Darpan Chakraborty | Mount Sinai School of Medicine (original) (raw)

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Papers by Darpan Chakraborty

Research paper thumbnail of α1-Na/K-ATPase inhibition rescues aberrant dendritic calcium dynamics and memory deficits in the hippocampus of an Angelman syndrome mouse model

Research paper thumbnail of GABAergic Synapses at the Axon Initial Segment of Basolateral Amygdala Projection Neurons Modulate Fear Extinction

Neuropsychopharmacology, 2016

Inhibitory synaptic transmission in the amygdala has a pivotal role in fear learning and its exti... more Inhibitory synaptic transmission in the amygdala has a pivotal role in fear learning and its extinction. However, the local circuits formed by GABAergic inhibitory interneurons within the amygdala and their detailed function in shaping these behaviors are not well understood. Here we used lentiviral-mediated knockdown of the cell adhesion molecule neurofascin in the basolateral amygdala (BLA) to specifically remove inhibitory synapses at the axon initial segment (AIS) of BLA projection neurons. Quantitative analysis of GABAergic synapse markers and measurement of miniature inhibitory postsynaptic currents in BLA projection neurons after neurofascin knockdown ex vivo confirmed the loss of GABAergic input. We then studied the impact of this manipulation on anxiety-like behavior and auditory cued fear conditioning and its extinction as BLA related behavioral paradigms, as well as on long-term potentiation (LTP) in the ventral subiculum-BLA pathway in vivo. BLA knockdown of neurofascin impaired ventral subiculum-BLA-LTP. While this manipulation did not affect anxiety-like behavior and fear memory acquisition and consolidation, it specifically impaired extinction. Our findings indicate that modification of inhibitory synapses at the AIS of BLA projection neurons is sufficient to selectively impair extinction behavior. A better understanding of the role of distinct GABAergic synapses may provide novel and more specific targets for therapeutic interventions in extinction-based therapies.

Research paper thumbnail of Selective ligands for Na(+)/K(+)-ATPase α isoforms differentially and cooperatively regulate excitability of pyramidal neurons in distinct brain regions

Neuropharmacology, Jan 19, 2017

Sodium-potassium ATPase (NaKA) is a plasma membrane enzyme responsible for influencing membrane p... more Sodium-potassium ATPase (NaKA) is a plasma membrane enzyme responsible for influencing membrane physiology by direct electrogenic activity. It determines cellular excitability and synaptic neurotransmission, thus affecting learning and memory processes. A principle catalytic α subunit of NaKA has development-specific expression pattern. There are two α isoforms, α1 and α3, in adult brain neurons. Although NaKA is a housekeeping enzyme, the physiological differences between these two α isoforms in different brain regions have not been well explored. Endogenous cardiotonic steroids, including Marinobufagenin and Ouabain, control the cell homeostasis and cell functions via inhibiting NaKA. Here we employed selective inhibition of α1 and α3 NaKA isoforms by Marinobufagenin and Ouabain respectively, to measure the contribution of α subunits in cellular physiology of three distinct mouse brain regions. The results of the whole cell recording demonstrated that α1 isoform predominated in la...

Research paper thumbnail of Neuromodulation of Axon Terminals

Understanding which cellular compartments are influenced during neuromodulation underpins any rat... more Understanding which cellular compartments are influenced during neuromodulation underpins any rational effort to explain and optimize outcomes. Axon terminals have long been speculated to be sensitive to polarization, but experimentally informed models for CNS stimulation are lacking. We conducted simultaneous intracellular recording from the neuron soma and axon terminal (blebs) during extracellular stimulation with weak sustained (DC) uniform electric fields in mouse cortical slices. Use of weak direct current stimulation (DCS) allowed isolation and quantification of changes in axon terminal biophysics, relevant to both suprathreshold (e.g., deep brain stimulation, spinal cord stimulation, and transcranial magnetic stimulation) and subthreshold (e.g., transcranial DCS and transcranial alternating current stimulation) neuromodulation approaches. Axon terminals polarized with sensitivity (mV of membrane polarization per V/ m electric field) 4 times than somas. Even weak polarization (<2 mV) of axon terminals significantly changes action potential dynamics (including amplitude, duration, conduction velocity) in response to an intracellular pulse. Regarding a cellular theory of neuromodulation, we explain how suprathreshold CNS stimulation activates the action potential at terminals while subthreshold approaches modulate synaptic efficacy through axon terminal polarization. We demonstrate that by virtue of axon polarization and resulting changes in action potential dynamics, neuromodulation can influence analog– digital information processing.

