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, 8 (8), e70415

mGluR5 Ablation in Cortical Glutamatergic Neurons Increases Novelty-Induced Locomotion

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mGluR5 Ablation in Cortical Glutamatergic Neurons Increases Novelty-Induced Locomotion

Chris P Jew et al. PLoS One.

Abstract

The group I metabotropic glutamate receptor 5 (mGluR5) has been implicated in the pathology of various neurological disorders including schizophrenia, ADHD, and autism. mGluR5-dependent synaptic plasticity has been described at a variety of neural connections and its signaling has been implicated in several behaviors. These behaviors include locomotor reactivity to novel environment, sensorimotor gating, anxiety, and cognition. mGluR5 is expressed in glutamatergic neurons, inhibitory neurons, and glia in various brain regions. In this study, we show that deleting mGluR5 expression only in principal cortical neurons leads to defective cannabinoid receptor 1 (CB1R) dependent synaptic plasticity in the prefrontal cortex. These cortical glutamatergic mGluR5 knockout mice exhibit increased novelty-induced locomotion, and their locomotion can be further enhanced by treatment with the psychostimulant methylphenidate. Despite a modest reduction in repetitive behaviors, cortical glutamatergic mGluR5 knockout mice are normal in sensorimotor gating, anxiety, motor balance/learning and fear conditioning behaviors. These results show that mGluR5 signaling in cortical glutamatergic neurons is required for precisely modulating locomotor reactivity to a novel environment but not for sensorimotor gating, anxiety, motor coordination, several forms of learning or social interactions.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Reduced mGluR5 expression in the cortex of Cx-mGluR5 KO mice.
(A) Examples of the Western blots used to quantify the abundance of mGluR5, mGluR1 and β-actin in cortex isolated from 6-month old Cx-mGluR5 KO mice and their littermate controls. (B,C) Summaries for the levels of mGluR5/β-actin (B) and mGluR1/β-actin (C). (D) Summaries show reduced mGluR5 levels in the developing cortex of Cx-mGluR5 KO mice. Data are presented as mean ± SEM as % of normalized mGluR5 or mGluR1 in control mice for each specific brain region (**, p<0.01, ***, p<0.0001, Student’s t-test).
Figure 2
Figure 2. Reduced mGluR5 expression in the layer V of mPFC of Cx-mGluR5 KO mice.
Low-magnification images of double immunofluorescence with anti-mGluR5 and anti-CB1 antibodies on mPFC sections of control and Cx-mGluR5 KO mice (A1, B1). A2 and B2 depict merged staining of mGluR5, CB1 and DAPI within the white square from the left panel. The expression of mGluR5 was dramatically reduced in the cortex of Cx-mGlu5 KO mice (B3), while the CB1 expression was similar to littermate controls (A4, B4). (Roman numerals indicated different layers in mPFC. Scale bars in A1, B1∶500 µm; A2, A3, A4, B2, B3, B4∶50 µm.
Figure 3
Figure 3. LTD formation is impaired in layer V of mPFC of Cx-mGlu5 KO mice.
(A). Averaged fEPSP time courses of the LTD experiments in which the 10-minutes, 10 Hz protocol was applied to slices from control (blue; n = 12 at 6 mice) and cKO mice (red; n = 10 at 5 mice). Stimulation is indicated by the arrow. Right panel: sample traces are representative of averaged fEPSP’s (from six recordings) recorded before (1) and after (2) 10 Hz stimulation. (B). Scatter plots showed a significant change of %fEPSP between control and cKO mice (**p<0.01, Student's t-test). The average magnitude of LTD was assessed 20 minutes after stimulation. fEPSP amplitudes are expressed as percent of the baseline amplitude.
Figure 4
Figure 4. Cx-mGlu5 KO mice exhibit enhanced locomotor responses to a novel environment.
(A) Total distance traveled, (B) movement time, (C) movement speed, and (D) vertical activity (numbers of rearing) during 30 minutes of open field assays are presented in 10-minutes bins as well as 0–30 minutes in bar graphs (blue for wild type and red for Cx-mGluR5 KO mice).
Figure 5
Figure 5. Cx-mGlu5 KO mice exhibit normal locomotion in familiar environment.
(A) Home cage activity was plotted in one-hour bins. Light and dark phases over twenty-four hours are indicated as open and closed boxes, respectively. (B) Summary for the total activity during the first six hours in the light or dark phases.
Figure 6
Figure 6. Enhanced activity levels in the open field assay for Cx-mGlu5 mice after MPEP administration.
(A) Total distance traveled is presented in 10-minute time bins before and after vehicle or MPEP injection, ‘0′ represents injection time (arrow). (B) Total distance traveled (WT: vehicle = 0.74±0.31 m, MPEP = 1.98±0.63 m; KO: vehicle = 1.51±0.74 m, MPEP = 10.92±3.03 m), (C) movement time (WT: vehicle = 51.65±16.33 s, MPEP = 117.16±21.29 s; KO: vehicle = 89.58±28.76 s, MPEP = 301.53±27.97 s), and (D) vertical activity (WT: vehicle = 3.85±1.87, MPEP = 10.90±5.17; KO: vehicle = 6.33±2.56, MPEP = 36.33±11.69), are summarized as a 10-minute time bin, 31–40 minute after injection. (E) Summaries of response index for fold changes in distance travelled induced by MPEP (WT = 2.27±0.41, KO = 3.37±0.31). Data are presented as mean ± SEM.
Figure 7
Figure 7. Enhanced activity levels in the open field assay for Cx-mGlu5 mice after methylphenidate administration.
(A) Total distance traveled is presented in 10-minute time bins before and after vehicle or methylphenidate injection, ‘0′ represents injection time (arrow). (B) Total distance traveled (WT: vehicle = 0.74±0.42 m, methylphenidate = 22.91±6.27 m; KO: vehicle = 5.25±3.16 m, methylphenidate = 48.08±4.63 m), (C) movement time (WT: vehicle = 59.38±32.02 s, methylphenidate = 382.74±44.53 s; KO: vehicle = 141.89±46.33 s, methylphenidate = 522.93±13.73 s), and (D) vertical activity (WT: vehicle = 2.11±0.11, methylphenidate = 42.78±21.66; KO: vehicle = 12.42±6.03, methylphenidate = 90.33±16.36) are summarized as a 10-minute time bin, 31–40 minute after injection. (E) Summaries of response index for fold changes in distance travelled triggered by methylphenidate (WT = 30.67±8.39, KO = 64.36±6.20). Data are presented as mean ± SEM.
Figure 8
Figure 8. Cx-mGlu5 mice exhibit normal sensorimotor gating and a slight reduction in repetitive behaviors.
(A,B) Sensorimotor gating was measured by prepulse inhibition (PPI) of the acoustic startle response in Cx-mGlu5 KO mice in C57/129 mixed (A) or in C57BL/6 background (B) and their littermate controls. Summaries of the maximum startle response to a 120 dB white noise sound burst are shown in the left panel. Summaries for the inhibition of the acoustic startle response by either one of three prepulse levels (74, 78 and 82 dB) are shown on the right. (C) Summaries for the number of marbles buried by Cx-mGlu5 KO and control mice in C57BL6 background.

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