Cortical region interactions and the functional role of apical dendrites

The basal and distal apical dendrites of pyramidal cells occupy distinct cortical layers and are targeted by axons originating in different cortical regions. Hence, apical and basal dendrites receive information from distinct sources. Physiological evidence suggests that this anatomically observed segregation of input sources may have functional significance. This possibility has been explored in various connectionist models that employ neurons with functionally distinct apical and basal compartments. A neuron in which separate sets of inputs can be integrated independently has the potential to operate in a variety of ways which are not possible for the conventional model of a neuron in which all inputs are treated equally. This article thus considers how functionally distinct apical and basal dendrites can contribute to the information processing capacities of single neurons and, in particular, how information from different cortical regions could have disparate affects on neural activity and learning

The context dependence of network response properties in the primary visual cortex of the primate and cat

In the mammalian visual system, stimulus context was investigated with respect to the ways it influenced neuronal mean response magnitude (the average number of spikes fired per second), response temporal structure (the timing of spikes with respect to one another), and the extent to which distributed neurones fired spikes synchronous due to synaptic interaction between them. Neurones were presented with bipartite grating stimuli, in which the spatio-temporal relationship between the grating activating the excitatory receptive field and that presented to the surrounding visual space could be varied systematically. Simultaneous extracellular recordings were made of the responses of up to four single neurones separated by 750-1000µm, in the lateral geniculate nucleus (LGN) of the thalamus in the cat, or the primary visual cortex (V1) of non-human primates or cats. Changing context systematically influenced the activity of groups of cells. The responses of 83% of primate V1 cells to discontinuous stimuli, in which the centre/surround orientation difference was greater than 45°, contained stronger oscillations at frequencies below 80Hz, than responses to continuous stimuli. Many cat and primate V1 neurones exhibited elevated response magnitudes to such stimuli. In primate V1, the strength of a cell's oscillatory discharge was dependent on stimulus configuration rather than response magnitude. In the LGN and V1, cell pairs with different orientation preferences fired synchronised responses when stimulated by specific discontinuous grating configurations. Stimulus specific synchronised LGN input, and reciprocal excitatory and inhibitory cortico-cortical connections could generate these properties of cells, and the network in which they exist. A model is proposed to account for the function significance of contour discontinuities in generating coherent neural representations of objects in the visual world. It involves response synchronisation in horizontal, feedforward and feedback interactions, within and between the LGN, V1, V2 and V4

Tbr1 instructs laminar patterning of retinal ganglion cell dendrites.

Visual information is delivered to the brain by >40 types of retinal ganglion cells (RGCs). Diversity in this representation arises within the inner plexiform layer (IPL), where dendrites of each RGC type are restricted to specific sublaminae, limiting the interneuronal types that can innervate them. How such dendritic restriction arises is unclear. We show that the transcription factor Tbr1 is expressed by four mouse RGC types with dendrites in the outer IPL and is required for their laminar specification. Loss of Tbr1 results in elaboration of dendrites within the inner IPL, while misexpression in other cells retargets their neurites to the outer IPL. Two transmembrane molecules, Sorcs3 and Cdh8, act as effectors of the Tbr1-controlled lamination program. However, they are expressed in just one Tbr1+ RGC type, supporting a model in which a single transcription factor implements similar laminar choices in distinct cell types by recruiting partially non-overlapping effectors

Full UPF3B function is critical for neuronal differentiation of neural stem cells

Acknowledgments We thank Fred H Gage (Salk Institute, La Jolla, CA, USA) for HCN-A94 cells and Niels Gehring (University of Cologne, Germany) for constructs. We gratefully acknowledge Tenovus Scotland (Project Grant G11-06), Moonlight Prowl (FS) and the Saudi Arabian Ministry of Higher Education via King Abdullah Program for Scholarships for support (TA). JA is supported by a PhD studentship from Medical Research Scotland (PhD-654-2012) and Dundee Cell Products.Peer reviewedPublisher PD

Regulation of mRNA transport, localization and translation in the nervous system of mammals (Review).

Post-transcriptional control of mRNA trafficking and metabolism plays a critical role in the actualization and fine tuning of the genetic program of cells, both in development and in differentiated tissues. Cis-acting signals, responsible for post-transcriptional regulation, reside in the RNA message itself, usually in untranslated regions, 5' or 3' to the coding sequence, and are recognized by trans-acting factors: RNA-binding proteins (RBPs) and/or non-coding RNAs (ncRNAs). ncRNAs bind short mRNA sequences usually present in the 3'-untranslated (3'-UTR) region of their target messages. RBPs recognize specific nucleotide sequences and/or secondary/tertiary structures. Most RBPs assemble on mRNA at the moment of transcription and shepherd it to its destination, somehow determining its final fate. Regulation of mRNA localization and metabolism has a particularly important role in the nervous system where local translation of pre-localized mRNAs has been implicated in developing axon and dendrite pathfinding, and in synapse formation. Moreover, activity-dependent mRNA trafficking and local translation may underlie long-lasting changes in synaptic efficacy, responsible for learning and memory. This review focuses on the role of RBPs in neuronal development and plasticity, as well as possible connections between ncRNAs and RBPs

