Cellular/Molecular
LAR-Like Receptor Tyrosine Kinases in C. elegans
Brian D. Ackley, Robert J. Harrington, Martin L. Hudson, Lisa Williams, Cynthia J. Kenyon, Andrew D. Chisholm, and Yishi Jin
(see pages 7517-7528)
Receptor protein tyrosine phosphatases include the leukocyte-common antigen related (LAR) family of cell adhesion molecules. In Caenorhabditis elegans, the LAR-like gene ptp-3 encodes two distinct isoforms, PTP-3A and PTP-3B. Compared with PTP-3A, the extracellular domain of PTP-3B lacks the Ig-like domain and the first four fibronectin type III repeats, but their intracellular domains are identical. This week, Ackley et al. delineate independent roles for these isoforms in axon guidance and synapse formation. They created isoform-specific green fluorescent protein fusion transgenes to determine expression patterns. Whereas PTP-3A overlapped with UNC-10 and SYD-2 at presynaptic sites, PTP-3B was expressed extrasynaptically in a temporally regulated pattern. The PTP-3 mutations mu256 and op147 exhibited axon projection defects that were rescued only by expression of PTP-3B. In contrast, synaptic defects in the mutants were rescued by PTP-3A expression. From genetic double-mutant analysis, the authors surmised that PTP-3A links the extracellular matrix protein nidogen and the intracellular adaptor α-liprin, perhaps stabilizing synapses.
Inhibition precedes excitation in Po cells when the ZI is intact. In this recording from a Po cell, whisker deflection evoked an IPSP followed by an EPSP. See the article by Lavallée et al. for details.
Development/Plasticity/Repair
Metaplasticity and CaMKII
Lian Zhang, Timo Kirschstein, Britta Sommersberg, Malte Merkens, Denise Manahan-Vaughan, Ype Elgersma, and Heinz Beck
(see pages 7697-7707)
The plasticity of synapses depends in part on their history of activity. This metaplasticity may enhance the dynamic range of synapses by preventing saturation of long-term potentiation (LTP) and long-term depression (LTD). Zhang et al. now define a role for Ca2+/calmodulin-dependent kinase II (CaMKII) in metaplasticity in the perforant path-dentate granule cell synapse. Low-frequency stimulation induced LTD, and higher frequencies induced LTP, whereas 10 Hz stimulation, perhaps the crossover point between these opposing changes, induced little change in basal transmission. However, a 10 Hz priming stimulation reduced LTP induction in the lateral perforant pathway without affecting LTD. The metaplasticity depended on NMDA receptor activation and on inhibitory autophosphorylation of CaMKII at Thr305/Thr306. Phosphorylation of this site interferes with the binding of calcium/calmodulin, unlike autophosphorylation at Thr286, which maintains CaMKII activity. The medial perforant pathway was unaffected by priming, perhaps because CaMKII is not required for induction of LTP in that pathway.
Behavioral/Systems/Cognitive
Incerting Inhibition into the Posterior Thalamic Nuclear Group
Philippe Lavallée, Nadia Urbain, Caroline Dufresne, Hajnalka Bokor, László Acsády, and Martin Deschênes
(see pages 7489-7498)
Sensory input typically results in robust excitation of neurons in first-order thalamic nuclei as that information is relayed to the neocortex. However, the story is different in thalamic association nuclei. For example, neurons in the rodent posterior thalamic nuclear group (Po) show weak responses to whisker deflection despite significant somatosensory input from the trigeminal complex. This week, Lavallée et al. chart out fast feedforward GABAergic inhibition mediated by neurons of the zona incerta (ZI). Whisker-responsive ZI neurons fired rapidly and provided shunting inhibition of Po neurons that in turn responded weakly if at all to peripheral stimuli. Excitotoxic lesioning of ZI removed the inhibitory inputs, unmasking excitatory responses in Po neurons. The inhibitory ZI input to Po precedes excitatory sensory input, thus allowing this paralemniscal pathway to forward information to the cortex only after disinhibition. The authors suggest that disinhibition is driven by motor instructions from the cortex, a so-called top-down mechanism.
Neurobiology of Disease
Reversing Rat Catalepsy with Subthalamic Stimulation
Bertrand Degos, Jean-Michel Deniau, Anne-Marie Thierry, Jacques Glowinski, Laurent Pezard, and Nicolas Maurice
(see pages 7687-7696)
The efficacy of clinical treatments can sometimes precede our understanding of the underlying mechanisms. High-frequency stimulation (HFS) of the subthalamic nucleus (STN) is such a case. It can improve symptoms in Parkinson's disease in ways that are only partly understood. In this week's Journal, Degos et al. tested subthalamic HFS in a rat model of acute dopamine receptor blockade. The authors monitored the firing of neurons in the basal ganglia output nucleus, the substantia nigra pars reticulata (SNR). Injection of the D1- and D2-type receptor antagonists SCH-23390 [R(+)- 7-chloro- 8-hydroxy- 3-methyl- 1-phenyl-2, 3, 4, 5, - tetrahydro - 1H- 3 - benzazepine] and raclopride produced cataplexy in the rats and disrupted the tonic regular firing pattern of SNR neurons, producing more irregular bursting. STN HFS rapidly reversed the drug-induced catalepsy. Some SNR neurons were inhibited, whereas others were activated. However, in all cases SNR firing was more regular and the averaged firing rate increased, suggesting that HFS in some ways restores a more normal activity pattern in the SNR.