Research paper thumbnail of Selective ligands for Na + /K + -ATPase a isoforms differentially and cooperatively regulate excitability of pyramidal neurons in distinct brain regions

Sodium-potassium ATPase (NaKA) is a plasma membrane enzyme responsible for influencing membrane p... more Sodium-potassium ATPase (NaKA) is a plasma membrane enzyme responsible for influencing membrane physiology by direct electrogenic activity. It determines cellular excitability and synaptic neurotransmission, thus affecting learning and memory processes. A principle catalytic a subunit of NaKA has development-specific expression pattern. There are two a isoforms, a1 and a3, in adult brain neurons. Although NaKA is a housekeeping enzyme, the physiological differences between these two a isoforms in different brain regions have not been well explored. Endogenous cardiotonic steroids, including Marinobufagenin and Ouabain, control the cell homeostasis and cell functions via inhibiting NaKA. Here we employed selective inhibition of a1 and a3 NaKA isoforms by Marinobufagenin and Ouabain respectively,
to measure the contribution of a subunits in cellular physiology of three distinct mouse brain regions. The results of the whole cell recording demonstrated that a1 isoform predominated in layer-5 pyramidal
cells at rostral motor cortex, while a3 isoform governed the pyramidal neurons at hippocampal CA1
region and to a lesser extent the layer-5 pyramidal neurons of parietal cortex. Furthermore, selective a
isoform inhibition induced differential effects on distinct physiological properties even within the same
brain region. In addition, our results supported the existence of synergism between two NaKA a isoforms.
To conclude, this systematic study of NaKA a isoforms demonstrated their broader roles in neuronal
functioning in a region-specific manner.

Research paper thumbnail of GABAergic Synapses at the Axon Initial Segment of Basolateral Amygdala Projection Neurons Modulate Fear Extinction

Inhibitory synaptic transmission in the amygdala has a pivotal role in fear learning and its exti... more Inhibitory synaptic transmission in the amygdala has a pivotal role in fear learning and its extinction. However, the local circuits formed by GABAergic inhibitory interneurons within the amygdala and their detailed function in shaping these behaviors are not well understood. Here we used lentiviral-mediated knockdown of the cell adhesion molecule neurofascin in the basolateral amygdala (BLA) to specifically remove inhibitory synapses at the axon initial segment (AIS) of BLA projection neurons. Quantitative analysis of GABAergic synapse markers and measurement of miniature inhibitory postsynaptic currents in BLA projection neurons after neurofascin knockdown ex vivo confirmed the loss of GABAergic input. We then studied the impact of this manipulation on anxiety-like behavior and auditory cued fear conditioning and its extinction as BLA related behavioral paradigms, as well as on long-term potentiation (LTP) in the ventral subiculum– BLA pathway in vivo. BLA knockdown of neurofascin impaired ventral subiculum–BLA–LTP. While this manipulation did not affect anxiety-like behavior and fear memory acquisition and consolidation, it specifically impaired extinction. Our findings indicate that modification of inhibitory synapses at the AIS of BLA projection neurons is sufficient to selectively impair extinction behavior. A better understanding of the role of distinct GABAergic synapses may provide novel and more specific targets for therapeutic interventions in extinction-based therapies.

Research paper thumbnail of GABAergic Synapses at the Axon Initial Segment of Basolateral Amygdala Projection Neurons Modulate Fear Extinction

Inhibitory synaptic transmission in the amygdala has a pivotal role in fear learning and its exti... more Inhibitory synaptic transmission in the amygdala has a pivotal role in fear learning and its extinction. However, the local circuits formed by GABAergic inhibitory interneurons within the amygdala and their detailed function in shaping these behaviors are not well understood. Here we used lentiviral-mediated knockdown of the cell adhesion molecule neurofascin in the basolateral amygdala (BLA) to specifically remove inhibitory synapses at the axon initial segment (AIS) of BLA projection neurons. Quantitative analysis of GABAergic synapse markers and measurement of miniature inhibitory postsynaptic currents in BLA projection neurons after neurofascin knockdown ex vivo confirmed the loss of GABAergic input. We then studied the impact of this manipulation on anxiety-like behavior and auditory cued fear conditioning and its extinction as BLA related behavioral paradigms, as well as on long-term potentiation (LTP) in the ventral subiculum– BLA pathway in vivo. BLA knockdown of neurofascin impaired ventral subiculum–BLA–LTP. While this manipulation did not affect anxiety-like behavior and fear memory acquisition and consolidation, it specifically impaired extinction. Our findings indicate that modification of inhibitory synapses at the AIS of BLA projection neurons is sufficient to selectively impair extinction behavior. A better understanding of the role of distinct GABAergic synapses may provide novel and more specific targets for therapeutic interventions in extinction-based therapies.

