynaptic site. Interestingly, this molecular effect was in agreement with the reduction in the NMDA-AMPA ratio and specifically in NMDA(NR2A)-AMPA ratio as demonstrated by electrophysiological recordings. Considering the effect of this pharmacological approach on the NMDA subunit composition, we used SKF38393 in a model of \u201cearly\u201d Parkinson's Disease (PD), the so called \u201cpartial lesion\u201d model. In this condition, mild motor impairments were observed, compared to the more severe alterations occurring in the full lesion model. In addition, in corticostriatal slices recorded from partial lesioned animals (PL) a lack of Long Term Potentiation (LTP) was found, as well as a strong increase in the NR2A subunit abundance at the postsynaptic site. In the attempt to restore synaptic plasticity in PL, SKF38393 was administered in vivo. Surprisingly, the treatment successfully restored LTP in striatal neurons, by reducing the NR2A subunit levels at the postsynaptic site and it improved the motor performances. Finally, in order to avoid the typical side effects deriving from the dopaminergic treatment in PD, we used an alternative tool able to mimic the effect of the D1 agonist on the NMDAR subunit composition. To this end, we directly targeted NMDAR via a cell permeable peptide, TAT2A, acting towards the interruption of the NR2A subunit delivery to the NMDAR complex. Notably, TAT2A determined a significant improvement in motor behaviour and it rescued LTP thus representing a new therapeutic strategy in P