Abstract
The medial prefrontal cortex plays a key role in higher order cognitive functions like decision making and social cognition. These complex behaviors emerge from the coordinated firing of prefrontal neurons. Fast-spiking interneurons (FSIs) control the timing of excitatory neuron firing via somatic inhibition and generate gamma (30-100 Hz) oscillations. Therefore, factors that regulate how FSIs respond to gamma-frequency input could affect both prefrontal circuit activity and behavior. Here, we show that serotonin (5HT), which is known to regulate gamma power, acts via 5HT2A receptors to suppress an inward-rectifying potassium conductance in FSIs. This leads to depolarization, increased input resistance, enhanced spiking, and slowed decay of excitatory post-synaptic potentials (EPSPs). Notably, we found that slowed EPSP decay preferentially enhanced temporal summation and firing elicited by gamma frequency inputs. These findings show how changes in passive membrane properties can affect not only neuronal excitability but also the temporal filtering of synaptic inputs.
Highlights
The prefrontal cortex (PFC) organizes higher order cognitive functions ranging from decision making to social cognition (Euston et al, 2012; Dias et al, 1996; Ray and Zald, 2012).These complex behaviors emerge from the coordinated firing of PFC neurons, resulting in neuronal oscillations (Buzsaki and Chrobak, 1995; Buzsaki and Wang, 2012)
We found this concentration of 30 mM to be sub-saturating, eliciting approximately 80% of the maximal response (Figure 1—figure supplement 2). 5HT depolarized Fast-spiking interneurons (FSIs) even in the presence of ionotropic glutamatergic (10 mM CNQX, 100 mM DL-AP5) and GABAergic (10 mM SR95531) antagonists (Figure 1C–D, p=0.043 for Vm and p=0.05 for Rin, 5HT + syn block n = 9 vs. time-locked controls n = 8, post-hoc Tukey comparison after one-way ANOVAs with p=0.005 for Vrest and p=0.004 for Rin), but effects were blocked (n = 7) by the 5HT2A antagonist MDL100907 (1 mM, Figure 1C–D, p=0.024 for Vm and p=0.026 for Rin, 5HT vs. 5HT + 2A antagonist post-hoc Tukey comparison after one- way ANOVAs with p=0.005 for Vrest and p=0.004 for Rin)
We find that by closing potassium channels, serotonin increases the excitability of FSIs, and promotes synaptic integration in a frequency-specific manner, leading to preferential enhancement of responses to gamma frequency inputs, both in terms of excitatory postsynaptic potentials (EPSPs) summation, spiking, and network inhibition
Summary
The prefrontal cortex (PFC) organizes higher order cognitive functions ranging from decision making to social cognition (Euston et al, 2012; Dias et al, 1996; Ray and Zald, 2012).These complex behaviors emerge from the coordinated firing of PFC neurons, resulting in neuronal oscillations (Buzsaki and Chrobak, 1995; Buzsaki and Wang, 2012). Synchronized oscillations of neuronal activity in the gamma frequency range (30–100 Hz) play a key role in information encoding (Buzsaki and Chrobak, 1995; Buzsaki and Wang, 2012) and prefrontal gamma oscillations influence the performance of tasks related to cognitive flexibility and attention (Cho et al, 2015; Kim et al, 2016). Neuropsychiatric disease associated with deficits in PFC gamma synchrony, including schizophrenia and depression, are currently treated with medications that have high affinity for serotonin receptors (Meltzer and Massey, 2011).
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