Paper by Darpan Chakraborty

Research paper thumbnail of α1-Na/K-ATPase inhibition rescues aberrant dendritic calcium dynamics and memory deficits in the hippocampus of an Angelman syndrome mouse model

Research paper thumbnail of GABAergic Synapses at the Axon Initial Segment of Basolateral Amygdala Projection Neurons Modulate Fear Extinction

Neuropsychopharmacology, 2016

Inhibitory synaptic transmission in the amygdala has a pivotal role in fear learning and its exti... more Inhibitory synaptic transmission in the amygdala has a pivotal role in fear learning and its extinction. However, the local circuits formed by GABAergic inhibitory interneurons within the amygdala and their detailed function in shaping these behaviors are not well understood. Here we used lentiviral-mediated knockdown of the cell adhesion molecule neurofascin in the basolateral amygdala (BLA) to specifically remove inhibitory synapses at the axon initial segment (AIS) of BLA projection neurons. Quantitative analysis of GABAergic synapse markers and measurement of miniature inhibitory postsynaptic currents in BLA projection neurons after neurofascin knockdown ex vivo confirmed the loss of GABAergic input. We then studied the impact of this manipulation on anxiety-like behavior and auditory cued fear conditioning and its extinction as BLA related behavioral paradigms, as well as on long-term potentiation (LTP) in the ventral subiculum-BLA pathway in vivo. BLA knockdown of neurofascin impaired ventral subiculum-BLA-LTP. While this manipulation did not affect anxiety-like behavior and fear memory acquisition and consolidation, it specifically impaired extinction. Our findings indicate that modification of inhibitory synapses at the AIS of BLA projection neurons is sufficient to selectively impair extinction behavior. A better understanding of the role of distinct GABAergic synapses may provide novel and more specific targets for therapeutic interventions in extinction-based therapies.

Research paper thumbnail of Selective ligands for Na(+)/K(+)-ATPase α isoforms differentially and cooperatively regulate excitability of pyramidal neurons in distinct brain regions

Neuropharmacology, Jan 19, 2017

Sodium-potassium ATPase (NaKA) is a plasma membrane enzyme responsible for influencing membrane p... more Sodium-potassium ATPase (NaKA) is a plasma membrane enzyme responsible for influencing membrane physiology by direct electrogenic activity. It determines cellular excitability and synaptic neurotransmission, thus affecting learning and memory processes. A principle catalytic α subunit of NaKA has development-specific expression pattern. There are two α isoforms, α1 and α3, in adult brain neurons. Although NaKA is a housekeeping enzyme, the physiological differences between these two α isoforms in different brain regions have not been well explored. Endogenous cardiotonic steroids, including Marinobufagenin and Ouabain, control the cell homeostasis and cell functions via inhibiting NaKA. Here we employed selective inhibition of α1 and α3 NaKA isoforms by Marinobufagenin and Ouabain respectively, to measure the contribution of α subunits in cellular physiology of three distinct mouse brain regions. The results of the whole cell recording demonstrated that α1 isoform predominated in la...

Research paper thumbnail of Neuromodulation of Axon Terminals

Understanding which cellular compartments are influenced during neuromodulation underpins any rat... more Understanding which cellular compartments are influenced during neuromodulation underpins any rational effort to explain and optimize outcomes. Axon terminals have long been speculated to be sensitive to polarization, but experimentally informed models for CNS stimulation are lacking. We conducted simultaneous intracellular recording from the neuron soma and axon terminal (blebs) during extracellular stimulation with weak sustained (DC) uniform electric fields in mouse cortical slices. Use of weak direct current stimulation (DCS) allowed isolation and quantification of changes in axon terminal biophysics, relevant to both suprathreshold (e.g., deep brain stimulation, spinal cord stimulation, and transcranial magnetic stimulation) and subthreshold (e.g., transcranial DCS and transcranial alternating current stimulation) neuromodulation approaches. Axon terminals polarized with sensitivity (mV of membrane polarization per V/ m electric field) 4 times than somas. Even weak polarization (<2 mV) of axon terminals significantly changes action potential dynamics (including amplitude, duration, conduction velocity) in response to an intracellular pulse. Regarding a cellular theory of neuromodulation, we explain how suprathreshold CNS stimulation activates the action potential at terminals while subthreshold approaches modulate synaptic efficacy through axon terminal polarization. We demonstrate that by virtue of axon polarization and resulting changes in action potential dynamics, neuromodulation can influence analog– digital information processing.

