Brain-derived neurotrophic factor controls cannabinoid CB1 receptor function in the striatum.

Area of Science:

• Neuroscience
• Molecular Biology
• Neurochemistry

Background:

• Brain-derived neurotrophic factor (BDNF) and cannabinoid CB(1) receptors (CB(1)Rs) are implicated in emotional processing within the striatum.
• Understanding their interplay is crucial for deciphering the neurobiological underpinnings of stress and reward responses.

Purpose of the Study:

• To investigate the functional interaction between BDNF and CB(1)Rs in the striatum.
• To elucidate the molecular mechanisms underlying this interaction and its dependence on dopamine signaling.

Main Methods:

• Electrophysiological recordings of synaptic currents in striatal neurons.
• Genetic manipulation (BDNF+/- mice) and pharmacological interventions (haloperidol).
• Assessment of cholesterol metabolism and lipid raft function.

Main Results:

• BDNF inhibits CB(1)R function specifically for GABA-mediated inhibitory postsynaptic currents (IPSCs) via altered cholesterol and lipid raft function.
• This inhibition is tyrosine kinase-dependent and persists despite receptor sensitization.
• In BDNF(+/-) mice, CB(1)R(GABA) responses are enhanced and resistant to haloperidol, suggesting BDNF mediates D(2)R effects.
• Cocaine exposure reduces BDNF and increases CB(1)R(GABA) activity, dependent on D(2)Rs.

Conclusions:

• BDNF represents a novel regulator of striatal CB(1)R function through cholesterol metabolism.
• Dopamine D(2) receptor-mediated modulation of striatal CB(1)R activity is, at least in part, achieved through BDNF signaling.
• This provides new insights into the neurochemical regulation of emotional states and reward pathways.