Enhanced Infragranular and Supragranular Synaptic Input onto Layer 5 Pyramidal Neurons in a Rat Model of Cortical Dysplasia

Focal cortical dysplasia is associated with the development of seizures in children and is present in up to 40% of intractable childhood epilepsies. Transcortical freeze lesions in newborn rats reproduce many of the anatomical and physiological characteristics of human cortical dysplasia. Rats with freeze lesions have increased seizure susceptibility and a region of hyperexcitable cortex adjacent to the lesion. Since alterations in hyperpolarization-activated nonspecific cation (HCN) channels are often associated with epilepsy, we used whole cell patch-clamp recording and voltage-sensitive dye imaging to examine alterations in HCN channels and inwardly rectifying hyperpolarization-activated currents ( Ih) in cortical dysplasia. (L5) pyramidal neurons in lesioned animals had hyperpolarized resting membrane potentials, increased input resistances and reduced voltage “sag” associated with Ih activation. These differences became nonsignificant after application of the Ih blocker ZD7288. Temporal excitatory postsynaptic potential (EPSP) summation and intrinsic excitability were increased in neurons near the freeze lesion. Using voltage-sensitive dye imaging of neocortical slices, we found that inhibiting Ih with ZD7288 increased the half-width of dye signals. The anticonvulsant lamotrigine produced a significant decrease in spread of activity. The ability of lamotrigine to decrease network activity was reduced in the hyperexcitable cortex near the freeze lesion. These results suggest that Ih serves to constrain network activity in addition to its role in regulating cellular excitability. Reduced Ih may contribute to increased network excitability in cortical dysplasia.

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Development of cortical malformations in BCNU-treated rat, model of cortical dysplasia

Neuroscience ◽

10.1016/j.neuroscience.2010.11.061 ◽

2011 ◽

Vol 175 ◽

pp. 380-393 ◽

Cited By ~ 13

Author(s):

R.F. Moroni ◽

B. Cipelletti ◽

F. Inverardi ◽

M.C. Regondi ◽

R. Spreafico ◽

...

Keyword(s):

Rat Model ◽

Cortical Dysplasia ◽

Cortical Malformations

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Increased Signal Delays and Unaltered Synaptic Input Pattern Recognition in Layer III Neocortical Pyramidal Neurons of the rTg4510 Mouse Model of Tauopathy: A Computer Simulation Study With Passive Membrane

Frontiers in Neuroscience ◽

10.3389/fnins.2021.721773 ◽

2021 ◽

Vol 15 ◽

Author(s):

Attila Somogyi ◽

Ervin Wolf

Keyword(s):

Pattern Recognition ◽

Tau Protein ◽

Synaptic Input ◽

Pyramidal Neurons ◽

Signal Propagation ◽

Input Pattern ◽

Tau Proteins ◽

Chromosome 17 ◽

Neuronal Membrane ◽

Excitatory Postsynaptic Potential

Abnormal tau proteins are involved in pathology of many neurodegenerative disorders. Transgenic rTg4510 mice express high levels of human tau protein with P301L mutation linked to chromosome 17 that has been associated with frontotemporal dementia with parkinsonism. By 9 months of age, these mice recapitulate key features of human tauopathies, including presence of hyperphosphorylated tau and neurofibrillary tangles (NFTs) in brain tissue, atrophy and loss of neurons and synapses, and hyperexcitability of neurons, as well as cognitive deficiencies. We investigated effects of such human mutant tau protein on neuronal membrane, subthreshold dendritic signaling, and synaptic input pattern recognition/discrimination in layer III frontal transgenic (TG) pyramidal neurons of 9-month-old rTg4510 mice and compared these characteristics to those of wild-type (WT) pyramidal neurons from age-matched control mice. Passive segmental cable models of WT and TG neurons were set up in the NEURON simulator by using three-dimensionally reconstructed morphology and electrophysiological data of these cells. Our computer simulations predict leakage resistance and capacitance of neuronal membrane to be unaffected by the mutant tau protein. Computer models of TG neurons showed only modest alterations in distance dependence of somatopetal voltage and current transfers along dendrites and in rise times and half-widths of somatic Excitatory Postsynaptic Potential (EPSPs) relative to WT control. In contrast, a consistent and statistically significant slowdown was detected in the speed of simulated subthreshold dendritic signal propagation in all regions of the dendritic surface of mutant neurons. Predictors of synaptic input pattern recognition/discrimination remained unaltered in model TG neurons. This suggests that tau pathology is primarily associated with failures/loss in synaptic connections rather than with altered intraneuronal synaptic integration in neurons of affected networks.

