Genetics tells us that abnormal synaptic and nuclear proteins are often at the root of major neuropsychiatric disorders. Autism, a prominent and often debilitating disorder of the brain, has been traced to small contributions of hundreds of genes, creating a formidable challenge for those interested in exploring pathophysiology and possible therapeutic interventions. A major interest of our laboratory is a form of autism known as Timothy Syndrome (TS), which arises from a point mutation in a signaling protein. Though rare, the mutation causes autism spectrum disorder (ASD) with 3:1 odds. The gene, known as CACNA1C, encodes a particular kind of calcium channel known as “L-type”. We have studied the behavior of mice bearing the TS mutation and find persistent behavior, altered communication, and reduced social interaction relative to their unaffected sibs, features reminiscent of the three characteristic hallmarks of autism. The mutation leads to over-activity of the ion channel, raising the prospect that it might be counteracted pharmacologically. Interestingly, the same CACNA1C gene has been repeatedly implicated in schizophrenia and in Major Depressive Disorder. The possibility arises that work on diverse neuropsychiatric diseases will prove more synergistic than previously appreciated.
Why does miscoding in CACNA1C exert such strong effects? Like its close relatives, this particular L-type calcium channel plays a central role in allowing a neuron to track its own activity. In a process called excitation-transcription coupling, neuronal firing drives the opening of the L-type channel, flow of calcium into the cell, activation of transcription factors, and expression of specific sets of genes. Ultimately, this supports neuronal autoregulation and plasticity. We are currently working out critical details of how the L-type channel transmits a packet of information to control nuclear gene transcription. Interestingly, elements of this signaling pathway are encoded by genes that have also been implicated in causing neuropsychiatric disorders.
Disorders at the cellular level are thought to engender aberrant function of neuronal circuits. Oxytocin is a key neuromodulator whose influence on neuronal circuitry has been linked to social memory and maternal behavior in animals, as well trust, emotion recognition and parenting in humans. Multiple clinical trials have uncovered promising actions of oxytocin on autistic behavior in teenagers, including processing of information about faces. By examining oxytocin actions in brain slices, we have found that activation of oxytocin receptors sharpens the responses of a canonical hippocampal circuit. The peptide increases the fidelity of signal transmission through the network, while simultaneously suppressing the noise of background spontaneous activity. These seemingly contradictory actions are both mediated through a selective depolarization of the fast-spiking interneurons by oxytocin. The resulting increase in inhibitory tone in principal cells dampens their spontaneous activity. Meanwhile, a use-dependent depression of the feed-forward inhibitory synapses permits enhanced spike transmission. By activating fast-spiking neurons with cholecystokinin, or with channelrhodopsin-2, we demonstrate that this novel circuit mechanism is generally applicable to any manipulation that elicits the firing of fast-spiking basket cells. We have begun testing the action of oxytocin agonists on reversal learning, to determine if perseverative behavior can be ameliorated. The prospect looms that actions of oxytocin at the circuit level might contribute to its behavioral impact in autistic individuals, but at the moment this is merely a hypothesis.
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