As engineers know, high-pass frequency filtering of signals makes communication poorer but not hopeless. Now suppose that we introduce high-pass filters in the communication lines between neurons in the brain. This is exactly what Xu et al., (2012) have accomplished, using molecular biological tools. They find that after such manipulation neuronal transmission becomes sluggish

but is not completely abolished. For some structures and tasks, such as the hippocampus-dependent contextual fear learning task, high-pass filtering is tolerated, whereas for a prefrontal cortex-dependent remote memory recall, sluggishness of spike communication leads to a serious behavioral impairment. Let’s examine first how communication between neurons was achieved. SP600125 Neurons communicate electrochemically. The upstream neuron generates a spike, which is broadcasted to all or most of its presynaptic terminals. Here, electricity is converted to chemically mediated synaptic transmission. This conversion process can be perturbed in multiple ways. For example, tetanus toxin (TetTox) can block transmitter release and thus completely eliminate synaptic communication. PI3K Inhibitor Library Other interventions can produce

a more subtle interference. Synaptotagmin-1 (Syt1), together with other vesicle proteins, is essential for the docking and/or fusion of synaptic vesicles with the presynaptic plasma membrane following depolarization and Ca2+ influx in presynaptic bouton. Eliminating or interfering with Syt1 also impairs synaptic transmission to single, isolated spikes yet when high enough amount of Ca2+ enters the terminal in response to high-frequency spike activity chemical transmission is resumed, although it remains sluggish due to the asynchronous release of the transmitter (Maximov and Südhof, 2005). Put simply, interfering with Syt1 amounts

to the introduction of a high-pass frequency filter: no or poor transmission at many low rates of spiking but gradual restoration of the transmitter release at increasing spike frequencies. What are the physiological and, ultimately, behavioral consequences of such frequency-selective mechanisms? To explore this question, Xu and colleagues (2012) used a virus-targeted approach to knock down Syt1 in the brain of mice. After demonstrating the proof of principle in cultured cortical neurons, the authors generated recombinant adeno-associated viruses (AAV-DJ) to express only enhanced green fluorescent protein (EGFP, which served as a control), or only TetTox, or to express both EGFP and the Syt1-coding shRNA. With such convenient tools in hand, Xu and colleagues (2012) infected neurons in the dorsal hippocampus, the entorhinal cortex, and prefrontal cortex. As expected, electrical stimulation of TetTox expressing CA1 pyramidal cells failed to excite their subicular targets.