Browsing by Subject "Somatosensory Cortex"
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Item Experience-Dependent and Input-Specific Regulation of Neocortical Circuit Development by Genes Linked to Neurodevelopmental Disorders(2022-05) Zhang, Zhe; Volk, Lenora J.; Huber, Kimberly M.; Gibson, Jay R.; Roberts, Todd; Chahrour, MariaAbnormal structural and functional brain connectivity has been widely observed in human neuropsychiatric diseases. Specifically, patients with neurodevelopmental disorders like autism often show an imbalance in the local versus long-range connectivity for cerebral cortex. Whether and how genes implicated in neurodevelopmental disorders regulate development of cortical synaptic connectivity in a pathway-specific manner remain largely unknown. Furthermore, environmental sensory experience can determine or significantly remodel the postnatal development of synaptic connections and neural circuits in sensory cortices. Knowledge on what intracellular proteins or mechanisms can mediate experience-dependent development of specific cortical synaptic connections is also lacking. In this work, I studied the roles of two neurodevelopment disease implicated genes, namely, fragile X mental retardation 1 (Fmr1) and myocyte enhancer factor 2c (Mef2c) in the postnatal experience-dependent development of input-specific synaptic connections. I report that postnatal, cell-autonomous deletion of Fmr1 in postsynaptic L2/3 or L5 neurons results in a selective weakening of AMPA receptor-, but not NMDA receptor-, mediated callosal synaptic function, indicative of immature synapses. Sensory deprivation by contralateral whisker trimming normalizes callosal input strength, suggesting that experience-driven activity of postsynaptic Fmr1 KO L2/3 neurons weakens callosal synapses. Unlike callosal inputs, synapses originating from local L4 and L2/3 circuits are normal with postsynaptic Fmr1 deletion, revealing an input-specific role for postsynaptic Fmr1 in regulation of synaptic connectivity within local and callosal neocortical circuits. Opposite to Fmr1 KO, postnatal deletion of Mef2c in L2/3 neurons leads to a cell autonomous and selective weakening of excitatory synapses from L4, whereas ipsilateral or contralateral long-range excitatory synaptic inputs are unaffected. Postsynaptic Mef2c only promotes the development but not the maintenance of L4-to-L2/3 excitatory synaptic connections and Fmr1 is not required for this process, in contrast to predictions from work in CA1 hippocampal neurons. Weakening of L4-L2/3 synaptic strength by sensory deprivation can be rescued by postnatal postsynaptic expression of a transcriptionally active form of MEF2C (MEF2-VP16), suggesting that MEF2C transcriptional activation drives experience-dependent development of L4-L2/3 synapses. Together, my findings on Fmr1 and Mef2c demonstrate an interaction of experience and gene functions in regulation of specific synaptic connections with important implications for neurodevelopmental disorders.Item In Vivo Sensory Cortex Dysfunction in Pyruvate Dehydrogenase Deficient Mice(2015-01-26) Terrill, Tyler A.; Jakkamsetti, Vikram; Good, Levi; Pascual, Juan M.BACKGROUND: Pyruvate Dehydrogenase (PDH) is a critical enzyme in all organisms, providing pyruvate for the Krebs cycle to generate ATP. As a result, PDH-deficient patients develop lactic acidosis and intellectual disability. Processing of sensory information in the cerebral cortex is crucial for intellectual function. We hypothesize that cortical thinning in these patients contributes to aberrant sensory processing and resulting intellectual disability. Specifically, we hypothesize that there exists a deficit in neurotransmission between cortical layers of the primary somatosensory cortex that can be tested in a novel mouse model of PDH deficiency that replicates the cardinal features of the human disorder. METHODS: Wild-type (WT, n=11), GFAP-CrePDHflox/+ heterozygous (GFAPhet, n=7), GFAP-CrePDHflox/flox knockout (GFAPKO, n=10), and Nestin-CrePDHflox/+ heterozygous mice (NChet, n=14) were anesthetized and their cortex exposed. A vertical linear electrode array was modified to stimulate in layer IV and record in layers IV and II. Synaptic activation and neuronal output were reflected on the recorded local field potentials (LFP) and action potentials. In each mouse, we examined spontaneous activity in layer II and IV, evoked response in layer II from stimulation in layer IV, and synchronized spontaneous activity between the two layers. RESULTS: Spontaneous oscillations of synaptic activation in layer II were significantly reduced in amplitude in both the GFAPKO and NChet mice (p=.02, p=.01). Thus, spontaneous synaptic input into a processing unit of the sensory cortex is severely impaired. Evoked LFPs in layer II were decreased in the GFAPhet, GFAPKO, and NChet mice (p<.001, p=.002, p=.02). Hence, neurotransmission from layer IV to layer II is significantly decreased. Synaptic oscillations in layer IV and II were less synchronized in NChet mice (p<.001) indicating a lack of normal cortical network activity. Additionally, there was electrophysiological evidence of paroxysmal, seizure-like activity in layer 2 of the GFAPKO mice (42% of animals, similar to the EEG of human patients. CONCLUSION: We have observed a significant loss of spontaneous electrophysiological activity, evoked response, and synchronization of LFP oscillations in the PDH mutant mice. This implies cortical dysfunction in sensory processing that could contribute to intellectual disability. Treatments targeting this aspect of the phenotype could be beneficial to PDH-deficient patients.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.