Cellular/Molecular
A Semaphorin and a Synapse
Amar Sahay, Chong-Hyun Kim, Jehuda P. Sepkuty, Edward Cho, Richard L. Huganir, David D. Ginty, and Alex L. Kolodkin
(see pages 3613-3620)
Semaphorins got their name and their fame from their roles in development. However, they are also expressed in the adult nervous system. This week, Sahay et al. report a possible function for the secreted class 3 semaphorins in the adult brain: modulation of synaptic transmission. The authors tagged the secreted semaphorins Sema3A and Sema3F with alkaline phosphatase (AP) to localize the neuropilin (Npn) receptors. Npn-1 and Npn-2 were expressed in neurons of the mouse hippocampus and accessory olfactory cortex by postnatal day 10 and persisted into adulthood. In hippocampal slices, low nanomolar applications of AP-Sema3F increased the frequency and amplitude of miniature EPSCs in dentate granule cells and CA1 pyramidal cells. Paired-pulse facilitation was unaffected by AP-Sema3F, suggesting that the effect was postsynaptic. Sema3F null mice were also prone to seizures, although this behavior may be related to altered circuit formation rather than to acute effects on synaptic transmission.
Development/Plasticity/Repair
Astrocytes as Synaptic Facilitators
Sarina B. Elmariah, Eun Joo Oh, Ethan G. Hughes, and Rita J. Balice-Gordon
(see pages 3638-3650)
Neuronal-glial interactions can be direct, but as Elmariah et al. show this week, astrocytes can also facilitate neuronal form and function in more circuitous ways. The authors used cultured neurons to track the influence of astrocytes on formation of GABAergic synapses. Coculture of hippocampal neurons with astrocytes, or with astrocyte-conditioned medium (ACM), increased the number of GABAergic nerve terminals and GABAA receptor clusters as well as the frequency of miniature IPSCs. Scavenging BDNF with tyrosine receptor kinase (Trk)-IgG fusion proteins prevented increased receptor clustering but not the increase in synapse number. Mixing and matching neurons and astrocytes from mice lacking BDNF or TrkB indicated that neurons, not astrocytes, are the source of the BDNF and TrkB required for receptor clustering. Thus the action of an astrocytic-derived factor stimulates synapse formation but also facilitates Trk signaling between neurons. It seems that the astrocytes make neurons do some of the work.
Behavioral/Systems/Cognitive
Chloride's Got Rhythm
Cristina Marchetti, Joel Tabak, Nikolai Chub, Michael J. O'Donovan, and John Rinzel
(see pages 3601-3612)
During development, neurons fire in rhythmic spontaneous patterns that help shape network formation. This activity operates over a wide range of time scales, from milliseconds to seconds and even minutes. Because intracellular chloride can be high in developing neurons, early circuit activity can be hyperexcitable as a result of the depolarizing effects of GABA- and glycine-gated chloride channels. This week, Marchetti et al. explore whether a network model with fast (∼1 Hz) and slow (minutes) “depression” can account for the spontaneous activity in the developing chick spinal cord. The slow component is too slow to be explained by conventional forms of synaptic depression; thus the authors modeled it as attributable to activity-dependent fluctuations in intracellular chloride. Their model with three variables (membrane potential, fast synaptic depression, and intracellular chloride concentration) was able to account for the observed spontaneous activity. Although the model does not incorporate all of the experimental details, it makes a case for chloride dynamics in slow rhythmic activity.
Neurobiology of Disease
A Mouse Glial Tauopathy
Mark S. Forman, Devika Lal, Bin Zhang, Deepa V. Dabir, Eric Swanson, Virginia M.-Y. Lee, and John Q. Trojanowski
(see pages 3539-3550)
Filamentous inclusions (“neurofibrillary tangles”) in neurons constitute the characteristic feature of the sporadic and familial neurodegenerative disorders known as tauopathies. Some of these disorders also show tau inclusions in oligodendrocytes and astrocytes. This week, Forman et al. create a mouse model to examine the sequelas of tau accumulation in astrocytes. The authors selectively overexpressed a human tau in astrocytes using the glial fibrillary acidic protein (GFAP) promoter. Tau accumulated in astrocytes throughout the brain and spinal cord to levels 25-100% above control. Interestingly, tau expression was associated with a redistribution of GFAP staining from white matter to gray matter, reminiscent of “reactive” astrocytes. The microtubule-assembling and -stabilizing functions of tau are compromised by hyperphosphorylation and ubiquitination. In older transgenic mice, astrocytic tau was heavily phosphorylated and ubiquitinated, and, accordingly, formed insoluble aggregates. Although neuronal numbers remained constant, there was evidence of associated axonal injury and myelin breakdown in mice that were >12 months of age.
Spinal cord sections from GFAP/tau transgenic mice show colocalization of GFAP and tau in astrocytes, particularly within gray matter. The arrows show the junction between gray and white matter. See the article by Forman et al. for details.
