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1.
bioRxiv ; 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38895393

ABSTRACT

Cholinergic receptor activation enables the persistent firing of cortical pyramidal neurons, providing a key cellular basis for theories of spatial navigation involving working memory, path integration, and head direction encoding. The granular retrosplenial cortex (RSG) is important for spatially-guided behaviors, but how acetylcholine impacts RSG neurons is unknown. Here, we show that a transcriptomically, morphologically, and biophysically distinct RSG cell-type - the low-rheobase (LR) neuron - has a very distinct expression profile of cholinergic muscarinic receptors compared to all other neighboring excitatory neuronal subtypes. LR neurons do not fire persistently in response to cholinergic agonists, in stark contrast to all other principal neuronal subtypes examined within the RSG and across midline cortex. This lack of persistence allows LR neuron models to rapidly compute angular head velocity (AHV), independent of cholinergic changes seen during navigation. Thus, LR neurons can consistently compute AHV across brain states, highlighting the specialized RSG neural codes supporting navigation.

2.
bioRxiv ; 2023 Oct 23.
Article in English | MEDLINE | ID: mdl-37961554

ABSTRACT

Classical psychedelic drugs are thought to increase excitability of pyramidal cells in prefrontal cortex via activation of serotonin 2A receptors (5-HT2ARs). Here, we instead find that multiple classes of psychedelics dose-dependently suppress intrinsic excitability of pyramidal neurons, and that extracellular delivery of psychedelics decreases excitability significantly more than intracellular delivery. A previously unknown mechanism underlies this psychedelic drug action: enhancement of ubiquitously expressed potassium "M-current" channels that is independent of 5-HT2R activation. Using machine-learning-based data assimilation models, we show that M-current activation interacts with previously described mechanisms to dramatically reduce intrinsic excitability and shorten working memory timespan. Thus, psychedelic drugs suppress intrinsic excitability by modulating ion channels that are expressed throughout the brain, potentially triggering homeostatic adjustments that can contribute to widespread therapeutic benefits.

3.
Elife ; 92020 11 05.
Article in English | MEDLINE | ID: mdl-33150866

ABSTRACT

Type I lissencephaly is a neuronal migration disorder caused by haploinsuffiency of the PAFAH1B1 (mouse: Pafah1b1) gene and is characterized by brain malformation, developmental delays, and epilepsy. Here, we investigate the impact of Pafah1b1 mutation on the cellular migration, morphophysiology, microcircuitry, and transcriptomics of mouse hippocampal CA1 parvalbumin-containing inhibitory interneurons (PV+INTs). We find that WT PV+INTs consist of two physiological subtypes (80% fast-spiking (FS), 20% non-fast-spiking (NFS)) and four morphological subtypes. We find that cell-autonomous mutations within interneurons disrupts morphophysiological development of PV+INTs and results in the emergence of a non-canonical 'intermediate spiking (IS)' subset of PV+INTs. We also find that now dominant IS/NFS cells are prone to entering depolarization block, causing them to temporarily lose the ability to initiate action potentials and control network excitation, potentially promoting seizures. Finally, single-cell nuclear RNAsequencing of PV+INTs revealed several misregulated genes related to morphogenesis, cellular excitability, and synapse formation.


Subject(s)
1-Alkyl-2-acetylglycerophosphocholine Esterase/metabolism , Classical Lissencephalies and Subcortical Band Heterotopias/pathology , Hippocampus/cytology , Interneurons/metabolism , Microtubule-Associated Proteins/metabolism , Parvalbumins/metabolism , 1-Alkyl-2-acetylglycerophosphocholine Esterase/genetics , Animals , Electrophysiological Phenomena , Gene Expression Regulation/physiology , Mice , Mice, Knockout , Microtubule-Associated Proteins/genetics
4.
JCI Insight ; 5(13)2020 07 09.
Article in English | MEDLINE | ID: mdl-32641584

ABSTRACT

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disorder caused by a polyglutamine expansion in the androgen receptor (AR). Using gene expression analysis and ChIP sequencing, we mapped transcriptional changes in genetically engineered patient stem cell-derived motor neurons. We found that transcriptional dysregulation in SBMA can occur through AR-mediated histone modification. We detected reduced histone acetylation, along with decreased expression of genes encoding compensatory metabolic proteins and reduced substrate availability for mitochondrial function. Furthermore, we found that pyruvate supplementation corrected this deficiency and improved mitochondrial function and SBMA motor neuron viability. We propose that epigenetic dysregulation of metabolic genes contributes to reduced mitochondrial ATP production. Our results show a molecular link between altered epigenetic regulation and mitochondrial metabolism that contributes to neurodegeneration.


