This Week in The Journal

Cellular/Molecular

Increased Vesicle Pool Size Supports Homeostatic Plasticity

Martin Müller, Karen Suk Yin Liu, Stephan Sigrist, and Graeme W. Davis

Neurons regulate their activity level, for example by increasing numbers of postsynaptic glutamate receptors after prolonged reduction in excitatory input. Such homeostatic processes can also act retrogradely across synapses: although inhibiting glutamate receptors at the Drosophila neuromuscular junction (NMJ) temporarily reduces the amplitude of spike-evoked EPSPs, the amplitude returns to baseline after several minutes because synaptic vesicle release increases. This presynaptic effect relies on increased calcium influx through voltage-gated calcium channels, as well as a new mechanism discovered by Müller and colleagues. Mutations in the rim gene—which encodes a Rab3-interacting molecule that is involved in clustering calcium channels and docking and priming synaptic vesicles—prevented retrograde homeostatic plasticity at the fly NMJ. Surprisingly, however, homeostatic increases in calcium influx still occurred in rim mutants. Instead, RIM loss impaired homeostatic plasticity by preventing an increase in the size of the readily releasable pool of vesicles, which occurred when glutamate receptors were inhibited in control flies.

Development/Plasticity/Repair

Reduced KCC2 Levels Increase Cortical Activity in Pain Model

Kei Eto, Hitoshi Ishibashi, Takeshi Yoshimura, Miho Watanabe, Akiko Miyamoto, et al.

(see pages 16552–16559)

Chronic pain can result from changes at multiple levels of the pain pathway, including sensitization of nociceptors, increased excitability of dorsal horn neurons, and increased activity in neurons of primary somatosensory cortex (S1). Eto and colleagues previously reported that increased excitatory input from cortical layer 4 (L4) increases the activity of L2/3 pyramidal neurons in a mouse model of chronic inflammatory pain. They now report that blocking GABAergic transmission in S1 further increased responses of L2/3 excitatory neurons, as well as further reducing pain thresholds. Conversely, enhancing GABAergic transmission increased pain thresholds to control levels. Although this suggests that reduced inhibition of L2/3 excitatory neurons contributes to chronic inflammatory pain, calcium imaging indicated that L2/3 inhibitory neurons were more active in the pain model than in control mice. Expression of the potassium–chloride cotransporter (KCC2) was reduced in S1 in the pain model, however, and therefore the Cl^– reversal potential of L2/3 excitatory neurons was more depolarized. As a result, these neurons were resistant to GABAergic inhibition.

Behavioral/Systems/Cognitive

Levodopa-Induced Cortical Oscillations Accompany Dyskinesia

Pär Halje, Martin Tamtè, Ulrike Richter, Mohsin Mohammed, M. Angela Cenci, et al.

(see pages 16541–16551)

Voluntary movements are controlled by a complex network involving motor cortex, basal ganglia, cerebellum, and brain stem nuclei. Loss of midbrain dopamine neurons in Parkinson's disease (PD) disrupts this network, impairing motor control. Motor symptoms can be attenuated by treatment with levodopa, but levodopa eventually produces abnormal involuntary movements (dyskinesia). How dopamine loss and levodopa treatment affect motor control circuitry remain poorly understood. Although most studies focus on the striatum, which is highly innervated by dopaminergic terminals, other parts of the motor control circuitry also receive dopaminergic projections. Projections to the motor cortex begin to degenerate early in PD, and Halje et al. suggest that this site is a primary driver of levodopa-induced dyskinesia. In a rat model, strong, synchronous 80 Hz oscillations emerged in local field potential recordings in the motor cortex in conjunction with levodopa-induced dyskinesia. Applying a dopamine receptor antagonist to the cortical surface caused proportional reductions in the power of these oscillations and the severity of dyskinetic movements.

After repeated application, levodopa induces 80 Hz oscillations (dark red in top panel) in the motor cortex, along with dyskinesia involving different muscle groups (different colors in bottom panel). Application of D1 dopamine receptor antagonist (black bar and faded regions) attenuated oscillations and dyskinesia. See the article by Halje et al. for details.

Neurobiology of Disease

Loss of ER Protein Leads to Motor Neuron Degeneration

Stephane Pelletier, Sebastien Gingras, Sherie Howell, Peter Vogel and James N. Ihle

(see pages 16560–16573)

During translation, transmembrane and secreted proteins enter the endoplasmic reticulum (ER), where they are folded into the proper conformation before being transported in vesicles to the Golgi apparatus for further processing. Proteins that reside primarily in the ER are required to form transport vesicles, and after the vesicular cargo is deposited in the Golgi, these proteins return to the ER. Many proteins regulate this process, and SCYL1 is thought to be one of them. A mutation in SCYL1 causes progressive motor neuron disease in mice, and Pelletier et al. report that knocking out SCYL1 produced similar phenotypes, including progressive loss of motor function, loss of large-diameter axons in sciatic nerves, and spinal cord inflammation. Interestingly, TDP-43, a protein involved in RNA processing, and ubiquilin 2, a protein involved in protein degradation, accumulated in cytoplasmic inclusions in SCYL1-deficient mice. This pathology is found in most cases of amyotrophic lateral sclerosis, suggesting common pathways are affected in these motor neuron diseases.