The human brain is made up of billions of neurons, specialized cells which form vast, intricate networks among themselves to process and sort through the barrage of sensory and internal stimuli we are constantly bombarded with and mediate the appropriate response.

Neurons are long thread-like cells with numerous branches projecting from each end to allow communication with other neurons. When excited, an electrical impulse travels through the neuron and, when it reaches the far end, chemical messengers are released into the synapse, a narrow (microscopic) space between the sending and receiving neurons. These messengers then act on the receiving end of the neighboring neuron to either excite or inhibit it.

In excitatory synapses a neuron sends its neighbor a message via these chemical mediators which tells it to fire, making that neuron active, or ‘excited’. Conversely, inhibitory synapses send a message which silences the neighboring neuron, thereby inhibiting its activity.

    Achieving a balance between inhibitory and excitatory synapses is essential to normal brain activity. The loss of this balance has been linked to a number of developmental and cognitive disorders in humans, including schizophrenia and autism, making maintenance of excitatory and inhibitory synapses in the brain particularly important. The molecular factors regulating the excitatory-inhibitory balance, however, are still not well understood.

Enter Npas4 (now say that three times fast). Npas 4 is a transcription factor, a protein with the ability to bind DNA and control the activity of one or many genes by turning its target genes on or off. Npas4 in particular appears to alter the activity of as many as 270 genes, making it an important regulator of gene activity. Npas4 is particularly abundant in the brain and appears to function in formation of inhibitory synapses, acting in response to excitation to counteract it by increasing the number of inhibitory synapses on the cell which sent the original excitatory message. 

There is evidence that alteration of inhibitory pathways may be a cause of schizophrenia, and so researchers at Stanford University set out to test this idea and see how impaired inhibitory pathways contributed to the symptoms of schizophrenia. Given its role in inhibitory synapse formation and regulation, Npas4 seemed like a good place to start. 

In a recent paper, researchers decided to test the effects of loss of Npas4 in mice by generating a strain of Npas4 knockout mice (KO) lacking the Npas4 gene. We have two copies of (almost) every gene, one inherited from each parent; and so mice which had lost one or both copies of Npas4 were studied and compared to mice that retained two functional copies of the Npas4 gene. They found that the mice with both copies of Npas4 often behaved very similarly to mice which had lost one copy of the gene. Npas4 knockout mice, however, showed a number of cognitive, social, and behavioral defects which closely mimicked the symptoms of schizophrenia in humans, including social anxiety (or at least a close approximation), and short- and long-term memory impairment.

Naturally, using mice as a model for human disease requires tests whose results can be 'translated' between humans and their furry, beady-eyed counterparts. One such test used by the authors is the pre-pulse inhibition test, which was initially found to be affected in schizophrenic patients. When we suddenly hear a loud noise, most of us are quick to startle and our attention is momentarily diverted to the intrusion. Researchers capitalize on this reaction experimentally, quantifying their subject’s response to the noise by measuring eye blink. When a softer noise precedes a loud noise, however, the startle response is attenuated. This phenomenon is referred to as pre-pulse inhibition, or PPI. 

In many symptomatic schizophrenics, however, this relationship does not hold true: even after hearing a softer noise, their reaction to the louder noise is still strong; their PPI, therefore, is decreased. Interestingly, schizophrenic patients treated with certain atypical antipsychotics revert to a ‘normal’ response. It has been postulated that impaired PPI can contribute to the sensory flooding&disorganized thinking experienced by many schizophrenics because they are unable to filter out unimportant stimuli. Normally, we tune out a considerable amount of incoming stimuli; in schizophrenics, however, this ability is lost, and so a normal level of background activity can quickly become overwhelming. 

Instead of measuring eye blinks, PPI in mice is measured as a whole-body shudder. Npas4 KO mice showed a strong decrease in PPI compared to mice with both copies of Npas4, while mice with only one functional copy of Npas4 fell somewhere in between the normal and KO mice. The authors point out that these results are most likely the result of deregulation of inhibitory synapses in mice lacking Npas4, however, the schizophrenia-mimicking behavior of these mice support the idea that maintenance of these inhibitory pathways may underlie or contribute to schizophrenia.

The behavior of mice lacking Npas4, therefore, closely parallels some of the primary symptoms associated with schizophrenia. The authors noted that the Npas4 gene is found on the 11th chromosome in the human genome, in a region which has previously been associated with schizophrenia in a study of a Japanese population. Other case studies have found that in many schizophrenics pieces of the 11th chromosome have erroneously joined, or translocated, onto other chromosomes.

Due to these findings, and others, it has been suggested that alterations to the 11th chromosome in general appear to be highly relevant in development of psychosis. These recent results open up two areas of study in developmental disorders such as schizophrenia: first, the need for an increased understanding of the role of maintaining a balance between excitatory-inhibitory pathways and the factors which regulate them; and second, further exploration of a possible connection between Npas4 and schizophrenia.

Coutellier L, Beraki S, Ardestani PM, Saw NL, Shamloo M (2012) Npas4: A Neuronal Transcription Factor with a Key Role in Social and Cognitive Functions Relevant to Developmental Disorders. PLoS ONE 7(9): e46604. doi:10.1371/journal.pone.0046604