Cannabinoids, or active ingradients of marijuana, have involved with human lives for more than thousands of years, but how they affect neuronal circuit formation is not well understood. We show cannabinoid signaling plays a major role in the formation of thalamocortical projection.
Mammalian sensory cortex shows remarkable plasticity during critical period, in which sensory experiences shape cortical circuits in an input dependent manner. It has been shown that spike timing-dependent plasticity (STDP) at L4-L2/3 synapse, which requires cannabinoid signaling, plays an important role in the critical period plasticity. We showed previously that tLTD at L4-L2/3 synapse appears only after the initiation of critical period, or P12-13, and this synapse exhibits only LTP in a timing-dependent manner (tLTP) before P12 in the rodent barrel cortex. In addition, we recently found that thalamic terminals to L2/3 express cannabinoid receptors (CB1R), and these synapses exhibit only tLTD. Global and cortical excitatory cell-specific knockouts for CB1R supported this finding. Thalamus to L4 synapses lack CB1R, thus these synapses did not exhibit STDP, either. Thus, thalamic activity could reorganize the cortical network by interaction of two STDPs without changing innervation to L4. Consistent with this, thalamocortical projections retracted strongly by exogenous administration of CB1R agonists, including 9-tetrahydrocannabinol (THC, active component of marijuana). We confirmed this by visualizing thalamocortical axons with VGluT2 staining. Similarly, CB1R mutants exhibits completely distracted thalamocortical innervation, which was detected by DiI staining of individual thalamocortical axons at P12. These findings indicate that age and location specific activation of CB1R plays an important role in shaping the cortical network, and abuse of these chemicals would result in a disruption of neural networks.