By studying specially bred mice with specific developmental and cognitive traits resembling those seen in schizophrenia, University of California, San Francisco (UCSF) researchers have provided new evidence that abnormal rhythmic activity in particular brain cells contributes to problems with learning, attention, and decision-making in individuals with that disorder.
As reported in the journal Neuron, when the researchers corrected these cells’ faulty rhythm, either by directly stimulating the cells or by administering low doses of a commonly used drug, cognitive deficits in the mice were reversed, results that point the way to possible therapies to address cognitive symptoms in individuals with schizophrenia.
According to Vikaas Sohal, MD, PhD, senior author of the new study, in addition to dealing with the burdens of schizophrenia’s so-called positive symptoms (such as delusions and hallucinations) and negative symptoms (such as social withdrawal and a lack of motivation), individuals with the disorder also grapple with cognitive deficits that create considerable challenges in the arenas of education, work, and interpersonal relationships.
“…when the team gave low doses of clonazepam, which modulates the GABA neurotransmitter system employed by FS interneurons, to mice lacking Dlx5 and Dlx6, the mice again performed the rule-shifting task normally.
The cognitive improvements following direct interneuron stimulation persisted for a week after the experiments, suggesting that targeting FS interneuron dysfunction may result in durable improvements in cognitive function in schizophrenia.
Clonazepam and other GABA-modulating drugs such as lorazepam (Ativan) and diazepam (Valium) are now used to treat anxiety associated with schizophrenia, but usually at higher doses that also increase sedation, which may mask any cognition-enhancing effect. Lower doses, or better-designed compounds that specifically target FS interneurons in the prefrontal cortex, might be better options, Sohal said, adding that measuring gamma oscillations may be a useful guide in developing these approaches.
On a more speculative level, Sohal added, it may be possible to increase gamma oscillations to improve cognition using recently developed, non-invasive brain stimulation technologies such as transcranial magnetic or direct-current stimulation (TMS or tDCS), or even by combining meditation with biofeedback.
“Meditation has been shown to potently increase gamma oscillations, and you may be able to teach patients to increase gamma oscillations by themselves,” said Sohal. “Now that we know that gamma oscillations are directly related to cognitive performance, it’s certainly an interesting idea to pursue.”
Abnormalities in GABAergic interneurons, particularly fast-spiking interneurons (FSINs) that generate gamma (γ; ∼30–120 Hz) oscillations, are hypothesized to disrupt prefrontal cortex (PFC)-dependent cognition in schizophrenia. Although γ rhythms are abnormal in schizophrenia, it remains unclear whether they directly influence cognition. Mechanisms underlying schizophrenia’s typical post-adolescent onset also remain elusive. We addressed these issues using mice heterozygous for Dlx5/6, which regulate GABAergic interneuron development. In Dlx5/6+/− mice, FSINs become abnormal following adolescence, coinciding with the onset of cognitive inflexibility and deficient task-evoked γ oscillations. Inhibiting PFC interneurons in control mice reproduced these deficits, whereas stimulating them at γ-frequencies restored cognitive flexibility in adult Dlx5/6+/− mice. These pro-cognitive effects were frequency specific and persistent. These findings elucidate a mechanism whereby abnormal FSIN development may contribute to the post-adolescent onset of schizophrenia endophenotypes. Furthermore, they demonstrate a causal, potentially therapeutic, role for PFC interneuron-driven γ oscillations in cognitive domains at the core of schizophrenia.
Enhancing GABAergic Transmission Rescues Task-Evoked γ Oscillations and Cognitive Flexibility in Dlx5/6+/− Mice
“The preceding results show that mPFC interneuron dysfunction is sufficient to disrupt rule shifts and identify specific abnormalities in mPFC interneurons that we hypothesize drive schizophrenia-like deficits in task-evoked γ oscillations and cognitive flexibility in Dlx5/6+/− mice. If this hypothesis is correct, then enhancing inhibitory output may rescue these EEG and cognitive abnormalities. Enhancing GABAergic signaling with the benzodiazepine clonazepam (CLZ), a positive allosteric modulator of the GABAA receptor, treats social deficits in a mouse model of Dravet’s syndrome ( Han et al., 2012). Therefore, we tested the same low dose of CLZ (0.0625 mg kg−1) in Dlx5/6+/− mice. While this low dose did not exert sedative or anxiolytic effects on either WT or Dlx5/6+/− mice, CLZ completely normalized rule shifting in Dlx5/6+/− mice
CLZ also abolished differences in rule shift-evoked γ oscillations between Dlx5/6+/− and WT mice. Note that we treated all mice with vehicle (VEH) on the day prior to CLZ treatment. On this day, mice performed the rule shift. Thus, in addition to comparing CLZ-treated Dlx5/6+/− mice to CLZ-treated WT mice, we could compare each Dlx5/6+/− mouse in the CLZ and VEH conditions. Indeed, we found that rule shifting evoked significantly stronger γ oscillations in Dlx5/6+/− mice during CLZ than during VEH treatment. Since rule shift-evoked γ oscillations were measured 1 day later in CLZ than in the VEH condition, this might reflect an effect of training rather than of CLZ treatment. To rule out the possibility that training induces changes in γ oscillations between the first and second day of testing, we repeated rule shifting in a separate cohort of Dlx5/6+/− mice treated with VEH on 2 consecutive days and found no change in rule shifting evoked γ oscillations over the 2 days of VEH treatment. Thus, CLZ treatment rescues both task-evoked γ oscillations and cognitive flexibility in Dlx5/6+/− mice. CLZ treatment also rescued cognitive flexibility in DlxI12b::Cre × Dlx5fl/−Dlx6+/− mice.”
“…Low-dose CLZ also restored prefrontal task-evoked γ oscillations and rescued cognitive flexibility in Dlx5/6+/− mice. While benzodiazepines are used to treat anxiety and agitation in schizophrenia, the cognitive effects of augmenting GABAergic function have been less well studied with mixed results ( Lewis et al., 2008). As in a previous study that used CLZ to rescue social deficits in a mouse model of Dravet’s syndrome ( Han et al., 2012), the low dose of CLZ we used may have been particularly important for its therapeutic effects by minimizing sedation and/or maximizing the relative selectivity of CLZ for α2 or α3 subunit-containing GABAA receptors, which have been proposed to exert pro-cognitive effects in schizophrenia ( Lewis et al., 2008).”