Abstract
H-current, also known as hyperpolarization-activated current (Ih), is an inward current generated by the hyperpolarization-activated cyclic nucleotide-gated (HCN) cation channels. Ih plays an essential role in regulating neuronal properties, synaptic integration and plasticity, and synchronous activity in the brain. As these biological factors change across development, the brain undergoes varying levels of vulnerability to disorders like schizophrenia that disrupt prefrontal cortex (PFC)-dependent function. However, developmental changes in Ih in PFC neurons remains untested. Here, we examine Ih in pyramidal neurons vs. gamma-aminobutyric acid (GABA)ergic parvalbumin-expressing (PV+) interneurons in developing mouse PFC. Our findings show that the amplitudes of Ih in these cell types are identical during the juvenile period but differ at later time points. In pyramidal neurons, Ih amplitude significantly increases from juvenile to adolescence and follows a similar trend into adulthood. In contrast, the amplitude of Ih in PV+ interneurons decreases from juvenile to adolescence, and does not change from adolescence to adulthood. Moreover, the kinetics of HCN channels in pyramidal neurons is significantly slower than in PV+ interneurons, with a gradual decrease in pyramidal neurons and a gradual increase in PV+ cells across development. Our study reveals distinct developmental trajectories of Ih in pyramidal neurons and PV+ interneurons. The cell-type specific alteration of Ih during the critical period from juvenile to adolescence reflects the contribution of Ih to the maturation of the PFC and PFC-dependent function. These findings are essential for a better understanding of normal PFC function, and for elucidating Ih’s crucial role in the pathophysiology of neurodevelopmental disorders.
Highlights
The prefrontal cortex (PFC) is extensively involved in cognitive and executive functions, and is a major area linked to the cognitive deficits observed in neurodevelopmental disorders such as depression, attention deficit hyperactivity disorder (ADHD) and schizophrenia (Diamond, 2011; Berridge et al, 2012; Monaco et al, 2015)
Compared to pyramidal neurons, the tau for PV+ interneurons was significantly smaller (main effect of cell-type: F(1,72) = 66.62, p < 0.001) with no significant change among the three age groups. These results suggest that the expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel subunits with fast kinetics, most likely HCN1, increased during development in pyramidal neurons, while in the prefrontal PV+ interneurons, HCN2 may have increased during development
Our study is the first to examine the development of hyperpolarization-activated current (Ih) in both types of neurons in the mouse PFC
Summary
The prefrontal cortex (PFC) is extensively involved in cognitive and executive functions, and is a major area linked to the cognitive deficits observed in neurodevelopmental disorders such as depression, attention deficit hyperactivity disorder (ADHD) and schizophrenia (Diamond, 2011; Berridge et al, 2012; Monaco et al, 2015). A distinct feature of the PFC is its delayed maturation, especially involving the gammaaminobutyric acid (GABA)ergic parvalbumin-expressing (PV+) interneurons (Lewis et al, 2005; Caballero and Tseng, 2016). This causes the PFC to become vulnerable to any genetic and environmental factors that may lead to a disruption of normal development. Ih contributes to regulating the neuronal excitability and synaptic activities of both pyramidal neurons and GABAergic interneurons by maintaining the resting membrane potential (RMP) and after-hyperpolarization potential (AHP; Aponte et al, 2006; Bonin et al, 2013; Glykos et al, 2015). Juvenile and adolescence are critical periods for PFC development and the progression of psychiatric disorders, the maturation process of Ih in prefrontal neurons during these critical developmental stages has not been characterized
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