Dr. Ávila-Macaya, Ariel

Protein interacting with C-kinase 1 (PICK1) is important for synaptic plasticity through directing transport of glutamate receptors and other proteins. PICK1 gene variants have been associated with schizophrenia. To examine the role of PICK1 in schizophrenia-related behaviors, mice with a mutation in the PICK1 lipid-interacting BAR domain were characterized. Male Pick1-S262T mice had disrupted AMPA receptor (AMPAR) subunit GluA1 and GluA2 protein expression in the hippocampus and prefrontal cortex (PFC). Young adult, but not juvenile (P21), Pick1-S262T mice showed decreased hippocampal synaptic transmission and deficits in long-term depression (LTD). Mutant males also had deficits in reversal learning in the Morris water maze (MWM). These observations suggest that the Pick1-S262T mutation affects AMPAR trafficking, disrupting synaptic transmission and plasticity, as well as cognitive flexibility, a core neuropsychological deficit in schizophrenia. This work suggests possible mechanisms by which a known schizophrenia susceptibility gene could contribute to clinical features of the disorder.

cAMP is a positive regulator tightly involved in certain types of synaptic plasticity and related memory functions. However, its spatiotemporal roles at the synaptic and neural circuit levels remain elusive. Using a combination of a cAMP optogenetics approach and voltage-sensitive dye (VSD) imaging with electrophysiological recording, we define a novel capacity of postsynaptic cAMP in enabling dentate gyrus long-term potentiation (LTP) and depolarization in acutely prepared murine hippocampal slices. To manipulate cAMP levels at medial perforant path to granule neuron (MPP-DG) synapses by light, we generated transgenic (Tg) mice expressing photoactivatable adenylyl cyclase (PAC) in DG granule neurons. Using these Tg(CMV-Camk2aRFP/bPAC)3Koka mice, we recorded field excitatory postsynaptic potentials (fEPSPs) from MPP-DG synapses and found that photoactivation of PAC during tetanic stimulation enabled synaptic potentiation that persisted for at least 30 min. This form of LTP was induced without the need for GABA receptor blockade that is typically required for inducing DG plasticity. The paired-pulse ratio (PPR) remained unchanged, indicating the cAMP-dependent LTP was likely postsynaptic. By employing fast fluorescent voltage-sensitive dye (VSD: di-4-ANEPPS) and fluorescence imaging, we found that photoactivation of the PAC actuator enhanced the intensity and extent of dentate gyrus depolarization triggered following tetanic stimulation. These results demonstrate that the elevation of cAMP in granule neurons is capable of rapidly enhancing synaptic strength and neuronal depolarization. The powerful actions of cAMP are consistent with this second messenger having a critical role in the regulation of synaptic function.