Mouse plasmacytoma-expressed transcript 1 knock out induced 5-HT disruption results in a lack of cognitive deficits and an anxiety phenotype complicated by hypoactivity and defensiveness

Abstract

Serotonin (5-HT) is involved in many developmental processes and influences behaviors including anxiety, aggression, and cognition. Disruption of the serotonergic system has been implicated in human disorders including autism, depression, schizophrenia, and ADHD. Although pharmacological, neurotoxin, and dietary manipulation of 5-HT and tryptophan hydroxylase has added to our understanding of the serotonergic system, the results are complicated by multiple factors. A newly identified ETS domain transcription factor, Pet-1, has direct control of major aspects of 5-HT neuronal development. Pet-1 is the only known factor that is restricted in the brain to 5-HT neurons during development and adulthood and exerts dominant control over 5-HT neuronal phenotype. Disruption of Pet-1 produces an approximately 80% loss of 5-HT neurons and content and results in increased aggression in male Pet-1(-/-) mice [Hendricks TJ, Fyodorov DV, Wegman LJ, Lelutiu NB, Pehek EA, Yamamoto B, Silver J, Weeber EJ, Sweatt JD, Deneris ES (2003) Neuron 37:233-247]. We hypothesized that Pet-1(-/-) mice would also exhibit changes in anxiety and cognition. Pet-1(-/-) mice were hypoactive which may have affected the observed lack of anxious behavior in the elevated zero maze and light-dark test. Pet-1(-/-) mice, however, were more defensive during marble burying and showed acoustic startle hyper-reactivity. No deficits in spatial, egocentric, or novel object recognition learning were found in Pet-1(-/-) mice. These findings were unexpected given that 5-HT depleting drugs given to adult or developing animals result in learning deficits [Mazer C, Muneyyirci J, Taheny K, Raio N, Borella A, Whitaker-Azmitia P (1997) Brain Res 760:68-73; Morford LL, Inman-Wood SL, Gudelsky GA, Williams MT, Vorhees CV (2002) Eur J Neurosci 16:491-500; Vorhees CV, Schaefer TL, Williams MT (2007) Synapse 61:488-499]. Lack of differences may be the result of compensatory mechanisms in reaction to a constitutive knock out of Pet-1 or 5-HT may not be as important in learning and memory as previously suspected.

Figure 1

Elevated Zero Maze: A) Time in open (s), B) Latency to enter the open (s), C) Open quadrant entries during a 5 min test session. LS mean ± LS-SEM with males and females combined. *p < 0.05 vs. WT.

Figure 2

Locomotor Activity: Mice were tested for 1 h during the light phase of the light/dark cycle. Total distance (cm) as a function of genotype in 5 min intervals. Data are LS mean ± LS-SEM with males and females combined. *p < 0.05, vs. WT.

Figure 3

Marble Burying: A) Latency to start burying (s); B) Marbles at least 2/3^rd buried. Mice were tested for 20 min. Data are LS mean ± LS-SEM with males and females combined. *p < 0.05, ^†p < 0.10 vs. WT.

Figure 4

Light-Dark Box Exploration: A) Latency to enter the dark (s); B) Number of entries into the light; C) Time in dark (s). Animals were tested for 10 min. Data are LS mean ± LS-SEM with males and females combined. *p < 0.05 vs. WT.

Figure 5

Morris water maze (MWM) hidden platform trials: A) acquisition path length males; B) acquisition path length females; C) reversal path length; D) reversal latency; E) shift path length; F) shift latency. Data are LS mean ± LS-SEM (path length was averaged across 4 trials/day). *p < 0.05 vs. same sex WT controls.

Figure 6

Initial heading error (degrees) during the Shift phase of the Morris water maze (MWM) hidden platform trials: A) males B) females. Data are LS mean ± LS-SEM (initial heading error was averaged across 4 trials/day). *p < 0.05 vs. same sex WT controls.

Figure 7

Cincinnati water maze (CWM): A) Latency (s) males; B) Latency (s) females; C) Errors males; D) Errors females; E) Start returns males and females combined. Data are LS mean ± LS-SEM averaged across trials (2 trials/day). *p < 0.05 vs. same sex WT for panels A, B, C, D; *p < 0.05 vs. WT with sexes combined.

Figure 8

Locomotor activity with methamphetamine challenge: Total distance (cm) for: A) males; B) females. Methamphetamine dose was 1 mg/kg given s.c. Data are LS mean ± LS-SEM shown in 5 min intervals. *p < 0.05 vs. same sex WT controls.