TrkB signaling is required for postnatal survival of CNS neurons and protects hippocampal and motor neurons from axotomy-induced cell death

Newborn mice carrying targeted mutations in genes encoding neurotrophins or their signaling Trk receptors display severe neuronal deficits in the peripheral nervous system but not in the CNS. In this study, we show that trkB (¿/¿) mice have a significant increase in apoptotic cell death in different regions of the brain during early postnatal life. The most affected region in the brain is the dentate gyrus of the hippocampus, although elevated levels of pyknotic nuclei were also detected in cortical layers II and III and V and VI, the striatum, and the thalamus. Furthermore, axotomized hippocampal and motor neurons of trkB (¿/¿) mice have significantly lower survival rates than those of wild-type littermates. These results suggest that neurotrophin signaling through TrkB receptors plays a role in the survival of CNS neurons during postnatal development. Moreover, they indicate that TrkB receptor signaling protects subpopulations of CNS neurons from injury- and axotomy-induced cell death

Model of the early development of thalamo-cortical connections and area patterning via signaling molecules

The mammalian cortex is divided into architectonic and functionally distinct areas. There is growing experimental evidence that their emergence and development is controlled by both epigenetic and genetic factors. The latter were recently implicated as dominating the early cortical area specification. In this paper, we present a theoretical model that explicitly considers the genetic factors and that is able to explain several sets of experiments on cortical area regulation involving transcription factors Emx2 and Pax6, and fibroblast growth factor FGF8. The model consists of the dynamics of thalamo- cortical connections modulated by signaling molecules that are regulated genetically, and by axonal competition for neocortical space. The model can make predictions and provides a basic mathematical framework for the early development of the thalamo-cortical connections and area patterning that can be further refined as more experimental facts become known.Comment: brain, model, neural development, cortical area patterning, signaling molecule

Adenosine A1 receptor activation mediates the developmental shift at layer 5 pyramidal cell synapses and is a determinant of mature synaptic strength

During the first postnatal month glutamatergic synapses between layer 5 pyramidal cells in the rodent neocortex switch from an immature state exhibiting high probability of neurotransmitter release, large unitary amplitude and synaptic depression to a mature state with decreased probability of release, smaller unitary amplitude and synaptic facilitation. Using paired recordings, we demonstrate that the developmental shift in release probability at synapses between rat somatosensory layer 5 thick-tufted pyramidal cells is due to a higher and more heterogeneous activation of presynaptic adenosine A1 receptors. Immature synapses under control conditions exhibited distributions of CV, failure rate and release probability that were almost coincident with the A1 receptor blocked condition; however, mature synapses under control conditions exhibited much broader distributions that spanned those of both the A1 receptor agonised and antagonised conditions. Immature and mature synapses expressed A1 receptors with no observable difference in functional efficacy and therefore the heterogeneous A1 receptor activation seen in the mature neocortex is due to increased adenosine concentrations that vary between synapses. Given the central role demonstrated for A1 receptor activation in determining synaptic amplitude and the statistics of transmission between mature layer 5 pyramidal cells, the emplacement of adenosine sources and sinks near the synaptic terminal could constitute a novel form of long-term synaptic plasticity

Distinctive Structural and Molecular Features of Myelinated Inhibitory Axons in Human Neocortex.

Numerous types of inhibitory neurons sculpt the performance of human neocortical circuits, with each type exhibiting a constellation of subcellular phenotypic features in support of its specialized functions. Axonal myelination has been absent among the characteristics used to distinguish inhibitory neuron types; in fact, very little is known about myelinated inhibitory axons in human neocortex. Here, using array tomography to analyze samples of neurosurgically excised human neocortex, we show that inhibitory myelinated axons originate predominantly from parvalbumin-containing interneurons. Compared to myelinated excitatory axons, they have higher neurofilament and lower microtubule content, shorter nodes of Ranvier, and more myelin basic protein (MBP) in their myelin sheath. Furthermore, these inhibitory axons have more mitochondria, likely to sustain the high energy demands of parvalbumin interneurons, as well as more 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), a protein enriched in the myelin cytoplasmic channels that are thought to facilitate the delivery of nutrients from ensheathing oligodendrocytes. Our results demonstrate that myelinated axons of parvalbumin inhibitory interneurons exhibit distinctive features that may support the specialized functions of this neuron type in human neocortical circuits

An Adaptive Threshold in Mammalian Neocortical Evolution

Expansion of the neocortex is a hallmark of human evolution. However, it remains an open question what adaptive mechanisms facilitated its expansion. Here we show, using gyrencephaly index (GI) and other physiological and life-history data for 102 mammalian species, that gyrencephaly is an ancestral mammalian trait. We provide evidence that the evolution of a highly folded neocortex, as observed in humans, requires the traversal of a threshold of 10^9 neurons, and that species above and below the threshold exhibit a bimodal distribution of physiological and life-history traits, establishing two phenotypic groups. We identify, using discrete mathematical models, proliferative divisions of progenitors in the basal compartment of the developing neocortex as evolutionarily necessary and sufficient for generating a fourteen-fold increase in daily prenatal neuron production and thus traversal of the neuronal threshold. We demonstrate that length of neurogenic period, rather than any novel progenitor-type, is sufficient to distinguish cortical neuron number between species within the same phenotypic group.Comment: Currently under review; 38 pages, 5 Figures, 13 Supplementary Figures, 2 Table

Increased expression of matrix metalloproteinase-9 in patients with temporal lobe epilepsy

Aim: The molecular mechanism of epileptogenesis in temporal lobe epilepsy is still unclear. Experimental studies have suggested that matrix metalloproteinases have important roles in this process, but human studies are limited. The aim of this study was to assess the expression of MMP-9, MMP-2 and their tissue inhibitors (TIMP-1 and TIMP-2) in patients with temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). Material and Methods: The tissue samples from temporal neocortex and hippocampus were obtained from patients with temporal lobe epilepsy with hippocampal sclerosis who had undergone anterior temporal lobectomy for recurrent medically resistant seizures. Immunohistochemical methods were used to determine the expression of MMP-9, MMP-2 and their tissue inhibitors. Tissue samples were also analyzed with transmission electron microscopy. Results: The immunoreactivity for MMP-9 both in hippocampal and temporal neocortical neurons was stronger than that of MMP-2. Additionally, there was a mild reaction for its tissue inhibitor TIMP-1 as with TIMP-2. The TEM analysis of the hippocampus revealed that there was apparent ultra-structural damage on the pericarya and neuropil of some neurons. There was obvious damage in the mitochondria and the nuclear membrane. Conclusion: The preliminary results of this study revealed that MMP-9 may have a role in patients with drug resistant TLE-HS