Dataset Information

Subtype-specific effects of dopaminergic D2 receptor activation on synaptic trains in layer V pyramidal neurons in the mouse prefrontal cortex.

ABSTRACT: In humans, prefrontal cortical areas are known to support executive functions. In mice, these functions are mediated by homologous regions in the medial prefrontal cortex (mPFC). Executive processes are critically dependent on optimal levels of dopamine (DA), but the cellular mechanisms of DA modulation are incompletely understood. Stable patterns of neuronal activity may be sensitive to frequency-dependent changes in synaptic transmission. We characterized the effects of D2 receptor (D2R) activation on short-term excitatory postsynaptic potential (EPSP) dynamics evoked at varying frequencies in the two subtypes of layer V pyramidal neurons in mouse mPFC We isolated NMDA receptor and non-NMDA receptor-mediated components of EPSP trains evoked by stimulating fibers within layer V or layer I. All significant effects of D2 receptor activation were confined to type I (corticopontine) cells. First, we found that with layer I stimulation, D2R activation reduces the amplitude of NMDAR-mediated EPSPs, with no effect on facilitation or depression of these responses at lower frequencies, but leading to facilitation with high frequency stimulation. Further, the non-NMDA component also underwent synaptic depression at low frequencies. Second, with layer V stimulation, D2R activation had no effect on NMDA or non-NMDA receptor-mediated EPSP components. Overall, our results suggest that D2R activation may modulate memory functions by inhibiting 'top-down' influences from apical tuft inputs activated at low frequencies, while promoting 'top-down' influences from inputs activated at higher frequencies. These data provide further insight into mechanisms of dopamine's modulation of executive functions.

SUBMITTER: Leyrer-Jackson JM

PROVIDER: S-EPMC5704077 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Subtype-specific effects of dopaminergic D2 receptor activation on synaptic trains in layer V pyramidal neurons in the mouse prefrontal cortex.

Leyrer-Jackson Jonna M JM Thomas Mark P MP

Physiological reports 20171101 22

In humans, prefrontal cortical areas are known to support executive functions. In mice, these functions are mediated by homologous regions in the medial prefrontal cortex (mPFC). Executive processes are critically dependent on optimal levels of dopamine (DA), but the cellular mechanisms of DA modulation are incompletely understood. Stable patterns of neuronal activity may be sensitive to frequency-dependent changes in synaptic transmission. We characterized the effects of D2 receptor (D2R) activ ...[more]

PMID: 29150590

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Project description:Exposure to unpredictable environmental stress is widely recognized as a major determinant for risk and severity in neuropsychiatric disorders such as major depressive disorder, anxiety, schizophrenia, and PTSD. The ability of ostensibly unrelated disorders to give rise to seemingly similar psychiatric phenotypes highlights a need to identify circuit-level concepts that could unify diverse factors under a common pathophysiology. Although difficult to disentangle a causative effect of stress from other factors on medial prefrontal cortex (PFC) dysfunction, a wealth of data from humans and rodents demonstrates that the PFC is a key target of stress. The present study sought to identify a model of chronic unpredictable stress (CUS) which induces affective behaviors in C57BL6J mice and once established, measure stress-related alterations in intrinsic excitability and synaptic regulation of mPFC layer 5/6 pyramidal neurons. Adult male mice received 2 weeks of 'less intense' stress or 2 or 4 weeks of 'more intense' CUS followed by sucrose preference for assessment of anhedonia, elevated plus maze for assessment of anxiety and forced swim test for assessment of depressive-like behaviors. Our findings indicate that more intense CUS exposure results in increased anhedonia, anxiety, and depressive behaviors, while the less intense stress results in no measured behavioral phenotypes. Once a behavioral model was established, mice were euthanized approximately 21 days post-stress for whole-cell patch clamp recordings from layer 5/6 pyramidal neurons in the prelimbic (PrL) and infralimbic (IL) cortices. No significant differences were initially observed in intrinsic cell excitability in either region. However, post-hoc analysis and subsequent confirmation using transgenic mice expressing tdtomato or eGFP under control of dopamine D1-or D2-type receptor showed that D1-expressing pyramidal neurons (D1-PYR) in the PrL exhibit reduced thresholds to fire an action potential (increased excitability) but impaired firing capacity at more depolarized potentials, whereas D2-expressing pyramidal neurons (D2-PYR) showed an overall reduction in excitability and spike firing frequency. Examination of synaptic transmission showed that D1-and D2-PYR exhibit differences in basal excitatory and inhibitory signaling under naïve conditions. In CUS mice, D1-PYR showed increased frequency of both miniature excitatory and inhibitory postsynaptic currents, whereas D2-PYR only showed a reduction in excitatory currents. These findings demonstrate that D1-and D2-PYR subpopulations differentially undergo stress-induced intrinsic and synaptic plasticity that may have functional implications for stress-related pathology, and that these adaptations may reflect unique differences in basal properties regulating output of these cells.

Dataset Information

Subtype-specific effects of dopaminergic D2 receptor activation on synaptic trains in layer V pyramidal neurons in the mouse prefrontal cortex.

Publications

Subtype-specific effects of dopaminergic D2 receptor activation on synaptic trains in layer V pyramidal neurons in the mouse prefrontal cortex.

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