Auditory Event-Related Potentials in Two Rat Models of Attention-Deficit Hyperactivity Disorder: Evidence of Automatic Attention Deficits in Spontaneously Hypertensive Rats but Not in Latrophilin-3 Knockout Rats

Abstract

Background/objectives: Variations of the latrophilin-3 (Lphn3) gene have been associated with attention-deficit hyperactivity disorder (ADHD). To explore the functional influence of this gene, Lphn3 knockout (KO) rats were generated and have thus far demonstrated deficits in ADHD-relevant phenotypes, including working memory, impulsivity, and hyperactivity. However, inattention remains unexplored.

Methods: We assessed automatic attention in Lphn3 KO (n = 19) and their control line (wildtype/WT, n = 20) through use of the following auditory event-related potentials (ERPs): P1, N1, P2, and N2. We also extended this exploratory study by comparing these same ERPs in spontaneously hypertensive rats (SHRs, n = 16), the most commonly studied animal model of ADHD, to their control line (Wistar-Kyoto/WKY, n = 20). Electroencephalograms (EEG) were recorded using subdermal needle electrodes at frontocentral sites while freely moving rats were presented with five-tone trains (50 ms tones, 400 ms tone onset asynchronies) with varying short (1 s) and long (5 s) inter-train intervals. Peak amplitudes and latencies were analyzed using GLM-mixed ANOVAs to assess differences across genotypes (KO vs. WTs) and strains (SHRs vs. WKYs).

Results: The KOs did not demonstrate any significant differences in peak amplitudes relative to the WT controls, suggesting that the null expression of Lphn3 does not result in the development of inefficiencies in automatic attention. However, the SHRs exhibited significantly reduced peak P1 (and peak-to-peak P1-N1) values relative to the WKYs. These attenuations likely reflect inefficiencies in bottom-up arousal networks that are necessary for efficient automatic processing.

Conclusions: Distinct findings between these animal models likely reflect differing alterations in dopamine and noradrenaline neurotransmission that may underlie ADHD-relevant phenotypes.

Keywords: ADHD; Lphn3; SHR; animal; auditory processing; auditory-evoked potential; genetic models.

Figure A1

Peak-to-peak P1–N1 (A), N1–P2 (B), and P2–N2 (C) amplitudes in both Lphn3 KOs and WT controls, not separated by sex, for both 1 s and 5 s (long) ITIs. Error bars represent the standard error of the mean (SEM).

Figure A2

Peak-to-peak P1–N1 (A), N1–P2 (B), and P2–N2 (C) amplitudes in both SHRs and WKY controls, not separated by sex, for both 1 s and 5 s (long) ITIs. Error bars represent the standard error of the mean (SEM).

Figure 1

Outline of 5-tone train paradigm. Trains were separated randomly by either 1 or 5 s of silence (offset to onset). Each rat was presented with 320 tone trains, with 160 being preceded by a 1 s ITI (i.e., short) or a 5 s ITI (long). Tones were 50 ms in duration with a 400 ms SOA.

Figure 2

Average ERP waveforms for KOs and WTs to 5-tone trains following both the 5 s (i.e., long) and 1 s (i.e., short) ITIs. Black hollow rectangles indicate the presentation of each 50 ms tone in the train.

Figure 3

Peak amplitudes of P1 (A), N1 (B), P2 (C), and N2 (D) for both Lphn3 KOs and WT controls not separated by sex for both 1 s and 5 s (long) ITIs. Error bars represent the standard error of the mean (SEM).

Figure 4

Average ERP waveforms for SHRs and WKYs to a 5-tone train following both the 5 s (i.e., long) and 1 s (i.e., short) ITIs. Black hollow rectangles indicate the presentation of each 50 ms tone in the tone train.

Figure 5

Peak amplitudes of P1 (A), N1 (B), P2 (C), and N2 (D) for both SHRs and WKY controls, not separated by sex, for both 1 s and 5 s (long) ITIs. Error bars represent the standard error of the mean (SEM).