Astrocyte-Specific Disruption of SynCAM1 Signaling Results in ADHD-Like Behavioral Manifestations

SynCAM1 is an adhesion molecule involved in synaptic differentiation and organization. SynCAM1 is also expressed in astroglial cells where it mediates astrocyte-to astrocyte and glial-neuronal adhesive communication. In astrocytes, SynCAM1 is functionally linked to erbB4 receptors, which are involved in the control of both neuronal/glial development and mature neuronal and glial function. Here we report that mice carrying a dominant-negative form of SynCAM1 specifically targeted to astrocytes (termed GFAP-DNSynCAM1 mice) exhibit disrupted diurnal locomotor activity with enhanced and more frequent episodes of activity than control littermates during the day (when the animals are normally sleeping) accompanied by shorter periods of rest. GFAP-DNSynCAM1 mice also display high levels of basal activity in the dark period (the rodent's awake/active time) that are attenuated by the psychostimulant D,L-amphetamine, and reduced anxiety levels in response to both avoidable and unavoidable provoking stimuli. These results indicate that disruption of SynCAM1-dependent astroglial function results in behavioral abnormalities similar to those described in animals model of attention-deficit hyperactive disorder (ADHD), and suggest a hitherto unappreciated contribution of glial cells to the pathophysiology of this disorder

GFAP-DNSynCAM1 mice have reduced anxiety in the acoustic startle paradigm.

<p>(<b>A</b>) Startle amplitudes for the GFAP-DNSynCAM1 (black bars; n = 8) and WT (white bars; n = 7) mice for each of the sound intensities tested. Data points represent means ± SEM. Data were analyzed with ANOVA for repeated measures. (<b>B</b>) The average startle amplitudes for each genotype during baseline (0 db) and after different stimulation intensities (80–120 db). (<b>C</b>) Percent response of GFAP-DNSynCAM1 (black bars; n = 9) and WT (white bars; n = 8) in the PPI test using two different stimuli intensities (110 and 120 db). The data are represented as the mean ± SEM and analyzed by two- way ANOVA (intensity by genotype) followed by unpaired t test post hoc analysis. * p<0.05.</p

GFAP-DNSynCAM1 mice have increased spontaneous locomotor activity that is attenuated by amphetamine.

<p>(<b>A</b>) Illustration depicting the behavior paradigm used to assess spontaneous locomotor activity and response to amphetamine in the open field. Adult male GFAP-DNSynCAM1 (n = 8) and WT littermates (n = 5) were subjected to the following paradigm during the dark (active) phase of the light cycle: 4 h of habituation, followed by 2 h of spontaneous locomotor activity post saline injection, followed by 2 h of locomotor activity after injection of D,L- amphetamine (4 mg/kg). (<b>B</b>) Total distance traveled (cm) in 1 hour time bins by GFAP-DNSynCAM1 (black circles) and WT littermates (white squares) during the habituation period. (<b>C</b>) Total distance traveled (cm) in 10 minute time bins by GFAP-DNSynCAM1 (black circles) and WT littermates (white squares) immediately following a subcutaneous injection of saline. Inset is the average distance traveled (cm) by each mouse during the first and second hours of behavior assessment. (<b>D</b>) Total distance traveled (cm) in 10 min bins by GFAP-DNSynCAM1 (black circles) and WT littermates (white squares) immediately following a subcutaneous injection of D,L- amphetamine (4 mg/kg). For all graphs the data points are represented as means ± SEM. Panels B–D were analyzed using a repeated measures ANOVA (time by genotype) followed by an unpaired t-test for each time point (panel D). Data shown in the inset to panel C were analyzed by a two way ANOVA (time by genotype) followed by a Student-Newman-Keuls post hoc test. * p<0.05.</p

DN-SynCAM1 mice display behaviors of reduced anxiety in the zero maze.

<p>(<b>A</b>) Total distance traveled (cm) by GFAP-DNSynCAM1 (black bars; n = 9) and WT littermates (white bars, n = 8) in the open areas of the zero maze. (<b>B</b>) Total active time (seconds) in the open areas for GFAP-DNSynCAM1 (black bars) and WT littermates (white bars). (<b>C</b>) Total rest time (seconds) in the open areas for GFAP-DNSynCAM1 (black bars) and WT littermates (white bars). (<b>D</b>) Total distance traveled in the open and closed areas of the zero maze by GFAP-DNSynCAM1 (black bars) and WT littermates (white bars). Data are represented as the mean ± SEM and compared using an unpaired t-test. * p<0.05.</p

GFAP-DNSynCAM1 mice have increased locomotor activity and shortened resting intervals during a 24 h period.

<p>Adult male GFAP-DNSynCAM1 L27 (n = 8), L45 (n = 6) mice and WT littermates (n = 8) were housed individually and 24-hour activity was recorded in 6-minute bins for a period of one week using MiniMitter telemetry devices. (<b>A</b>) Representative 24-hour activity profiles from one WT littermate (upper panel) and two GFAP-DNSynCAM1 adult male mice (Line 27, middle panel; L45, lower panel). (<b>B</b>) Average cumulative daily activity counts for both light and dark periods. (<b>C</b>) Average amplitude of activity spikes during light and dark periods (number of activity counts per 6-minute bin). (<b>D</b>) Average frequency of activity peaks (minutes) for light and dark periods. (<b>E</b>) Average cumulative time spent resting (minutes) during light and dark periods (6-minute bins recorded as zero movement). (<b>F</b>) Average duration of each rest period (minutes) for both light and dark periods. Activity was analyzed in the light and dark periods for WT (white bars), DN-SynCAM1 L27 (grey bars) and DN-SynCAM1 L45 (black bars). For all graphs data are expressed as the mean ± SEM. Data are analyzed using a two way ANOVA (period by genotype) followed by Student-Newman-Keuls post hoc analysis, * p<0.05; ** p<0.01; *** p<0.001.</p

SynCAM1, a Synaptic Adhesion Molecule, Is Expressed in Astrocytes and Contributes to erbB4 Receptor-Mediated Control of Female Sexual Development

erbB4 receptor-mediated facilitation of glial-neuronal interactions in the neuroendocrine brain involves SynCAM1-dependent signaling, and this interaction is required for normal female reproductive function