Dopamine regulates working memory and its cellularcorrelates in the PFC

Adapted from: Sawaguchi et al. (1986; 1988; 1990a,b)

How does dopamine regulate working memory at the cellular level in the PFC?

• Study effects of dopamine on intrinsic properties of PFC neurons.

• Study effects of dopamine on synaptic inputs to PFC neurons.

• Make a model incorporating these data and see if you can answer the above question.

Experimental Set-up

Overview

Effects of D1 receptor activation on pyramidal cell firing

D1 receptor activation enhances evoked firing by shifting INAP activation

D1 receptor activation sustains evoked firing by Slowing INAP inactivation by 42%

D1 receptor activation also sustains evoked firing by reducing a slowly-inactivating K+ current

Effects of dopamine on excitatory transmission

D1 agonists have no effect on low frequency inputs but enhance high frequency inputs.

D1 receptor activation increases NMDA EPSCs selectively

D1 receptor stimulation reduces release probability very slightly.

Minimal Stimulation

MK-801 Blocking Function

12.2 ± 7%

D1 receptor activation increases post-synaptic NMDA conductance

GNMDA= 5.9 1+e-0.0038(v-(-35))

GNMDA= 5.07 1+e-0.0038(v-(-25))

GNMDA

Vm

2.5pA

100ms

ControlD1 Agonist

Control

D1 Agonist

Voltage-Clamp(Cs, TTX, Cd)

D1 agonists do not enhance response to trains when NMDA receptors are blocked

Models indicate that the selective increase in depolarization is due to both reduced Pr and

enhanced NMDA conductance

DataSimulation

GNMDA shift + depression shift

GNMDA shift alone

Data

Simulated D1

controlD1 condition

Effects of dopamine on inhibitory transmission

Dopamine has bi-directional effects on IPSCs

D2 D1

Dopamine can switch IPSCs from a reduced state (D2-mediated) to an enhanced state (D1-mediated)

D1 agonists increase action-potential evoked Spontaneous IPSCs but not Mini IPSCs.

Dopamine via D1 but not D2 receptors directly excites interneurons

D2-mediated reduction of IPSCs is blocked by a muscarinic acetylcholine antagonist (Atropine)

Summary of the Physiological Effects of Dopamine

Linking cellular mechanisms to the functions of dopamine in the PFC

Computational Modeling

(Daniel Durstewitz)

Simulation of D1 effects leads to reduction in spontaneous but large enhancement in evoked “delay-period” activity

The model reproduces qualitative aspects of dopamine’s actions in vivo

How does dopamine regulate working memory at the cellular level in the PFC?

• It gates the flow of synaptic input into the PFC and regulates network activity via its effects on inhibition.

• It aids in establishing and stabilizing up-states (delay-period activity) via its actions on INAP, IKS, INMDA, & glutamate release.

SupervisorsAnthony Phillips (UBC)

Charles Yang (UBC, Lilly Research Labs. )

Natalia Gorelova (UBC)

Terry Sejnowski (Salk Institute)

Charles Stevens (Salk Institute)

CollaboratorsStan Floresco (UBC)

Daniel Durstewitz (Salk Institute)