CC BY
34
OM&P
Section MOLECULAR NEUROSCIENCE
neurogenesis, while low level allows upper layers generation. We further show that TrkC-T1 controls neocortical cell fate by preventing activation of adapter molecule ShcA, which in turn leads to inhibition of MAP kinase pathway. Manipulating the levels of activity of TrkC-T1, ShcA or Erk has a direct effect on fate determination of cortical progenitors. We further demonstrate that down-regulation of TrkC-T1 levels in late progenitors allows activation of ShcA with consecutive activation of Erk (MAP kinase) and instructs late progenitors to generate upper layer neurons.
Molecular Mechanisms Underlying Area-Specific Circuit Formation in the Mouse Neocortex
Michele Studer*
Institute of Biology Valrose, France. * Presenting e-mail: [email protected]
Despite an apparently similar laminar and cell-type organization, neocortical areas have distinct features in terms of molecular identity, morphology and long-range connectivity of residing projection neurons, leading ultimately to area-specific circuits. Despite its well-defined anatomical character and functional significance, the molecular mechanisms by which neuronal subtypes are specified within cortical layers and across domains as well as their precise assembly into distinct functional neocortical areas, remains largely unknown. Since neocortical areas are first pre-patterned by a set of transcription factors expressed in gradients during development and then acquire a distinct function postnatally (sensory-input versus motor-output), a complex interplay between intrinsic and extrinsic activity-dependent mechanisms might exist during formation of area-specific circuits. This talk will focus on how factors expressed in distinct prospective areas and layers control the ratio and distribution of projection neuron subtypes (intracortical versus subcortical) and how these factors modulate activity-dependent mechanisms in the motor and somatosensory postnatal cortex. Together with epigenetic modifications, we propose that the great variety of projection neurons in the mammalian cerebral cortex is not only due to the existence of genetic programs directing the development of each single neuronal subtype, but also to mechanisms that modify and refine after birth the processes specifying major projection neuron classes. Overall, our data contribute in unraveling some of the developmental mechanisms of how diverse populations of cortical projection neurons are coordinated into high-functional territories and how they interact during assembly of cortical circuits into distinct functional areas.
References
1. Harb K., Magrinelli E., Nicolas C.S, Lukianets N., Frangeul L., Pietri M., Sun T., Sandoz G., Grammont F., Jabaudon D., Studer M.* and Alfano C.* Area-specific development of distinct neocortical neuron subclasses is regulated by postnatal epigenetic modifications. eLife, 2016, Jan 27;5.
2. Alfano C., Magrinelli E., Harb K., Hevner R. F. and Studer M. Postmitotic control of sensory area specification during neocortical development. Nature Communications, 2014 Dec 5;5:5632.
3. Tomassy Srubek G., De Leonibus E., Jabaudon D., Lodato S., Alfano C., Mele A., Macklis J.D. and Studer M. Area-specific temporal control of corticospinal motor neuron differentiation by COUP-TFI. PNAS, 2010, 107(8): 3576-81.
Behavioral Characterization of SATB 1 (+/-) Heterozygous Mice
I.I. Belousova*, E.A. Epifanova, A.A. Babaev, I.V. Mukhina, V.S. Tarabykin
Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia. * Presenting e-mail: [email protected]
Satb1 (special AT-rich sequence binding protein 1) gene encodes a matrix protein that regulates chromatin structure and gene expression. In the present study, Satb1 heterozygous (+/-) mice were investigated to unravel the functional role of Satb1 in the brain.
Section MOLECULAR NEUROSCIENCE Materials and Methods
The heterozygous knockout mutant of the Satbl gene has been generated using the Cre-loxP system. Thirty two male (8 WT/8 SATB1 (+/-)) and female (8 WT/8 SATB1 (+/-)) mice at an age of two months were used. A battery of sensorimotor tasks was performed to assess coordination, climbing, locomotion and orienting reactions). In each test, the time was measured with the criterion of 120 s to complete. The mice were subjected to: walking initiation, bridges (1, 2 and 4 cm), wire suspension, turning in an alley, turning on an inclined screen. Spontaneous horizontal and vertical (rearing) locomotor activities and average speed were measured during 5 min using a Infrared Actimeter (Actitrack, Panlab, Barcelona, Spain). For assessment short-term memory in passive avoidance tests the Shuttle Boxes LE918 (Panlab, Barcelona, Spain) were used. During the acquisition/conditioning phase the animal is placed in the white compartment. When the animal innately crosses to the black compartment it receives a mild foot shock. During the test phase the animal is again placed in the white compartment and the latency of the entrance to the black compartment is evaluated. Startle response and prepulse inhibition of acoustic startle responses were measured by the Start and Fear Combined system (Panlab, Barcelona, Spain). Statistical analysis was performed using Satistica 10.0 software.
Results
Sensorimotor tests showed no impairment in locomotor activity of Satbl (+/-) male and female mice. The four tested groups completed all the sensorimotor tasks. However in the locomotor activity test Satbl (+/-) mice demonstrated an increased locomotion compared with WT mice. Distance moved in the central zone by male and female Satbl (+/-) mice was significantly higher compared with WT mice. Significant increase in number of rearing in Satb1(+/-) female mice were showed. There were no significant differences due to genotype in the startle response and prepulse inhibition test. There was no difference in latency of the entrance to the black compartment between conditioning and test phase in passive avoidance task in Satbl (+/-) male and female mice which indicates about deficit in retention of memory for an aversive experience in Satbl (+/-) compared with WT mice.
Conclusions
Taken together, our findings suggest that Satbl (+/-) presented behavioral alterations compared to their wildtype littermates, such as: hyperlocomotion and deficit in learning capacity.
Acknowledgements
Research carried out with the financial support of the grant of the Russian Scientific Foundation (project №l5-l4-l002l)
Postnatal Dlx1&2 Functions in Cortical Interneuron Development
John Rubenstein*
UCSF Weill Institute for Neurosciences, University of California at San Francisco, San Francisco, CA 94143, USA. * Presenting e-mail: [email protected]
The postnatal functions of the Dlxl&2 transcription factors in cortical interneurons (CINs) are unknown. Here, using conditional Dlxl, Dlx2 and Dlxl&2 knockouts (CKOs), we defined their roles in specific CINs. The CKOs had dendritic, synaptic and survival defects, affecting even PV+ CINs. We provide evidence that DLX2 directly drives GADl, GAD2 and VGat expression, and show that mutants had reduced mIPSC amplitude. Furthermore, the mutants formed fewer GABAergic synapses on excitatory neurons and had reduced mIPSC frequency. Furthermore, Dlxl/2 CKO had hy-poplastic dendrites, fewer excitatory synapses, and reduced excitatory input. We provide evidence that some of these phenotypes were due to reduced expression of GRIN2B (a subunit of the NMDA receptor), a high confidence Autism gene. Thus, Dlxl&2 direct coordinate key components of CIN postnatal development by promoting their excitability, inhibitory functions and survival.
OM&P
