How do children learn to play instruments and speak languages so much easier than adults, and why does brain damage result in worse outcomes in the mature brain vs. the young brain? These questions are central to the study of how “critical periods” are regulated in the brain.
Electron micrograph from a single 70 nm cross-section through a fast-spiking parvalbumin-containing (gold labeling = white dots) presynaptic terminal forming a synapse (red dots) with a pyramidal soma. Original colors are inverted, contours have been raised and membranous structures are highlighted in aqua for ease of visualization. Presynaptic vesicles (colored ovals) within perisomatic fast spiking terminals mostly cluster within ∼200 nm of the synapse, with a few close enough (≤2 nm) to be deemed docked.
Critical periods in brain development define temporal windows when neuronal physiology and anatomy are most sensitive to changes in sensory input or experience (e.g. sound, touch, light, etc.). The maturation of inhibitory cells that release the neurotransmitter GABA, especially a subset called fast-spiking (FS) interneurons, is thought to gate this period of neuronal ‘plasticity’ in the mammalian primary visual cortex. However, it has remained unclear what aspects of FS cell development are important for permitting this period of neuronal malleability in the visual cortex. A new paper in Journal of Neuroscience from the Turrigiano lab addresses the question.
To explore how FS cell development might be linked to critical period plasticity, Brandeis postdoc Marc Nahmani and Professor Gina Turrigiano employed a well-established assay for cortical plasticity in visual cortex called monocular deprivation (MD), and measured FS cell connections using confocal and electron microscopy, as well as optogenetic stimulation of the FS cell population (i.e. shining light onto FS cells possessing light-gated channels to make them fire action potentials).
Following up on previous work from the Turrigiano lab (Maffei et al., 2006), they found that MD induces a coordinated increase in FS interneuron to pyramidal cell (the major excitatory output cells of the cortex) pre- and postsynaptic strength. These changes occur if MD is performed during, but not before the critical period in visual cortex, suggesting they may play a role in gating this period of heightened neuronal plasticity. Future studies are aimed at determining the timeline for these changes across the extent of the critical period in visual cortex.
see: Nahmani M, Turrigiano GG (2014) Deprivation-Induced Strengthening of Presynaptic and Postsynaptic Inhibitory Transmission in Layer 4 of Visual Cortex during the Critical Period. Journal of Neuroscience 34:2571-2582.
Marissa Kuzirian and Amy Ghiretti, graduate students in the lab of Dr. Suzanne Paradis, were each recently awarded Ruth L. Kirschstein National Research Service Awards for Individual Predoctoral Fellows (F31s) from the National Institutes of Health. Marissa’s 2.5-year award from the National Institute of Neurological Disorders and Stroke funds research to explore the role of Semaphorin4D and its receptor, PlexinB1, in regulating inhibitory synapse development and ultimately setting up proper neural connections in the mammalian CNS. Amy’s 2-year award from the National Institute on Drug Abuse funds a collaborative project between the Paradis, Lau, and Van Hooser labs here at Brandeis to elucidate the function of Rem2 in mediating experience-dependent changes in dendritic morphology in a living, intact animal system.
The basis for Marissa and Amy’s work comes from research into neurodevelopmental disorders such as Autism Spectrum Disorders (ASDs), as well as drug abuse and addiction. Proteins that regulate neurodevelopmental processes such as synapse development and dendritic morphology are important in both neurological disorders and drug addiction. Proper communication between neurons depends on the precise assembly and development of synaptic connections. The transmembrane protein Semaphorin4D (Sema4D) is necessary for proper GABAergic synapse formation, as knockdown of expression in the postsynaptic neuron by RNAi leads to a decrease in GABAergic synaptic density in cultured neurons (Paradis et al 2007). Marissa’s work will further explore this role of Sema4D in GABAergic synapse development.
Inhibitory synapses are identified in white along dendrites of a rat hippocampal neuron. Synapses are defined as sites of overlap between the postsynaptic protein GABAA receptor subunit γ2 (red) and the presynaptic protein GAD65 (blue) visualized by immunostaining. Neurons are visualized by immunostaining for MAP2 (green).
