Faculty Opinions recommendation of Neurotensin activates GABAergic interneurons in the prefrontal cortex.

Background Evidence continues to build suggesting that the GABAergic neurotransmitter system is altered in brains of patients with major depressive disorder. However, there is little information available related to the extent of these changes or the potential mechanisms associated with these alterations. As stress is a well-established precipitant to depressive episodes, we sought to explore the impact of chronic stress on GABAergic interneurons. Methods Using western blot analyses and quantitative real-time polymerase chain reaction, we assessed the effects of five-weeks of chronic unpredictable stress exposure on the expression of GABA-synthesizing enzymes (GAD65 and GAD67), calcium-binding proteins (calbindin, parvalbumin, and calretinin), and neuropeptides co-expressed in GABAergic neurons (somatostatin, neuropeptide Y, vasoactive intestinal peptide, and cholecystokinin) in the prefrontal cortex and hippocampus of rats. We also investigated the effects of corticosterone and dexamethasone exposure on these markers in vitro in primary cortical and hippocampal cultures. Results We found that chronic unpredictable stress induced significant reductions of GAD67 protein levels in both the prefrontal cortex and hippocampus of chronic unpredictable stress-exposed rats but did not detect changes in GAD65 protein expression. Similar protein expression changes were found in vitro in cortical neurons. In addition, our results provide clear evidence of reduced markers of interneuron population(s), namely somatostatin and neuropeptide Y, in the prefrontal cortex, suggesting these cell types may be selectively vulnerable to chronic stress. Conclusion Together, this work highlights that chronic stress induces regional and cell type-selective effects on GABAergic interneurons in rats. These findings provide additional supporting evidence that stress-induced GABA neuron dysfunction and cell vulnerability play critical roles in the pathophysiology of stress-related illnesses, including major depressive disorder.

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Dopamine D5 receptor immunoreactivity is differentially distributed in GABAergic interneurons and pyramidal cells in the rat medial prefrontal cortex

Neuroscience Research ◽

10.1016/j.neures.2010.07.1295 ◽

2010 ◽

Vol 68 ◽

pp. e291

Author(s):

Satoko Oda ◽

Hiromasa Funato ◽

Hiroaki Igarashi ◽

Junko Yokofujita ◽

Masaru Kuroda

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Pyramidal Cells ◽

Gabaergic Interneurons ◽

Dopamine D5 Receptor

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Polysialylated NCAM and EphrinA/EphA Regulate Synaptic Development of GABAergic Interneurons in Prefrontal Cortex

Cerebral Cortex ◽

10.1093/cercor/bhr392 ◽

2012 ◽

Vol 23 (1) ◽

pp. 162-177 ◽

Cited By ~ 26

Author(s):

Leann H. Brennaman ◽

Xuying Zhang ◽

Hanjun Guan ◽

Jason W. Triplett ◽

Arthur Brown ◽

...

Keyword(s):

Prefrontal Cortex ◽

Gabaergic Interneurons ◽

Synaptic Development

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Mechanisms of Dopamine Activation of Fast-Spiking Interneurons That Exert Inhibition in Rat Prefrontal Cortex

Journal of Neurophysiology ◽

10.1152/jn.00335.2002 ◽

2002 ◽

Vol 88 (6) ◽

pp. 3150-3166 ◽

Cited By ~ 186

Author(s):

Natalia Gorelova ◽

Jeremy K. Seamans ◽

Charles R. Yang

Keyword(s):