Research paper thumbnail of Selective ligands for Na + /K + -ATPase a isoforms differentially and cooperatively regulate excitability of pyramidal neurons in distinct brain regions

Sodium-potassium ATPase (NaKA) is a plasma membrane enzyme responsible for influencing membrane p... more Sodium-potassium ATPase (NaKA) is a plasma membrane enzyme responsible for influencing membrane physiology by direct electrogenic activity. It determines cellular excitability and synaptic neurotransmission, thus affecting learning and memory processes. A principle catalytic a subunit of NaKA has development-specific expression pattern. There are two a isoforms, a1 and a3, in adult brain neurons. Although NaKA is a housekeeping enzyme, the physiological differences between these two a isoforms in different brain regions have not been well explored. Endogenous cardiotonic steroids, including Marinobufagenin and Ouabain, control the cell homeostasis and cell functions via inhibiting NaKA. Here we employed selective inhibition of a1 and a3 NaKA isoforms by Marinobufagenin and Ouabain respectively,
to measure the contribution of a subunits in cellular physiology of three distinct mouse brain regions. The results of the whole cell recording demonstrated that a1 isoform predominated in layer-5 pyramidal
cells at rostral motor cortex, while a3 isoform governed the pyramidal neurons at hippocampal CA1
region and to a lesser extent the layer-5 pyramidal neurons of parietal cortex. Furthermore, selective a
isoform inhibition induced differential effects on distinct physiological properties even within the same
brain region. In addition, our results supported the existence of synergism between two NaKA a isoforms.
To conclude, this systematic study of NaKA a isoforms demonstrated their broader roles in neuronal
functioning in a region-specific manner.

Research paper thumbnail of GABAergic Synapses at the Axon Initial Segment of Basolateral Amygdala Projection Neurons Modulate Fear Extinction

Inhibitory synaptic transmission in the amygdala has a pivotal role in fear learning and its exti... more Inhibitory synaptic transmission in the amygdala has a pivotal role in fear learning and its extinction. However, the local circuits formed by GABAergic inhibitory interneurons within the amygdala and their detailed function in shaping these behaviors are not well understood. Here we used lentiviral-mediated knockdown of the cell adhesion molecule neurofascin in the basolateral amygdala (BLA) to specifically remove inhibitory synapses at the axon initial segment (AIS) of BLA projection neurons. Quantitative analysis of GABAergic synapse markers and measurement of miniature inhibitory postsynaptic currents in BLA projection neurons after neurofascin knockdown ex vivo confirmed the loss of GABAergic input. We then studied the impact of this manipulation on anxiety-like behavior and auditory cued fear conditioning and its extinction as BLA related behavioral paradigms, as well as on long-term potentiation (LTP) in the ventral subiculum– BLA pathway in vivo. BLA knockdown of neurofascin impaired ventral subiculum–BLA–LTP. While this manipulation did not affect anxiety-like behavior and fear memory acquisition and consolidation, it specifically impaired extinction. Our findings indicate that modification of inhibitory synapses at the AIS of BLA projection neurons is sufficient to selectively impair extinction behavior. A better understanding of the role of distinct GABAergic synapses may provide novel and more specific targets for therapeutic interventions in extinction-based therapies.

Research paper thumbnail of GABAergic Synapses at the Axon Initial Segment of Basolateral Amygdala Projection Neurons Modulate Fear Extinction

Inhibitory synaptic transmission in the amygdala has a pivotal role in fear learning and its exti... more Inhibitory synaptic transmission in the amygdala has a pivotal role in fear learning and its extinction. However, the local circuits formed by GABAergic inhibitory interneurons within the amygdala and their detailed function in shaping these behaviors are not well understood. Here we used lentiviral-mediated knockdown of the cell adhesion molecule neurofascin in the basolateral amygdala (BLA) to specifically remove inhibitory synapses at the axon initial segment (AIS) of BLA projection neurons. Quantitative analysis of GABAergic synapse markers and measurement of miniature inhibitory postsynaptic currents in BLA projection neurons after neurofascin knockdown ex vivo confirmed the loss of GABAergic input. We then studied the impact of this manipulation on anxiety-like behavior and auditory cued fear conditioning and its extinction as BLA related behavioral paradigms, as well as on long-term potentiation (LTP) in the ventral subiculum– BLA pathway in vivo. BLA knockdown of neurofascin impaired ventral subiculum–BLA–LTP. While this manipulation did not affect anxiety-like behavior and fear memory acquisition and consolidation, it specifically impaired extinction. Our findings indicate that modification of inhibitory synapses at the AIS of BLA projection neurons is sufficient to selectively impair extinction behavior. A better understanding of the role of distinct GABAergic synapses may provide novel and more specific targets for therapeutic interventions in extinction-based therapies.