Browsing by Subject "Neocortex"
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Item Activity-Dependent Regulation of Inhibition from Different Inhibitory Subtypes(2007-08-08) Bartley, Aundrea Frances; Gibson, Jay R.Neuronal activity, in the form of action potential firing, is critical in the maturation and maintenance of neocortical circuitry. A negative feedback mechanism by which neuronal circuits adapt to changing levels of average activity on a time scale of hours to days is known as homeostatic plasticity. At the simplest level, homeostatic adaptations occur to maintain firing rate of neurons at a particular set-point. To better understand homeostatic plasticity at the network level, one must understand the activity-dependent adaptations that occur in the different neocortical cells types. To this end, I examined the regulation of inhibitory neurons and their synapses. I used chronic pharmacological block of activity in a neocortical slice cultures to examine the role activity plays in regulating feedback inhibition defined by two biochemical inhibitory neuron subtypes - parvalbumin-positive (Parv+) and somatostatin-positive (Som+). The cellular and synaptic components of local feedback inhibition were examined. I found that chronic activity blockade caused the following: 1) an increase in the intrinsic excitability of Som+ neurons through the downregulation of 2 substhreshold currents. While not thoroughly examined in Parv+ neurons, a similar, but weaker, increase in excitability may occur in these neurons as well. These< changes are consistent with a homeostatic maintenance of firing rate in these neurons. 2) a differential regulation of monosynaptic inhibition based on subtype that was frequency dependent. At low frequency action potential firing, Parv+ mediated inhibitory drive was downregulated while Som+ was unchanged. Both subtypes were likely downregulated at high frequency firing. 3) an upregulation of excitatory drive onto both Parv+ and Som+ neurons. This was most dramatic at low frequency firing where both subtypes displayed an almost 3-fold increase. This is also consistent with homeostatic maintenance of firing rate in inhibitory neurons. 4) based on the above, a clear change in recurrent inhibition occurred at low frequency firing. First, net recurrent inhibition was increased for both subtypes, but the relative influence of the two changed, such that Som+ recurrent inhibition contributed more relative to that of Parv+ circuitry. At high frequency firing, a slight, but less resolvable, increase in net recurrent inhibition may have occurred in both subtypes without any change in relative contribution. 5) all of the synaptic changes were likely due to increases in presynaptic release probability and/or decreases in synapse number.Item Development of Neocortical Circuits: a Cell Autonomous Examination of mGluR5 and MEF2C(2015-04-08) Loerwald, Kristofer William; Johnson, Jane E.; Meeks, Julian P.; Powell, Craig M.; Huber, Kimberly M.; Gibson, Jay R.Development of neocortical circuits requires both genetic programs and sensory experience-dependent modification of synaptic function. The rules that dictate how synapses develop and respond to changing patterns of input influence both the emergence of receptive fields and the capacity for learning. In turn, the factors that determine the rules for synaptic plasticity are defined by the proteins functioning at the synapse. This project investigates two proteins situated to have wide-reaching impacts on synaptic function. One of the challenges in detailing the roles a protein plays in regulating synapses is discerning not only its acute role on synaptic function, but also its long-term impact on circuit development. Therefore, studying how a protein is engaged by physiological patterns of input in vivo over an extended period of time will provide a broader picture of how it influences synaptic function and circuit development. mGluR5 has previously been implicated in several forms of plasticity that act to directly weaken synaptic function. In this document, I provide evidence that the net-effect of mGluR5 on synaptic function throughout the first few weeks of postnatal development is to promote synaptic input pathway strength, as demonstrated in 2 prominent and well-characterized input pathways to L2/3 pyramidal cells of barrel cortex. Furthermore, I demonstrate a possible role for mGluR5 in a homeostatic mechanism, offsetting the enhanced evoked synaptic input by suppressing both spontaneous transmission and intrinsic excitability. The transcription factor MEF2 also has established roles in regulating synaptic function. However, much less is known about the synaptic mechanisms through which MEF2 mediates its effects. Here, I implicate MEF2C as the critical MEF2 family member involved in regulating synaptic function in L2/3 pyramidal cells in barrel cortex, and provide potential synaptic and molecular mechanisms by which MEF2C regulates pathway input.Item An Examination of the Mechanisms of Neocortical Network Excitability in a Mouse Model of Fragile X Syndrome(2012-07-16) Hays, Seth Alanson; Huber, Kimberly M.; Gibson, Jay R.; Smith, Dean P.; Cannon, Stephen C.; Kavalali, Ege T.Fragile X Syndrome (FXS) is the most common heritable form of mental retardation. FXS is caused by loss of function mutations in the product of the Fmr1 gene, the Fragile X Mental Retardation Protein (FMRP). Many FXS patients display symptoms that are indicative of hyperexcitable circuitry, including epilepsy, bursting patterns in their EEG, and sensory hypersensitivity. Similarly, the mouse model of FXS, the Fmr1 KO mouse, displays a propensity for audiogenic seizures and altered sensory processing, recapitulating many of the symptoms observed in human patients. An imbalance in excitation to inhibition ratio is thought to underlie many autism spectrum disorders. The hyperexcitability in the Fmr1 KO may reflect a shift in E/I balance. However, despite the evidence for hyperexcitability, no studies have previously examined basal circuit function in the Fmr1 KO. In this study, I report that neocortical networks are hyperexcitable in the Fmr1 KO. This hyperexcitability is manifest as prolonged persistent activity states, or UP