Prefrontal Cortex ◽

Receptor Antagonist ◽

Pyramidal Neurons ◽

Sch 23390 ◽

Membrane Depolarization ◽

Inward Rectifier ◽

Repetitive Firing ◽

Gabaergic Interneurons ◽

Fast Spiking

Prefrontal cortical dopamine (DA) modulates pyramidal cell excitability directly and indirectly by way of its actions on local circuit GABAergic interneurons. DA modulation of interneuronal functions is implicated in the computational properties of prefrontal networks during cognitive processes and in schizophrenia. Morphologically and electrophysiologically distinct classes of putative GABAergic interneurons are found in layers II-V of rat prefrontal cortex. Our whole cell patch-clamp study shows that DA induced a direct, TTX-insensitive, reversible membrane depolarization, and increased the excitability of fast-spiking (FS) interneurons. The DA-induced membrane depolarization was reduced significantly by D1/D5 receptor antagonist SCH 23390, but not by the D2 receptor antagonist (−)sulpiride, D4 receptor antagonists U101958 or L-745870, α1-adrenoreceptor antagonist prazosin, or serotoninergic receptor antagonist mianserin. The D1/5 agonists SKF81297 or dihydrexidine, but not D2 agonist quinpirole, also induced a prolonged membrane depolarization. Voltage-clamp analyses of the voltage-dependence of DA-sensitive currents, and the effects of changing [K+]O on reversal potentials of DA responses, revealed that DA suppressed a Cs+-sensitive inward rectifier K+ current and a resting leak K+ current. D1/D5, but not D2 agonists mimicked the suppressive effects of DA on the leak current, but the DA effects on the inward rectifier K+ current were not mimicked by either agonist. In a subgroup of FS interneurons, the slowly inactivating membrane outward rectification evoked by depolarizing voltage steps was also attenuated by DA. Collectively, these data showed that DA depolarizes FS interneurons by suppressing a voltage-independent ‘leak’ K+ current (via D1/D5 receptor mechanism) and an inwardly rectifying K+ current (via unknown DA mechanisms). Additional suppression of a slowly inactivating K+ current led to increase in repetitive firing in response to depolarizing inputs. This D1-induced increase in interneuron excitability enhances GABAergic transmission to PFC pyramidal neurons and could represent a mechanism via which DA suppresses persistent firing of pyramidal neurons in vivo.

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Dopamine D5 receptor immunoreactivity is differentially distributed in GABAergic interneurons and pyramidal cells in the rat medial prefrontal cortex

Brain Research ◽

10.1016/j.brainres.2010.03.011 ◽

2010 ◽

Vol 1329 ◽

pp. 89-102 ◽

Cited By ~ 18

Author(s):

Satoko Oda ◽

Hiromasa Funato ◽

Satomi Adachi-Akahane ◽

Masanori Ito ◽

Akiko Okada ◽

...

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Pyramidal Cells ◽

Gabaergic Interneurons ◽

Dopamine D5 Receptor

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Chemogenetic Inhibition of Infralimbic Prefrontal Cortex GABA-ergic Parvalbumin Interneurons Attenuates Chronic Stress Adaptions in Male Mice

10.1101/792721 ◽

2019 ◽

Author(s):

Nawshaba Nawreen ◽

Rachel Morano ◽

Parinaz Mahbod ◽

Evelin M. Cotella ◽

Khushali Dalal ◽

...

Keyword(s):

Prefrontal Cortex ◽

Chronic Stress ◽

Stress Responses ◽

Acute Stress ◽

Forced Swim Test ◽

Designer Drugs ◽

Gabaergic Interneurons ◽

Coping Behaviors ◽

Passive Coping ◽

Parvalbumin Interneurons

ABSTRACTHypofunction of the prefrontal cortex (PFC) contributes to stress-related neuropsychiatric illnesses. Mechanisms leading to prefrontal hypoactivity remain to be determined. Prior evidence suggests that enhanced activity of parvalbumin (PV) expressing GABAergic interneurons (INs) play a role in chronic stress related pathologies. In this study, the role of PFC PV INs in stress related phenotypes were explored using Cre inducible inhibitory DREADDs (Designer Receptors Exclusively Activated by Designer Drugs). Mice were first tested in the tail suspension test (TST) to determine the effects of PV IN inhibition during acute stress. Following this, the long term impact of PV IN inhibition during chronic variable stress (CVS) was tested in the forced swim test (FST). Acute PV IN inhibition reduced active (struggling) and increased passive coping behaviors (immobility) in the TST. In contrast, inhibition of PV INs during CVS increased active and reduced passive coping behaviors in the FST. Moreover, chronic inhibition of PV INs attenuated CVS-induced changes in Fos expression in the prelimbic cortex, basolateral amygdala and ventrolateral periaqueductal gray and also prevented adrenal hypertrophy and body weight loss associated with chronic stress. Our results suggest differential roles of PV INs to acute vs chronic stress, indicative of distinct biological mechanisms underlying acute vs. chronic stress responses. Our results also indicate a role for PV INs in driving chronic stress adaptation and support literature evidence suggesting cortical GABAergic interneurons as a therapeutic target in stress related diseases.SIGNIFICANCEStress related diseases are associated with prefrontal hypoactivity, the mechanism of which is currently not known. In this study we showed that by inhibiting prefrontal GABA-ergic Parvalbumin interneurons (PV INs) using DREADDs, we can attenuate some of chronic stress related phenotypes. Additionally, we showed that modulation of PV IN activity during acute vs chronic stress had opposing effects on stress coping strategies, suggesting different underlying mechanisms behind acute vs chronic stress paradigms. Our findings indicate that GABA-ergic PV INs may be involved in driving stress related phenotypes and thereby an important target for treatment of stress-related illnesses. Our data suggest that reducing PV IN activity to promote prefrontal output may be an effective treatment strategy for stress related disorders.

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