Histamine Release in the Prefrontal Cortex Excites Fast-Spiking Interneurons while GABA Released from the Same Axons Inhibits Pyramidal Cells

Abstract

We studied how histamine and GABA release from axons originating from the hypothalamic tuberomammillary nucleus (TMN) and projecting to the prefrontal cortex (PFC) influence circuit processing. We optostimulated histamine/GABA from genetically defined TMN axons that express the histidine decarboxylase gene (TMNHDCaxons). Whole-cell recordings from PFC neurons in layer 2/3 of prelimbic, anterior cingulate, and infralimbic regions were used to monitor excitability before and after optostimulated histamine/GABA release in male and female mice. We found that histamine-GABA release influences the PFC through actions on distinct neuronal types: the histamine stimulates fast-spiking interneurons; and the released GABA enhances tonic (extrasynaptic) inhibition on pyramidal cells (PyrNs). For fast-spiking nonaccommodating interneurons, histamine released from TMNHDCaxons induced additive gain changes, which were blocked by histamine H1 and H2 receptor antagonists. The excitability of other fast-spiking interneurons in the PFC was not altered. In contrast, the GABA released from TMNHDCaxons predominantly produced divisive gain changes in PyrNs, increasing their resting input conductance, and decreasing the slope of the input–output relationship. This inhibitory effect on PyrNs was not blocked by histamine receptor antagonists but was blocked by GABAAreceptor antagonists. Across the adult life span (from 3 to 18 months of age), the GABA released from TMNHDCaxons in the PFC inhibited PyrN excitability significantly more in older mice. For individuals who maintain cognitive performance into later life, the increases in TMNHDCGABA modulation of PyrNs during aging could enhance information processing and be an adaptive mechanism to buttress cognition.SIGNIFICANCE STATEMENTThe hypothalamus controls arousal state by releasing chemical neurotransmitters throughout the brain to modulate neuronal excitability. Evidence is emerging that the release of multiple types of neurotransmitters may have opposing actions on neuronal populations in key cortical regions. This study demonstrates for the first time that the neurotransmitters histamine and GABA are released in the prefrontal cortex from axons originating from the tuberomammillary nucleus of the hypothalamus. This work demonstrates how hypothalamic modulation of neuronal excitability is maintained throughout adult life, highlighting an unexpected aspect of the aging process that may help maintain cognitive abilities.

Histamine originating from the BNST modulates corticostriatal synaptic transmission during early postnatal development

“…The neuromodulator histamine is synthesized by neurons located in the tuberomammillary nucleus (TMN) of the hypothalamus which send wide-spread axonal projections and release histamine throughout the central nervous system (Haas & Panula, 2003;Haas et al, 2008;Lin et al, 2023). Although classically assumed to mainly regulate the sleep-wake cycle, the histaminergic system is now thought to have many more diverse physiological roles in a multitude of brain regions and stages of life (Schwartz et al, 1991;Takahashi et al, 2006;Panula et al, 2014;Han et al, 2020;Lucaci et al, 2023), and has been shown to be dysfunctional in various neurological and neurodevelopmental disorders (Ercan-Sencicek, 2010; Shan et al, 2015;Carthy & Ellender, 2021;Xu et al, 2022;Ma et al, 2023). For example, Tourette's syndrome (TS) is an earlyonset disorder that is characterized by involuntary motor and vocal tics often comorbid with obsessive-compulsive disorder (OCD) and depression (Robertson et al, 2017) and parallel findings in patients and mouse models suggest that a disruption of the histaminergic system and reduced levels of histamine can be part of the etiology (Ercan-Sencicek, 2010;Fernandez et al, 2012;Karagiannidis et al, 2013;Baldan et al, 2014).…”