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Loss of Presynaptic and Postsynaptic Structures Is Accompanied by Compensatory Increase in Action Potential-Dependent Synaptic Input to Layer V Neocortical Pyramidal Neurons in Aged Rats

Journal of Neuroscience ◽

10.1523/jneurosci.20-22-08596.2000 ◽

2000 ◽

Vol 20 (22) ◽

pp. 8596-8606 ◽

Cited By ~ 50

Author(s):

Tak Pan Wong ◽

Giorgio Marchese ◽

Maria Antonietta Casu ◽

Alfredo Ribeiro-da-Silva ◽

A. Claudio Cuello ◽

...

Keyword(s):

Action Potential ◽

Synaptic Input ◽

Pyramidal Neurons ◽

Aged Rats ◽

Compensatory Increase ◽

Layer V ◽

Neocortical Pyramidal Neurons

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NR2B antagonists restrict spatiotemporal spread of activity in a rat model of cortical dysplasia

Epilepsy Research ◽

10.1016/j.eplepsyres.2006.07.013 ◽

2006 ◽

Vol 72 (2-3) ◽

pp. 127-139 ◽

Cited By ~ 11

Author(s):

Susanta Bandyopadhyay ◽

John J. Hablitz

Keyword(s):

Rat Model ◽

Cortical Dysplasia

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Reduced chemical and electrical connections of fast-spiking interneurons in experimental cortical dysplasia

Journal of Neurophysiology ◽

10.1152/jn.00126.2014 ◽

2014 ◽

Vol 112 (6) ◽

pp. 1277-1290 ◽

Cited By ~ 9

Author(s):

Fu-Wen Zhou ◽

Steven N. Roper

Keyword(s):

Action Potentials ◽

Pyramidal Neurons ◽

Cortical Dysplasia ◽

Coupling Coefficients ◽

Neural Connections ◽

Synaptic Release ◽

Pulse Ratio ◽

Fast Spiking ◽

Chemical Synapses ◽

Electrical Connections

Aberrant neural connections are regarded as a principal factor contributing to epileptogenesis. This study examined chemical and electrical connections between fast-spiking (FS), parvalbumin (PV)-immunoreactive (FS-PV) interneurons and regular-spiking (RS) neurons (pyramidal neurons or spiny stellate neurons) in a rat model of prenatal irradiation-induced cortical dysplasia. Presynaptic action potentials were evoked by current injection and the elicited unitary inhibitory or excitatory postsynaptic potentials (uIPSPs or uEPSPs) were recorded in the postsynaptic cell. In dysplastic cortex, connection rates between presynaptic FS-PV interneurons and postsynaptic RS neurons and FS-PV interneurons, and uIPSP amplitudes were significantly smaller than controls, but both failure rates and coefficient of variation of uIPSP amplitudes were larger than controls. In contrast, connection rates from RS neurons to FS-PV interneurons and uEPSPs amplitude were similar in the two groups. Assessment of the paired pulse ratio showed a significant decrease in synaptic release probability at FS-PV interneuronal terminals, and the density of terminal boutons on axons of biocytin-filled FS-PV interneurons was also decreased, suggesting presynaptic dysfunction in chemical synapses formed by FS-PV interneurons. Electrical connections were observed between FS-PV interneurons, and the connection rates and coupling coefficients were smaller in dysplastic cortex than controls. In dysplastic cortex, we found a reduced synaptic efficiency for uIPSPs originating from FS-PV interneurons regardless of the type of target cell, and impaired electrical connections between FS-PV interneurons. This expands our understanding of the fundamental impairment of inhibition in this model and may have relevance for certain types of human cortical dysplasia.

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