Marissa’s preliminary results demonstrate that adding the soluble, extracellular domain of Sema4D to cultured hippocampal neurons is sufficient to drive GABAergic synapse formation. This increase depends on the expression of Sema4D’s receptor, PlexinB1. Thus, Marissa’s work defines PlexinB1 as a novel receptor mediating GABAergic synapse formation in response to Sema4D in the mammalian CNS. The goal of Marissa’s project is to elucidate the role of Sema4D and its receptor, PlexinB1, in GABAergic synapse development. In experiments she proposed, she hypothesizes that Sema4D acts to initiate assembly of GABAergic synaptic proteins such as GABAA receptors and gephyrin through its receptor PlexinB1. This will be tested using a variety of imaging techniques in cultured hippocampal neurons, including confocal and time-lapse imaging, to measure the mobility and accumulation of GABAergic synaptic proteins in neurons after treatment with soluble Sema4D. The experiments will not only greatly expand our understanding of a novel receptor-ligand pair in GABAergic synapse development, it will inform as to some of the basic mechanisms underlying GABAergic synaptogenesis.
Molecular mechanisms, such as the Sema4D-PlexB1 interaction described above, are critical for the ability of the central nervous system (CNS) to respond to extracellular stimuli and make corresponding changes in the structure and function of a neuron. At the behavioral level, this plasticity allows an organism to respond to a changing environment appropriately in order to survive. At the level of individual neurons, this is reflected in changes in gene expression that occur in response to a variety of stimuli, including alterations in neuronal network activity. The goal of Amy’s work is to characterize a direct molecular link between changes in neuronal activity and changes in dendritic morphology.
A neuron in the optic tectum of a Xenopus tadpole; Green Fluorescent Protein expression allows the dendrites to be visualized.
Amy has previously implicated the protein Rem2, a type of signaling molecule known as a GTPase, as a mediator of such neurodevelopmental processes as excitatory synapse formation and dendritic morphology (Ghiretti & Paradis 2011). The expression of Rem2 in individual neurons is upregulated following increased neuronal activity, suggesting that it may serve as a direct link between changes in activity and corresponding changes in the structure and function of neurons. Her recently funded work will utilize Xenopus laevis tadpoles to study the effects of visual experience (by exposing the tadpoles to a light stimulus) on Rem2 expression, and in turn, how Rem2 mediates experience-dependent changes in the morphology of neurons in a region of the brain known as the optic tectum, where visual processing takes place. Ultimately, a full understanding of how Rem2 functions to shape the morphology of neurons in an intact system may help to inform knowledge of how the human brain changes as a result of neurological disorders or drug abuse, and aid in the development of more effective treatments to prevent these changes from occurring.
Sandhya P. Koushika, a gradute of Brandeis’s Molecular and Cell Biology program (PhD, 1999), and currently running a lab at the National Center for Biological Sciences in Bangalore, has been named an HHMI International Early Career Scientist. This pilot program of the Howard Hughes Medical Institute seeks to identify scientists working abroad with the potential to become scientific leaders, and awards each with $650,000 over five years to help establish independent research programs. Of 28 scientists from 12 countries so named, Koushika was the only recipient in India. While at Brandeis, Koushika worked in Kalpana White‘s lab on the role of ELAV in neural develeopment in Drosophila. In her postdoc, Koushika switched systems to work in the worm C. elegans, and her lab is currently focused on genetic techniques to study axonal transport, a key feature of nerve cells, in the worm model.
Can you say that three times fast? Glumatergic (excitatory) synapses respond to the neurotransmitter glutamate, and GABAergic (inhibitory) synapses respond to gamma-aminobutyric acid (GABA). GABA is formed by decarboxylating glutamate. These are the “workhorse” neurotransmitters in the brain.
Neuroscience grad stduent Marissa Stearns Kuzirian and Assistant Professor of Biology Suzanne Paradis discuss what’s known about how GABAergic synapses form, and the relationships to the previously better-studied formation of glutamergic synapses, in a new review entitled “Emerging themes in GABAergic synapse development” in Progress in Neurobiology.
Desplan will speak on Monday, March 21 at 4:00 pm in Gerstenzang 121. The title of his talk will be “Processing of Color Information in Drosophilia”. Desplan will speak again at Neurobiology Journal Club on March 22 at 12:05 pm in Gerstenzang 121.
Desplan is the funniest, nicest guy ever. At first you may not be able to understand him too too easily due to his french accent but after a few days that’s not a problem. Desplan went pretty slow and went over concepts that people didn’t seem to understand. Even then he held very helpful review sessions. Great professor.
