Parallel loss of hippocampal LTD and cognitive flexibility in a genetic model of hyperdopaminergia

Abstract

Dopamine-mediated neurotransmission has been implicated in the modulation of synaptic plasticity and in the mechanisms underlying learning and memory. In the present study, we tested different forms of activity-dependent neuronal and behavioral plasticity in knockout mice for the dopamine transporter (DAT-KO), which constitute a unique genetic model of constitutive hyperdopaminergia. We report that DAT-KO mice exhibit slightly increased long-term potentiation and severely decreased long-term depression at hippocampal CA3-CA1 excitatory synapses. Mutant mice also show impaired adaptation to environmental changes in the Morris watermaze. Both the electrophysiological and behavioral phenotypes are reversed by the dopamine antagonist haloperidol, suggesting that hyperdopaminergia is involved in these deficits. These findings support the modulation by dopamine of synaptic plasticity and cognitive flexibility. The behavioral deficits seen in DAT-KO mice are reminiscent of the deficits in executive functions observed in dopamine-related neuropsychiatric disorders, suggesting that the study of DAT-KO mice can contribute to the understanding of the molecular basis of these disorders.

Figure 1

DAT-KO mice exhibit enhanced LTP but impaired LTD. (a, left) Time course of mean theta-burst stimulation-induced LTP (arrow) in hippocampal slices of WT (N = 7), HT (N = 4), and KO (N = 13) mice, (a, right) Summary histograms of the percent in fEPSP slope averaged from the last 15 min of recordings, (b, left) Time course of mean high frequency stimulation-induced LTP (arrow) in WT (N = 7) and KO (N = 6) mice, (b, right) Summary histograms of the percent in fEPSP slope averaged from the last 15 min of recordings, (c, left) Time course of mean low frequency stimulation-induced LTD (arrow) in WT (N = 8), HT (N = 5), and KO (N = 9) mice, (c, right) Summary histograms of the percentage in fEPSP slope averaged from the last 15 min of recordings. The dotted line represents percentage of baseline. Values represent means ± s.e.m. (n) represent numbers of slices per group. *P< 0.05 and **P< 0.01.

Figure 2

Haloperidol, but not methylphenidate, fully restores LTD in DAT-KO mice, (a, left) Time course of mean low frequency stimulation-induced LTD (arrow) calculated from slices of WT (N = 8) and KO (N = 5) mice in the presence of haloperidol. (a, right) Summary histograms of the percent in fEPSP slope averaged from the last 15 min of recordings performed in the presence of haloperidol. (b, left) Time course of mean low frequency stimulation-induced LTD (arrow) in WT (N = 6) and KO (N = 6) mice in the presence of methylphenidate. (b, right) Summary histograms of the percent in fEPSP slope averaged from the last 15 min of recordings performed in the presence of methylphenidate. The dotted line represents percentage of baseline. Values represent means ± s.e.m. (n) represent numbers of slices per group. **P< 0.01.

Figure 3

DAT-KO mice exhibit normal spatial reference memory, but show disrupted reversal learning in the Morris watermaze. Performance of WT, HT, and KO mice during acquisition trials of the place (a) and reversal (c) learning. The results are expressed as distance traveled (cm) and proportion of successful trials. Probe trial of the place (b) and reversal learning (d). Mice were scored for the percentage of distance traveled in the four quadrants: north-est (NE), south-est (SE), south-west (SW), and north-west (NW), and for the number of annulus crossings. The targeted quadrant and platform are indicated in black. The horizontal line indicates the distance traveled using a random search strategy. Values represent means ± s.e.m. (n = 8 mice per group).

Figure 4

DAT-KO mice are severely impaired in the cued version of the Morris watermaze. (a) Performance of WT, HT, and KO mice on the spontaneous cued version, (b) Performance of WT and KO mice in the cued version with the platform kept at a fixed position. Results are expressed as mean distance traveled (top) and proportion of successful trials (bottom). Values represent means ± s.e.m. (n = 5–7 mice per group).

Figure 5

Haloperidol improves the performances of DAT-KO mice in the cued version of the Morris watermaze. (a) Total locomotor horizontal activity in WT and KO mice automatically recorded over a 2-h period after acute injection of saline or haloperidol (n = 5–8 mice per group), (b) Performance of WT and KO mice in the cued version of the watermaze. Thirty minutes before each daily session, mutant mice were injected with haloperidol (0.075 mg/kg, i.p.) and WT mice received a saline injection. Results are expressed as mean distance traveled (top) and proportion of successful trials (bottom). Values represent means ± s.e.m. (n = 8 mice per group).

Figure 6

Methylphenidate does not improve the performance of DAT-KO mice in the cued version of the Morris watermaze. (a) Locomotor dose-response to administration of methylphenidate in DAT-KO mice over a 2-h period (n = 5–15 mice per group), (b) Performance of the WT and KO in the cued version following methylphenidate treatment. Fifteen minutes before each daily session, mutant mice were injected with methylphenidate (80 mg/kg, i.p.), and WT mice received a saline injection. All results are expressed as mean distance traveled (top) and proportion of successful trials (bottom). Values represent means ± s.e.m. (n = 8 mice per group).