DALTON SURMEIER

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..These studies also suggest that, although genetic and environmental factors can hasten its onset, Parkinson's disease stems from a distinctive neuronal design common to all human beings, making its appearance simply a matter of time...

..The review explores the literature on these issues and their translational implications...

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..These findings call for a fundamental reevaluation of the long-standing view that dopamine and acetylcholine "feud" over control of striatal circuitry...

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..These studies have also shown that long-term alterations in dopamine signaling produce profound and cell-type-specific reshaping of corticostriatal connectivity and function...

..in this issue of Neuron demonstrate that Ca2+ influx through L-type channels elevates dopamine synthesis to potentially toxic levels in vulnerable ventral mesencephalon neurons...

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..show that this modest overexpression of alpha-synuclein does not lead to obvious toxicity in the near term, but impairs glutamate and dopamine release, potentially leading to broad network dysfunction and eventual pathology...

..These tools also have enabled a rapid expansion of our understanding of the striatal adaptations in models of Parkinson's disease. This chapter highlights some of the major advances in these areas...

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..Such blocking ('rejuvenation') protects these neurons in both in vitro and in vivo models of Parkinson's disease, pointing to a new strategy that could slow or stop the progression of the disease...

..Their decades-long track record of safe use in the treatment of hypertension makes dihydropyridines particularly attractive as a therapeutic tool in PD...

..Together, these results suggest that normally D(2) MSN dendrites are more excitable than those of D(1) MSNs and that DA depletion exaggerates this asymmetry, potentially contributing to adaptations in PD models...

..Taken together, these studies establish a translational framework within which striatal adaptations linked to the symptoms of Parkinson's disease can be explored...

..Moreover, this recurrent collateral network appears to be disrupted in Parkinson's disease models, potentially contributing to pathological alterations in MSN activity patterns and psychomotor symptoms...

..In models of Parkinson's disease, this system is thrown out of balance, leading to unidirectional changes in plasticity that could underlie network pathology and symptoms...

..3 L-type Ca(2+) channels. The disconnection of striatopallidal neurons from motor command structures is likely to be a key step in the emergence of pathological activity that is responsible for symptoms in Parkinson disease...

..In addition to reconciling discordant tracts of the striatal literature, these findings point to cholinergic interneurons as key mediators of dopamine-dependent striatal plasticity and learning...

..We conclude with a discussion of potential therapeutic strategies for slowing the progression of PD...

..This differential regulation of the corticostriatal circuitry provides a neural substrate for attentional shifts and cessation of ongoing motor activity with the appearance of salient environmental stimuli...

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..Thus, rather than being an intrinsically homogenous population, striatal MSNs have dichotomous somatodendritic properties that mirror differences in their network connections and biochemistry...

..These observations suggest that RGS4-dependent attenuation of interneuronal autoreceptor signaling is a major factor in the elevation of striatal acetylcholine release in Parkinson disease...

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..This cell type-specific enhancement of dendritic excitability is an essential trigger for synaptic pruning after dopamine depletion, as pruning was prevented by genetic deletion of M1 muscarinic receptors...

..Our model provides a conceptual framework for understanding the functional significance of the short-term neuromodulatory actions of dopamine on signal processing in the striatum...

..Together, these results suggest that Shank promotes the assembly of a signaling complex at corticostriatal synapses that enables key GPCRs to regulate L-type Ca2+ channels and the integration of glutamatergic synaptic events...

..The results offer new insights into the workings of these clinically important yet mysterious neurons...

..This process is strictly associated with neuronal activity and develops over seconds, endowing neurons with a novel form of cellular plasticity shaping synaptic integration, dendritic electrogenesis, and repetitive discharge...

..3 L-type Ca2+ channels in pCREB signaling...

..2 L-type Ca(2+) currents. This modulation and its blockade by atypical neuroleptics could have wide-ranging effects on synaptic integration and long-term gene expression in deep-layer prefrontal pyramidal neurons...

..Together the data demonstrate that HCN channels in STN neurons selectively counteract GABA(A) receptor-mediated inhibition arising from the globus pallidus and thus promote single-spike activity rather than rebound burst firing...

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..6 Na+ channels with prominent resurgent gating...

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..3 channels play a more important role in pCREB signaling in striatal medium spiny neurons than in hippocampal neurons. Our results provide novel insights into the function of CaV1.2 and CaV1.3 L-type Ca2+ channels in the brain...

..These studies establish a cellular mechanism linking dopamine and the reduction in striatal cholinergic interneuron activity seen in the initial stages of associative learning...

..Why this strategy works is unclear. The work by Do and Bean shows that the Na channels in STN neurons have distinctive features--like resurgence--that regulate their spiking behavior, providing new insights into the mechanism of DBS...

..3 selectivity was only about twofold. These results support a highly similar dihydropyridine binding site at both Ca(V)1.2 and Ca(V)1.3 channels and suggests that other classes of compounds need to be identified for Ca(V)1.3 selectivity...

..These results implicate RGS9-2 as a specific regulator of dopamine receptor-mediated signaling in the striatum and identify a role for GAP activity modulation by the DEP-GGL domain...

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..These studies show that HCN channels are key regulators of synaptic integration in prefrontal pyramidal neurons but that their functional contribution is dependent on a partnership with Kir2 and Kleak channels...

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..These studies establish a clear functional role for somato-dendritic Kv1.2 channels in the regulation of state transitions and repetitive discharge in striatal medium spiny neurons...

..In the rostral ventral respiratory group (immediately caudal to preBötC), I(NaP) was also detected, but peak conductance, current density, and input resistance were smaller than in preBötC region cells...

..These observations suggest that feedback inhibition from the GP is critical for the emergence of coherent beta-oscillations between the cortex and STN in PD...

..Several of these deficits are delayed and age-dependent. Our study thus links spine morphogenic signaling with age-dependent, delayed, disease-related phenotypes, including cognitive dysfunction...

..These results suggest that manipulation of K3.4 subunit expression could be a useful means of controlling the dynamic range of FS neurons...

..These findings show that 5-HT2a,c receptor activation reduces dendritic excitability and may negatively modulate activity-dependent dendritic synaptic plasticity...

..Because I(h) expression is altered in models of several diseases, including temporal lobe epilepsy, TRIP8b may play a role in both normal neuronal function and in aberrant neuronal excitability associated with neurological disease...

..Therapeutic strategies based upon insights gained with these tools during the last grant period already have been tested in preclinical studies and yielded encouraging results, providing a strong motivation for continued study. ..

..Therapeutic strategies based upon insights gained with these tools during the last grant period already have been tested in preclinical studies and yielded encouraging results, providing a strong motivation for continued study. ..

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..Achieving these specific aims will provide the molecular and cellular framework necessary to begin building an accurate, integrative model of PFC function and dysfunction in schizophrenia. ..

..Particular emphasis will be placed on obtaining a diverse group of fellows with respect to parent institution, gender, and minority status. ..

..The program outlined attempts to exemplify the multidisciplinary and interactive type of neuroscience research training encouraged by NINDS. ..

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..Therapeutic strategies based upon insights gained with these tools during the last grant period already have been tested in preclinical studies and yielded encouraging results, providing a strong motivation for continued study. ..

..In so doing, it should open the door to the development of novel and powerful therapeutic strategies not only for Parkinson's disease but other disorders with neostriatal determinants such as schizophrenia. ..