You look at a photograph of a hiker in an alpine landscape. The hiker, her dog, the trees in the background, and the houses of a village in the distance are vividly reconstructed by your brain from the shades of light and color on the paper. The subjects of the picture are so distinct and clear that it is hard to see how difficult it was for your visual system to reconstruct it. A closer examination highlights some of the problems our brain has to overcome: The hiker in the foreground is higher and occupies a larger area than the houses and the trees in the background, yet you perceive her as being smaller. The dog is partially hidden by one of the legs of its master, yet you perceive it as a single animal, rather than two half-dogs. Theoretical models and psychological experiments led researchers to think that, in these examples and in countless other everyday situations, your brain makes use of an internal model of the world, built over a lifetime of experiences, to correctly interpret the image.
By analyzing the mathematical equivalents of the internal model, researchers in Jozsef Fiser’s lab in the Volen Center for Complex Systems at Brandeis and colleagues at Cambridge University (UK) deduce that, if the internal model works as hypothesized by theoreticians, traces of its functioning would be seen in neural activity recorded in complete darkness. Intuitively, an internal model would use its understanding of typical natural images to “fill-in” noisy and incomplete parts of a visual scene. As the brightness of an image is reduced, the visual system increasingly relies on prior expectations, until most of the neural activity is dominated by the internal model. This intuition is compatible with previous observations of neural data showing strong and coordinated activity in the visual system in the absence of visual stimulation, whose significance had remained unexplained.
Figure 1: The two panels show the distribution of all possible instantaneous activity patterns on 16 electrodes, in response to natural movies (M, x-axis) and during spontaneous activity in the dark (S, y-axis). Colors represent the number of electrodes detecting activity in each pattern, as shown in the legend on the left. In a young ferret, just after eye opening, the frequency with which the patterns occur is very different in the two conditions (left panel); instead, for an adult animal of about 4 months of age, the two distributions are very similar, as indicated by the patterns clustering around the diagonal.
In a paper published this week in Science, the authors analyzed neural activity in the primary visual cortex of ferrets watching natural scenes or artificial patterns, or just sitting in darkness. They found that, as predicted by the model, when the animal is in darkness the recorded patterns of neural activity closely resemble those recorded in response to natural visual scenes, but not those recorded in response to artificial stimuli. The fact that the similarity was specific to natural scenes indicates that the neural activity was due to the model’s expectations about the environment, and not to some other secondary effects. The authors repeated the measurements on animals at different stages of development, and found that the match of neural activity in the dark and in natural images was not present at birth, but rather gradually developed over the first four months of visual experience, as the internal model adapted to the statistics of the external world.
These results provide neural evidence for the internal models theorized by computational neuroscientists, and allow us to take a glance at the computations performed by the visual areas of the brain.
The development of the central nervous system involves a series of complex yet tightly-regulated processes, including the formation of synapses, the sites of communication between neurons, and the morphogenesis of the dendritic arbor, where the majority of synaptic contacts occur. Importantly, the misregulation of these processes is a hallmark of many neurodevelopmental disorders, including autism and mental retardation. However, the molecular mechanisms that underlie these structural and functional changes remain largely obscure.
The lab of Prof. Suzanne Paradis at Brandeis is working to identify and characterize molecules that regulate neural development in the rodent hippocampus. A recently accepted manuscript at Developmental Neurobiology by Brandeis Neurocience Ph.D. student Amy Ghiretti and Dr. Paradis uses RNAi in primary hippocampal cultures to identify novel roles for the GTPase Rem2 in several neurodevelopmental processes. The RNAi-mediated decrease of Rem2 leads to the formation of fewer excitatory synapses, and also results in increased dendritic complexity, suggesting that Rem2 functions normally to promote synapse formation and to inhibit dendritic branching. Additionally, the binding of Rem2 to the calcium-binding protein calmodulin was identified as a key interaction that distinguishes the signaling pathways through which Rem2 mediates synapse development and dendritic branching. Overall, this study identifies Rem2 as a novel regulator of several neurodevelopmental processes, and importantly, suggests that Rem2 regulates excitatory synapse development and dendritic morphology via separable and distinct signaling pathways.
Figure: Neurons in which Rem2 protein expression has been decreased by RNAi (top) show increased dendritic branching compared to control neurons (bottom), suggesting Rem2 acts to inhibit branching
Science at Brandeis 