Disrupted Synaptic Transmission and Abnormal Short-term Synaptic Plasticity in an Angelman Syndrome Mouse Model

abstract: Angelman syndrome (AS) is a neurodevelopmental disorder characterized by developmental delays, intellectual disabilities, impaired language and speech, and movement defects. Most AS cases are caused by dysfunction of a maternally-expressed E3 ubiquitin ligase (UBE3A, also known as E6 associated protein, E6-AP) in neurons. Currently, the mechanism on how loss-of-function of the enzyme influences the nervous system development remains unknown. We hypothesize that impaired metabolism of proteins, most likely those related to E6-AP substrates, may alter the developmental trajectory of neuronal structures including dendrites, spines and synaptic proteins, which leads to disrupted activity/experience-dependent synaptic plasticity and maturation. To test this hypothesis, we conducted a detailed investigation on neuronal morphology and electrophysiological properties in the prefrontal cortex (PFC) layer 5 (L5) corticostriatal pyramidal neurons (target neurons). We found smaller soma size in the maternal Ube3a deficient mice (m-/p+; 'AS' mice) at postnatal 17-19 (P17-19), P28-35 and older than 70 days (>P70), and decreased basal dendritic processes at P28-35. Surprisingly, both excitatory and inhibitory miniature postsynaptic currents (mEPSCs and mIPSCs) decreased on these neurons. These neurons also exhibited abnormalities in the local neural circuits, short-term synaptic plasticity and AMPA/NMDA ratio: the excitatory inputs from L2/3 and L5A, and inhibitory inputs from L5 significantly reduced in AS mice from P17-19; Both the release probability (Pr) and readily-releasable vesicle (RRV) pool replenishment of presynaptic neurons of the target neurons were disrupted at P17-19 and P28-35, and the change of RRV pool replenishment maintained through adulthood (>P70). The AMPA/NMDA ratio showed abnormality in the L5 corticostriatal neurons of PFC in AS mice older than P28-35, during which it decreased significantly compared to that of age-matched WT littermates. Western Blot analysis revealed that the expression level of a key regulator of the cytoskeleton system, Rho family small GTPase cell division control protein 42 homolog (cdc42), reduced significantly in the PFC of AS mice at P28-35.These impairments of synaptic transmission and short-term synaptic plasticity may account for the impaired neuronal morphology and synaptic deficits observed in the PFC target neurons, and contribute to the phenotypes in AS model mice. The present work reveals for the first time that the E6-AP deficiency influences brain function in both brain region-specific and age-dependent ways, demonstrates the functional impairment at the neural circuit level, and reveals that the presynaptic mechanisms are disrupted in AS model. These novel findings shed light on our understanding of the AS pathogenesis and inform potential novel therapeutic explorations.Dissertation/ThesisDoctoral Dissertation Neuroscience 201

The brain-specific double-stranded RNA-binding protein Staufen2 is required for dendritic spine morphogenesis

Mammalian Staufen2 (Stau2) is a member of the double-stranded RNA-binding protein family. Its expression is largely restricted to the brain. It is thought to play a role in the delivery of RNA to dendrites of polarized neurons. To investigate the function of Stau2 in mature neurons, we interfered with Stau2 expression by RNA interference (RNAi). Mature neurons lacking Stau2 displayed a significant reduction in the number of dendritic spines and an increase in filopodia-like structures. The number of PSD95-positive synapses and miniature excitatory postsynaptic currents were markedly reduced in Stau2 down-regulated neurons. Akin effects were caused by overexpression of dominant-negative Stau2. The observed phenotype could be rescued by overexpression of two RNAi cleavage-resistant Stau2 isoforms. In situ hybridization revealed reduced expression levels of β-actin mRNA and fewer dendritic β-actin mRNPs in Stau2 down-regulated neurons. Thus, our data suggest an important role for Stau2 in the formation and maintenance of dendritic spines of hippocampal neurons

Dendritic LSm1/CBP80-mRNPs mark the early steps of transport commitment and translational control

Messenger RNA (mRNA) transport to neuronal dendrites is crucial for synaptic plasticity, but little is known of assembly or translational regulation of dendritic messenger ribonucleoproteins (mRNPs). Here we characterize a novel mRNP complex that is found in neuronal dendrites throughout the central nervous system and in some axonal processes of the spinal cord. The complex is characterized by the LSm1 protein, which so far has been implicated in mRNA degradation in nonneuronal cells. In brain, it associates with intact mRNAs. Interestingly, the LSm1-mRNPs contain the cap-binding protein CBP80 that associates with (pre)mRNAs in the nucleus, suggesting that the dendritic LSm1 complex has been assembled in the nucleus. In support of this notion, neuronal LSm1 is partially nuclear and inhibition of mRNA synthesis increases its nuclear localization. Importantly, CBP80 is also present in the dendrites and both LSm1 and CBP80 shift significantly into the spines upon stimulation of glutamergic receptors, suggesting that these mRNPs are translationally activated and contribute to the regulated local protein synthesis

Caldendrin and Calneurons—EF-Hand CaM-Like Calcium Sensors With Unique Features and Specialized Neuronal Functions

The calmodulin (CaM)-like Ca2+-sensor proteins caldendrin, calneuron-1 and -2 are members of the neuronal calcium-binding protein (nCaBP)-family, a family that evolved relatively late during vertebrate evolution. All three proteins are abundant in brain but show a strikingly different subcellular localization. Whereas caldendrin is enriched in the postsynaptic density (PSD), calneuron-1 and -2 accumulate at the trans-Golgi-network (TGN). Caldendrin exhibit a unique bipartite structure with a basic and proline-rich N-terminus while calneurons are the only EF-Hand CaM-like transmembrane proteins. These uncommon structural features come along with highly specialized functions of calneurons in Golgi-to-plasma-membrane trafficking and for caldendrin in actin-remodeling in dendritic spine synapses. In this review article, we will provide a synthesis of available data on the structure and biophysical properties of all three proteins. We will then discuss their cellular function with special emphasis on synaptic neurotransmission. Finally, we will summarize the evidence for a role of these proteins in neuropsychiatric disorders