states. UP states are cyclic periods of depolarization that occur synchronously throughout local neocortical neurons. UP states arise from local recurrent connections and are regulated by intrinsic neuronal properties. As such, measurement of UP states provides insight into overall circuit properties. Furthermore, I observe that the increase in UP state duration in the Fmr1 KO is intrinsic to neocortical excitatory neurons. Deletion of FMRP in layer 4 or layers 5 and 6 fractionally increases UP state duration, suggesting that the hyperexcitability does not arise from one particular neuronal subtype, but rather all neurons partially contribute to the network hyperexcitation. Disruption of mGluR5 interactions with the scaffolding protein Homer, which results in consitituive mGluR5 signaling, is sufficient to prolong UP states. Futhermore, restoration of Homer-mGluR complexes in the Fmr1 KO reduces UP state duration to wildtype levels. Pharmacological or genetic reduction of metabotropic glutamate receptor 5 (mGluR5) signaling reduces UP state duration in the Fmr1 KO to normal levels, suggesting a potential therapy for Fragile X patients. These data characterize the novel phenotype of hyperexcitable cortical circuitry in the Fmr1 KO. In addition, this study provides support for an mGluR-Homer dependent mechanism underlying the network hyperexcitability that may be useful in developing additional treatments for FXS.Item The Role of MEF2 Transcription Factors in Neocortical Circuit and Synapse Development In Vivo(2016-08-10) Rajkovich, Kacey Elise; Konopka, Genevieve; Huber, Kimberly M.; Powell, Craig M.; Roberts, Todd; Gibson, Jay R.Proper neocortical circuit development requires postnatal experience and transcription. Neocortical neurons migrate to their proper layers and then undergo robust synapse proliferation to maximize contacts with presynaptic partners. Synapses are dynamic structures subjected to an equilibrium of formation and elimination rates to preserve meaningful and prune superfluous synapses, respectively. A neuron receives heterogeneous inputs and must tightly regulate connectivity with distinct presynaptic entities. Dysregulated connectivity causes aberrant circuit function and ultimately abnormal behavior linked with neurodevelopmental disorders such as autism. Therefore, a neuron must contain cellular machinery to regulate synaptic connectivity. The activity-dependent Myocyte Enhancer Factor-2 (MEF2) transcription factors - MEF2A-D - have distinct but overlapping expression profiles throughout the brain and typically suppress synapse number. The cell-autonomous role for specific MEF2 genes in neocortical circuit development has never been explored. Furthermore, a link between MEF2 and experience has never been identified within the neocortex. Lastly, whether MEF2 transcription factors regulate specific synaptic pathways is unknown. I report that MEF2A, MEF2C, and MEF2D non-redundantly regulate synapse development onto individual pyramidal neurons within layers 2 and 3 (L2/3) of the postnatal mouse primary somatosensory "barrel" cortex in vivo. Simultaneous deletion of Mef2a and Mef2d modestly decreases spontaneous glutamatergic synaptic transmission in comparison to neighboring control L2/3 neurons. MEF2C, however, cell-autonomously mediates several unique aspects of L2/3 circuit development at a postsynaptic locus. Sparse Mef2c deletion decreases excitatory synapse number onto basal dendrites of L2/3 neurons targeted by local inputs. Therefore, Mef2c promotes excitatory synapse formation and/or maintenance in neocortex. Additionally, MEF2C and sensory experience interact to promote strength of local L2/3 inputs. Mef2c deletion depresses these local inputs in spared barrel cortices comparably to the depression induced by sensory deprivation via whisker trimming onto wildtype (WT) L2/3 neurons; hence MEF2C is required for experience-dependent development of L2/3 circuitry. Lastly, MEF2C differentially suppresses long-range intercortical while promoting connectivity at local L2/3 synaptic input pathways. These data represent novel mechanisms through which MEF2C regulates neocortical synapse development in vivo and provides insight into how activity-dependent transcription within the nucleus interacts with experience to alter specific synapse populations at the neural plasma membrane.Item Understanding Synaptic and Circuit Disruptions of Excitatory and Inhibitory Function In Fragile X Mental Retardation(2013-04-11) Patel, Ankur 1983-; Huber, Kimberly M.; Gibson, Jay R.; Meeks, Julian P.; Kavalali, Ege T.; Johnson, Jane E.In the mouse model of Fragile X Syndrome, the Fmr1 knockout, local excitation of layer 4 fast-spiking (FS) inhibitory neurons is robustly decreased by 50%, but the mechanisms mediating this change are unknown. Here, I performed recordings in acutely prepared slices obtained from Fmr1 “mosaic” mice where Fmr1 is deleted in about half of all neurons, and I find that loss of presynaptic, but not postsynaptic, Fmr1 fully recapitulates the deficit. The change in connection strength is primarily due to a decrease in multivesicular release and release probability indicating that FMRP normally positively regulates these processes. This change in presynaptic neurotransmitter release is observed both in the mosaic mice and in the constitutive Fmr1 knockout mice. Manipulations in release probability enabled both the mimic and rescue of the impaired function in this synaptic pathway. Loss of presynaptic Fmr1 has no effect on excitatory synapses onto excitatory neurons, indicating a target-cell specific function for presynaptic FMRP. Finally, I demonstrate that the excitation decrement onto FS neurons also exists in layer 5 of the Fmr1 KO suggesting a widespread role for presynaptic Fmr1 in the excitation of inhibitory neurons. In summary, I identify a novel function for presynaptic FMRP in promoting presynaptic neurotransmitter release, and I show that loss of this function accounts for impaired excitation of neocortical FS inhibitory neurons. These changes may contribute to the cognitive dysfunction and circuit hyperexcitability associated with Fragile X Syndrome – including patients with complete deletion of FMRP and those with mosaic expression of FMRP.