Functional properties of the endocannabinoid system during postnatal development of the monkey prefrontal cortex

YOSHINO H; MIYAMAE T; PAFUNDO DE; ROTARU D; LEWIS DA; GONZALEZ-BURGOS G

Chicago, IL

Congreso; 39th annual meeting of the Society for Neuroscience; 2009

Society for Neuroscience

In cortical circuits, the endocannabinoid (eCB) system regulates the flow of neural activity by retrogradely modulating synaptic transmission. Characterizing the postnatal development of the eCB system in monkey prefrontal cortex (PFC) is particularly important because the postnatal maturation of PFC circuitry and function is significantly protracted in primates compared with rodents. Since the eCB system is the primary target of the effects of exogenous cannabinoids, the normal development of the eCB system may determine an age-dependent sensitivity of neocortical circuits to cannabis abuse. Importantly, heavy cannabis use during adolescence has been linked to increased risk for drug addiction and schizophrenia. To examine the postnatal development of the eCB system in primate PFC, we developed methods to study depolarization-induced suppression of inhibition (DSI) in deep layer 3 pyramidal neurons of macaque monkey PFC, using whole-cell patch clamp recordings in brain slices. IPSCs were evoked at 0.2 Hz by focal extracellular stimulation applied near the soma of the recorded pyramidal neurons in the presence of the P/Q type voltage-dependent calcium channel blocker agatoxin IVA (250 nM) to minimize eCB-insensitive GABA release. We induced DSI by applying 4 s voltage steps from -80 to 0 mV. In slices prepared from adolescent (34-35 month-old) animals, depolarizing steps induced DSI in 25 of 49 pyramidal neurons (probability of inducing DSI = 0.51). DSI significantly reduced the amplitude of IPSCs evoked 1.3 s after the end of the depolarizing steps (residual IPSC amplitude: 37.28 ± 3.58 % of control, n=25). The IPSCs recovered from DSI with a time course that was well-fit by a single exponential function with a time constant of 25.2 s. In 10 experiments in which significant DSI was induced (residual IPSC amplitude: 27.14 ± 7.08 % of control), subsequent application of the eCB receptor 1 (CB1) antagonist AM281 (10 µM) significantly attenuated DSI (residual IPSC amplitude: 63.69 ± 11.32 % of control, p < 0.05), showing that DSI in monkey PFC requires CB1 receptor activation. Additional studies are being performed to determine the properties of DSI (probability of induction, magnitude and time course of IPSC suppression) in PFC pyramidal cells from animals of different postnatal age groups.