Subject(s)
Epigenesis, Genetic/physiology , Mitochondria/metabolism , Motor Neurons/metabolism , Muscular Atrophy, Spinal/physiopathology , Humans , Muscular Atrophy, Spinal/metabolism , Peptides/metabolism , Receptors, Androgen/metabolism
5.
Elife ; 92020 06 19.
Article in English | MEDLINE | ID: mdl-32558643

ABSTRACT

Layering has been a long-appreciated feature of higher order mammalian brain structures but the extent to which it plays an instructive role in synaptic specification remains unknown. Here we examine the formation of synaptic circuitry under cellular heterotopia in hippocampal CA1, using a mouse model of the human neurodevelopmental disorder Type I Lissencephaly. We identify calbindin-expressing principal cells which are mispositioned under cellular heterotopia. Ectopic calbindin-expressing principal cells develop relatively normal morphological features and stunted intrinsic physiological features. Regarding network development, a connectivity preference for cholecystokinin-expressing interneurons to target calbindin-expressing principal cells is diminished. Moreover, in vitro gamma oscillatory activity is less synchronous across heterotopic bands and mutants are less responsive to pharmacological inhibition of cholecystokinin-containing interneurons. This study will aid not only in our understanding of how cellular networks form but highlight vulnerable cellular circuit motifs that might be generalized across disease states.


Subject(s)
Calbindins/metabolism , Classical Lissencephalies and Subcortical Band Heterotopias/physiopathology , Hippocampus/physiopathology , Interneurons/physiology , Pyramidal Cells/physiology , Animals , Cholecystokinin/metabolism , Disease Models, Animal , Female , Humans , Male , Mice
6.
Elife ; 92020 02 13.
Article in English | MEDLINE | ID: mdl-32053107

ABSTRACT

In violation of Dale's principle several neuronal subtypes utilize more than one classical neurotransmitter. Molecular identification of vesicular glutamate transporter three and cholecystokinin expressing cortical interneurons (CCK+VGluT3+INTs) has prompted speculation of GABA/glutamate corelease from these cells for almost two decades despite a lack of direct evidence. We unequivocally demonstrate CCK+VGluT3+INT-mediated GABA/glutamate cotransmission onto principal cells in adult mice using paired recording and optogenetic approaches. Although under normal conditions, GABAergic inhibition dominates CCK+VGluT3+INT signaling, glutamatergic signaling becomes predominant when glutamate decarboxylase (GAD) function is compromised. CCK+VGluT3+INTs exhibit surprising anatomical diversity comprising subsets of all known dendrite targeting CCK+ interneurons in addition to the expected basket cells, and their extensive circuit innervation profoundly dampens circuit excitability under normal conditions. However, in contexts where the glutamatergic phenotype of CCK+VGluT3+INTs is amplified, they promote paradoxical network hyperexcitability which may be relevant to disorders involving GAD dysfunction such as schizophrenia or vitamin B6 deficiency.


Subject(s)
Glutamic Acid/metabolism , Vesicular Glutamate Transport Proteins/metabolism , gamma-Aminobutyric Acid/metabolism , Animals , Interneurons/metabolism , Mice
7.
Addict Biol ; 22(5): 1304-1315, 2017 Sep.
Article in English | MEDLINE | ID: mdl-27417190

ABSTRACT

Methamphetamine (METH) markedly increases dopamine (DA) release in the mesolimbic DA system, which plays an important role in mediating the reinforcing effects of METH. METH-induced DA release results in the formation of reactive oxygen species (ROS), leading to oxidative damage. We have recently reported that ROS are implicated in behavior changes and DA release in the nucleus accumbens (NAc) following cocaine administration. The aim of this study was to evaluate the involvement of ROS in METH-induced locomotor activity, self-administration and enhancement of DA release in the NAc. Systemic administration of a non-specific ROS scavenger, N-tert-butyl-α-phenylnitrone (PBN; 0, 50 and 75 mg/kg, IP) or a superoxide-selective scavenger, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL; 0, 50 and 100 mg/kg, IP), attenuated METH-induced locomotor activity without affecting generalized behavior in METH-naïve rats. PBN and TEMPOL significantly attenuated METH self-administration without affecting food intake. Increased oxidative stress was found in neurons, but not astrocytes, microglia or oligodendrocytes, in the NAc of METH self-administering rats. In addition, TEMPOL significantly decreased METH enhancement of DA release in the NAc. Taken together, these results suggest that enhancement of ROS in the NAc contributes to the reinforcing effect of METH.


Subject(s)
Behavior, Animal/drug effects , Central Nervous System Stimulants/pharmacology , Dopamine/metabolism , Locomotion/drug effects , Methamphetamine/pharmacology , Nucleus Accumbens/drug effects , Reactive Oxygen Species/metabolism , Animals , Antioxidants/pharmacology , Astrocytes/drug effects , Astrocytes/metabolism , Cyclic N-Oxides/pharmacology , Feeding Behavior/drug effects , Free Radical Scavengers/pharmacology , Male , Microglia/drug effects , Microglia/metabolism , Neurons/drug effects , Neurons/metabolism , Neuroprotective Agents/pharmacology , Nucleus Accumbens/metabolism , Oligodendroglia/drug effects , Oligodendroglia/metabolism , Oxidative Stress/drug effects , Rats , Rats, Sprague-Dawley , Self Administration , Spin Labels
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