Converging sensory and motor cortical inputs onto the same striatal neurons: An in vivo intracellular investigation.

The striatum is involved in the completion and optimization of sensorimotor tasks. In rodents, its dorsolateral part receives converging glutamatergic corticostriatal (CS) inputs from whisker-related primary somatosensory (S1) and motor (M1) cortical areas, which are interconnected at the cortical level. Although it has been demonstrated that the medium-spiny neurons (MSNs) from the dorsolateral striatum process sensory information from the whiskers via the S1 CS pathway, the functional impact of the corresponding M1 CS inputs onto the same striatal neurons remained unknown. Here, by combining in vivo S1 electrocorticogram with intracellular recordings from somatosensory MSNs in the rat, we first confirmed the heterogeneity of striatal responsiveness to whisker stimuli, encompassing MSNs responding exclusively by subthreshold synaptic depolarizations, MSNs exhibiting sub- and suprathreshold responses over successive stimulations, and non-responding cells. All recorded MSNs also exhibited clear-cut monosynaptic depolarizing potentials in response to electrical stimulations of the corresponding ipsilateral M1 cortex, which were efficient to fire striatal cells. Since M1-evoked responses in MSNs could result from the intra-cortical recruitment of S1 CS neurons, we performed intracellular recordings of S1 pyramidal neurons and compared their firing latency following M1 stimuli to the latency of striatal synaptic responses. We found that the onset of M1-evoked synaptic responses in MSNs significantly preceded the firing of S1 neurons, demonstrating a direct synaptic excitation of MSNs by M1. However, the firing of MSNs seemed to require the combined excitatory effects of S1 and M1 CS inputs. This study directly demonstrates that the same somatosensory MSNs can process excitatory synaptic inputs from two functionally-related sensory and motor cortical regions converging into the same striatal sector. The effectiveness of these convergent cortical inputs in eliciting action potentials in MSNs may represent a key mechanism of striatum-related sensorimotor behaviors.

Origins of basal ganglia output signals in singing juvenile birds.

Across species, complex circuits inside the basal ganglia (BG) converge on pallidal output neurons that exhibit movement-locked firing patterns. Yet the origins of these firing patterns remain poorly understood. In songbirds during vocal babbling, BG output neurons homologous to those found in the primate internal pallidal segment are uniformly activated in the tens of milliseconds prior to syllable onsets. To test the origins of this remarkably homogenous BG output signal, we recorded from diverse upstream BG cell types during babbling. Prior to syllable onsets, at the same time that internal pallidal segment-like neurons were activated, putative medium spiny neurons, fast spiking and tonically active interneurons also exhibited transient rate increases. In contrast, pallidal neurons homologous to those found in primate external pallidal segment exhibited transient rate decreases. To test origins of these signals, we performed recordings following lesion of corticostriatal inputs from premotor nucleus HVC. HVC lesions largely abolished these syllable-locked signals. Altogether, these findings indicate a striking homogeneity of syllable timing signals in the songbird BG during babbling and are consistent with a role for the indirect and hyperdirect pathways in transforming cortical inputs into BG outputs during an exploratory behavior.

Integration and propagation of somatosensory responses in the corticostriatal pathway: an intracellular study in vivo.

The dorsolateral striatum is critically involved in the execution and learning of sensorimotor tasks. It is proposed that this striatal function is achieved by the integration of convergent somatosensory and motor corticostriatal (CS) inputs in striatal medium-spiny neurons (MSNs). However, the cellular mechanisms of integration and propagation of somatosensory information in the CS pathway remain unknown. Here, by means of in vivo intracellular recordings in the rat, we analysed how sensory events generated by multi-whisker deflection, which provide essential somaesthetic information in rodents, are processed in contralateral barrel cortex layer 5 neurons and in the related somatosensory striatal MSNs. Pyramidal layer 5 barrel cortex neurons, including neurons antidromically identified as CS, responded to whisker deflection by depolarizing post-synaptic potentials that could reliably generate action potential discharge. In contrast, only half of recorded somatosensory striatal MSNs displayed whisker-evoked synaptic depolarizations that were effective in eliciting action potentials in one-third of responding neurons. The remaining population of MSNs did not exhibit any detectable electrical events in response to whisker stimulation. The relative inconstancy of sensory-evoked responses in MSNs was due, at least in part, to a Cl(-)-dependent membrane conductance concomitant with the cortical inputs,which was probably caused by whisker-induced activation of striatal GABAergic interneurons. Our results suggest that the propagation of whisker-mediated sensory flow through the CS pathway results in a refinement of sensory information in the striatum, which might allow the selection of specific sets of MSNs that are functionally significant during a given somaesthetic-guided behaviour.

DLG1/SAP97 modulates transforming growth factor alpha bioavailability.

TGFalpha and its receptor EGFR participate in the development of a wide range of tumors including gliomas, the main adult primary brain tumors. TGFalpha soluble form results from the cleavage by the metalloprotease TACE/ADAM17 of the extracellular part of its transmembrane precursor, pro-TGFalpha. To gain insights into the mechanisms underlying TGFalpha bioavailability, a yeast two-hybrid screen was performed to identify proteins interacting with pro-TGFalpha intracellular domain (ICD). DLG1/SAP97 (Discs Large Gene 1 or Synapse Associated Protein 97) was found to interact with both pro-TGFalpha and TACE ICDs through distinct PDZ domains. An in vivo pro-TGFalpha-DLG1-TACE complex was detected in U251 glioma cells and in gliomas-derived tumor initiating cells. Interaction between DLG1 and TACE diminished in response to stimulations promoting pro-TGFalpha shedding. Manipulation of DLG1 levels revealed dual actions of DLG1 on pro-TGFalpha shedding, favoring approximation of pro-TGFalpha and TACE, while limiting TACE full shedding activity. These results show that DLG1 participates in the control of TGFalpha bioavailability through its dynamic interaction with the growth factor precursor and TACE.